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The Alinity m HCV assay is an in vitro reverse transcription-polymerase chain reaction (RT-PCR) assay for both the detection and quantitation of hepatitis C virus (HCV) RNA, in human plasma (EDTA, Acid Citrate Dextrose) or serum, from HCV antibody positive individuals. The assay is intended for use as an aid in the diagnosis of active HCV infection in individuals with antibody evidence of HCV infection, and to aid in the management of patients with known active HCV infection, including Sustained Virologic Response (SVR) determination.

The results from the Alinity m HCV assay must be interpreted within the context of all relevant clinical and laboratory findings.

The Alinity m HCV assay is not intended to be used in screening blood, plasma, serum, tissue or tissue donors for HCV.

Alinity m HCV is an in vitro polymerase chain reaction (PCR) assay for both the detection and quantitation of HCV RNA in human plasma (EDTA, Acid Citrate Dextrose) or serum, from HCV antibody positive individuals.

This device is similar to the predicate device originally approved (PMA P190025) with the exception that the subject device may use a new DNA Polymerase as an alternative to the original DNA Polymerase and a new Reverse Transcriptase as an alternative to the original Reverse Transcriptase in the reagent formulation of the assay. This formulation difference does not introduce any changes to sample processing, assay procedure, or data reduction.

Additional studies were initiated to support the formulation of the assay with alternative DNA Polymerase and Reverse Transcriptase. Supplemental data from these studies were used with data previously obtained from the analytical and clinical testing studies submitted in P190025.

The steps of the Alinity m HCV assay consist of sample preparation, real-time PCR assembly, amplification/detection, result calculation, and reporting. All steps of the Alinity m HCV assay procedure are executed automatically by the Alinity m System. Manual dilutions may be performed for low-volume specimens to meet the minimum volume requirement and for high-titer specimens above the upper limit of quantitation (ULoQ). The Alinity m System is designed to be a random-access analyzer that can perform the Alinity m HCV assay in parallel with other Alinity m assays on the same instrument.

Alinity m HCV requires three separate assay specific kits as follows:

• Alinity m HCV AMP Kit (List No. 08N50-095), consisting of 2 types of multi-well assay trays. The amplification trays (AMP Trays) contain lyophilized, unit-dose RT-PCR amplification/detection reagents and lyophilized, unit-dose IC in separate wells, and the activation trays (ACT Trays) contain liquid activation reagent. The intended storage condition for the Alinity m HCV AMP Kit is 2°C to 8°C.

• Alinity m HCV CTRL Kit (List No. 08N50-085), consisting of negative controls, low positive controls, and high positive controls, each supplied as liquid in single-use tubes. The intended storage condition for the Alinity m HCV CTRL Kit is –25°C to –15°C.

• Alinity m HCV CAL Kit (List No. 08N50-075), consisting of 2 calibrator levels, each supplied as liquid in single-use tubes. The intended storage condition for the Alinity m HCV CAL Kit is –25°C to –15°C.

HCV RNA from human plasma or serum is extracted automatically on-board in the Alinity m System using the Alinity m Sample Prep Kit 2, Alinity m Lysis Solution, and Alinity m Diluent Solution. The Alinity m System employs magnetic microparticle technology to facilitate nucleic acid capture, wash, and elution. The resulting purified nucleic acids are then combined with liquid unit-dose Alinity m HCV activation reagent and lyophilized unit-dose Alinity m HCV amplification/detection reagents and transferred into a reaction vessel. Alinity m Vapor Barrier Solution is then added to the reaction vessel which is then transferred to an amplification/detection unit for PCR amplification, and real-time fluorescence detection of HCV targets.

At the beginning of the Alinity m HCV sample preparation process, a lyophilized unit-dose IC on the AMP Tray is rehydrated by the Alinity m System and delivered into each sample preparation reaction. The IC is then processed through the entire sample preparation and real-time PCR procedure along with the specimens, calibrators, and controls to demonstrate proper sample processing and validity.

The Alinity m HCV amplification/detection reagents consist of enzymes, primers, probes, and activation reagents that enable reverse transcription, polymerization, and detection.

An HCV calibration curve is required for determination of HCV RNA concentration. Two levels of calibrators are processed through sample preparation and RT-PCR to generate the calibration curve. The concentration of HCV RNA in specimens and controls is then calculated from the stored calibration curve.

Assay controls are tested at or above an established minimum frequency to help ensure that instrument and reagent performance remains satisfactory. During each control event, a negative control, a low-positive control, and a high-positive control are processed through sample preparation and RT-PCR procedures that are identical to those used for specimens.

The Alinity m HCV assay also utilizes the following:

• Alinity m HCV Application Specification File, (List No. 08N50-03B)
• Alinity m System and System Software (List No. 08N53)
• Alinity m Sample Prep Kit 2 (List No. 09N12-001)
• Alinity m Specimen Dilution Kit I (List No. 09N50-001)
• Alinity m System Solutions, (List No. 09N20):
  • Alinity m Lysis Solution (List No. 09N20-001)
  • Alinity m Diluent Solution (List No. 09N20-003)
  • Alinity m Vapor Barrier Solution, (List No. 09N20-004)
• Alinity m Tubes and Caps (List No. 09N49):
  • Alinity m LRV Tube (List No. 09N49-001)
  • Alinity m Transport Tubes Pierceable Capped (List No. 09N49-010)
  • Alinity m Transport Tube (List No. 09N49-011)
  • Alinity m Pierceable Cap (List No. 09N49-012)
  • Alinity m Aliquot Tube (List No. 09N49-013)

N/A

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Alinity m EBV is an in vitro polymerase chain reaction (PCR) assay for the quantitation of Epstein-Barr Virus (EBV) DNA in human EDTA plasma on the automated Alinity m System.

Alinity m EBV is intended for use as an aid in the management of EBV in transplant patients. In patients undergoing monitoring of EBV, serial DNA measurements can be used to indicate the need for potential treatment changes and to assess viral response to treatment.

The results from Alinity m EBV must be interpreted within the context of all relevant clinical and laboratory findings.

Alinity m EBV is not cleared for use as a screening test for donors of blood, blood products, or human cells, tissues, and cellular and tissue-based products (HCT/Ps) for EBV.

Alinity m EBV is an in vitro polymerase chain reaction (PCR) assay for the quantitation of EBV DNA in human plasma.

This device is similar to the predicate device originally cleared (K212778) with the exception that the subject device may use MomentaTaq DNA Polymerase as an alternative to KAPA2G DNA Polymerase in the reagent formulation of the assay. This formulation difference does not introduce any changes to sample processing, assay procedure, or data reduction.

Additional studies were initiated to support the formulation of the assay with MomentaTaq DNA Polymerase. Supplemental data from these studies were used with data previously obtained from the analytical and clinical testing studies submitted in K212778.

The steps of the Alinity m EBV consist of sample preparation, real-time PCR assembly, amplification/detection, result calculation, and reporting. All stages of the Alinity m EBV procedure are executed automatically by the Alinity m System. No intermediate processing or transfer steps are performed by the user. The Alinity m System is designed to be a random-access analyzer that can perform the Alinity m EBV assay in parallel with other Alinity m assays on the same instrument.

Alinity m EBV requires three separate assay specific kits as follows:

• Alinity m EBV AMP Kit (List No. 09N43-095), consisting of 2 types of multi-well assay trays. The amplification trays (AMP TRAY 1) contain lyophilized, unit-dose PCR amplification/detection reagents and lyophilized, unit-dose IC in separate wells, and the activation trays (ACT TRAY 2) contain liquid unit-dose activation reagent. The intended storage condition for the Alinity m EBV AMP Kit is 2°C to 8°C.

• Alinity m EBV CTRL Kit (List No. 09N43-085), consisting of negative controls, low positive controls, and high positive controls, each supplied as liquid in single-use tubes. The intended storage condition for the Alinity m EBV CTRL Kit is –25°C to –15°C.

• Alinity m EBV CAL Kit (List No. 09N43-075), consisting of 2 calibrator levels, each supplied as liquid in single-use tubes. The intended storage condition for the Alinity m EBV CAL Kit is –25°C to –15°C.

EBV DNA from human plasma is extracted automatically on-board in the Alinity m System using the Alinity m Sample Prep Kit 2, Alinity m Lysis Solution, and Alinity m Diluent Solution. The Alinity m System employs magnetic microparticle technology to facilitate nucleic acid capture, wash, and elution. The resulting purified nucleic acids are then combined with liquid unit-dose Alinity m EBV activation reagent and lyophilized unit-dose Alinity m EBV amplification/detection reagents and transferred into a reaction vessel. Alinity m Vapor Barrier Solution is then added to the reaction vessel which is then transferred to an amplification/detection unit for PCR amplification, and real-time fluorescence detection of EBV targets.

At the beginning of the Alinity m EBV sample preparation process, a lyophilized unit-dose IC on the AMP Tray is rehydrated by the Alinity m System and delivered into each sample preparation reaction. The IC is then processed through the entire sample preparation and real-time PCR procedure along with the specimens, calibrators, and controls to demonstrate proper sample processing and validity.

The Alinity m EBV amplification/detection reagents consist of enzymes, primers, probes, and activation reagents that enable polymerization and detection.

An EBV calibration curve is required for determination of EBV DNA concentration. Two levels of calibrators are processed through sample preparation and PCR to generate the calibration curve. The concentration of EBV DNA in specimens and controls is then calculated from the stored calibration curve.

Assay controls are tested at or above an established minimum frequency to help ensure that instrument and reagent performance remains satisfactory. During each control event, a negative control, a low-positive control, and a high-positive control are processed through sample preparation and PCR procedures that are identical to those used for specimens.

The Alinity m EBV assay also utilizes the following:

• Alinity m EBV Application Specification File, (List No. 09N43-05B)
• Alinity m System and System Software (List No. 08N53-002)
• Alinity m Sample Prep Kit 2 (List No. 09N12-001)
• Alinity m Specimen Dilution Kit I (List No. 09N50-001)
• Alinity m System Solutions, (List No. 09N20):
  • Alinity m Lysis Solution (List No. 09N20-001)
  • Alinity m Diluent Solution (List No. 09N20-003)
  • Alinity m Vapor Barrier Solution, (List No. 09N20-004)
• Alinity m Tubes and Caps (List No. 09N49):
  • Alinity m LRV Tube (List No. 09N49-001)
  • Alinity m Transport Tubes Pierceable Capped (List No. 09N49-010)
  • Alinity m Transport Tube (List No. 09N49-011)
  • Alinity m Pierceable Cap (List No. 09N49-012)
  • Alinity m Aliquot Tube (List No. 09N49-013)

This document, K243489, is a 510(k) clearance letter for the Alinity m EBV assay, specifically focusing on the use of MomentaTaq DNA Polymerase as an alternative to KAPA2G DNA Polymerase. The primary goal of the studies described is to demonstrate that the device formulated with MomentaTaq DNA Polymerase performs equivalently to the previously cleared device formulated with KAPA2G DNA Polymerase (K212778).

Here's an analysis of the acceptance criteria and study information provided:

1. Table of Acceptance Criteria and Reported Device Performance

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

The document describes several additional studies conducted specifically for the MomentaTaq formulation, referring back to the K212778 submission for other characteristics.

• Limit of Detection (LoD):
  • Sample Size: For EBV type 1, tested dilutions with 3 lots of amplification reagents across multiple days. For 20 IU/mL, there were 142 replicates (47-48 per lot). Total replicates across all concentrations and lots were higher (e.g., 143 for 15 IU/mL, 142 for 100 IU/mL).
  • Data Provenance: Prepared in EBV negative human plasma using the 1st World Health Organization (WHO) International Standard for Epstein-Barr Virus. This suggests controlled laboratory samples.
• Linearity:
  • Sample Size: 16 panel members spanning the intended quantitation range.
  • Data Provenance: Prepared from plasmid DNA, cultured virus, and clinical specimens. The specific origin country for clinical specimens is not provided, but the use of the WHO International Standard points to internationally recognized reference material.
• Precision:
  • Sample Size: 8 panel members, with 270 replicates per panel member (3 lots x 3 operators x 15 days x 2 runs/day x 3 replicates/run, then averaged).
  • Data Provenance: Panel members prepared by diluting EBV-positive clinical specimens, EBV cultured virus, or synthetic DNA in human plasma. Quantitation traceable to the 1st WHO International Standard. Specific origin country not provided.
• Lower Limit of Quantitation (LLoQ):
  • Sample Size: Calculated from detected samples in the LoD study.
  • Data Provenance: Prepared in EBV-negative plasma using the 1st WHO International Standard.
• Clinical Reproducibility:
  • Sample Size: 9-member reproducibility panel (8 positive, 1 negative). 1 lot of kits used. Testing performed at 3 clinical sites on 5 non-consecutive days with 2 runs per day. 4 replicates of each panel member tested, ensuring a minimum of 3 valid replicates. For the positive panels, N ranged from 113 to 120. For the negative panel, N = 119 for all sites combined.
  • Data Provenance: Positive panel members were prepared using EBV positive clinical specimen, cultured virus, or plasmid DNA diluted in human EDTA plasma. Specific origin country for clinical specimens not provided.
• Clinical Performance (Method Comparison):
  • Sample Size: 124 samples with results within the common quantitation range of both assays.
  • Data Provenance: Samples used for method comparison between the MomentaTaq formulation and the KAPA2G formulation. Implies ex vivo clinical samples. Specific origin country not provided.

The studies for the MomentaTaq formulation are analytical performance studies and a method comparison to an already cleared device, not direct clinical outcome studies. They appear to be retrospective as they involve testing banked or prepared samples. The reference to "3 clinical sites" for reproducibility suggests a multi-site testing environment, but it's an analytical reproducibility study, not a clinical trial on patient outcomes.

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

The provided document does not mention the number or qualifications of experts used to establish ground truth for the test sets. The ground truth for quantitation appears to be established by:

• Using the 1st World Health Organization (WHO) International Standard for Epstein-Barr Virus for Nucleic Acid Amplification Techniques (NIBSC code 09/260) for LoD, Linearity, and LLoQ.
• Using EBV-positive clinical specimens, cultured virus, or plasmid DNA for precision and reproducibility, with quantitation traceable to the WHO standard.
• The "comparator" assay (on-market Alinity m EBV with KAPA2G DNA Polymerase) as a reference for clinical performance (method comparison).

For a quantitative viral load test, the ground truth is typically defined by reference materials (like WHO standards) or highly characterized samples, rather than by expert consensus on interpretation of results.

4. Adjudication Method for the Test Set

Given that the ground truth for these quantitative assays is based on reference standards and characterized samples, no expert adjudication method (like 2+1, 3+1, none) is described or would typically be applicable in this context. The output is a quantitative value, not a subjective interpretation.

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 more common for imaging diagnostics where human readers interpret results with and without AI assistance. This document describes an in vitro diagnostic (IVD) quantitative PCR assay, which is an automated device producing numerical results, not something that human readers interpret in the conventional sense of an MRMC study.

6. If a Standalone Study (Algorithm Only Without Human-in-the-Loop Performance) was Done

Yes, effectively, all the studies described are standalone performance studies. The Alinity m EBV device is an automated system that performs sample preparation, PCR, detection, and result calculation without human intervention in the actual assay run. The performance metrics (LoD, linearity, precision, reproducibility, method comparison) directly evaluate the algorithm's ability to accurately quantify EBV DNA in samples. There is no "human-in-the-loop" component in the performance of the assay itself.

7. The Type of Ground Truth Used

The ground truth used in these studies is primarily based on:

• Reference Materials: The 1st World Health Organization (WHO) International Standard for Epstein-Barr Virus (NIBSC code 09/260) is extensively used for establishing and verifying the quantitative values of the panel members.
• Characterized Samples: EBV positive clinical specimens, cultured virus, and synthetic plasmid DNA where their concentrations are known or precisely determined relative to the WHO standard.
• Comparison to Predicate Device: For the method comparison study, the performance of the new MomentaTaq formulation is benchmarked against the FDA-cleared Alinity m EBV assay (K212778), which serves as a clinical reference.

This is a form of "expert consensus" on the value of reference materials and highly characterized samples, rather than pathology or outcomes data in the usual sense for IVDs.

8. The Sample Size for the Training Set

The document does not specify the sample size used for the training set for the Alinity m EBV assay. Regulatory submissions like 510(k) clearances typically focus on the validation (test set) rather than the development and training data of the algorithm itself, especially for established PCR technologies that do not heavily rely on machine learning requiring distinct training sets in the same manner. This assay is based on PCR technology, where the "training" would involve optimizing reagent concentrations, primer/probe design, and thermocycling conditions, rather than training a machine learning model on a "training set" of patient data.

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

As mentioned above, specific "training set" details are not provided. For PCR-based assays, the "ground truth" during development (analogous to training) would involve:

• Known Viral Copies: Using synthetic nucleic acids or viral stock solutions with precisely quantified viral load to optimize assay components and parameters.
• Spiked Samples: Spiking known amounts of virus or viral nucleic acid into negative matrix (e.g., human plasma) to simulate different concentrations and evaluate early performance.
• Clinical Samples with Confirmed Status: Using retrospectively collected clinical samples with well-established EBV positive/negative status and viral loads determined by highly accurate laboratory methods or other validated assays to refine and confirm assay performance.

The development process would aim to ensure the assay accurately detected and quantified EBV DNA, aligning with established reference standards and biological knowledge of the virus.

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The Alinity m CMV assay is an in vitro polymerase chain reaction (PCR) assay for use with the automated Alinity m System to quantitate cytomegalovirus (CMV) DNA in human EDTA plasma. The Alinity m CMV assay is intended for use as an aid in the management of Hematopoietic Stem Cell Transplant and Solid Organ Transplant patients who are undergoing anti-cytomegalovirus therapy. The Alinity m CMV assay can be used to assess virological response to anti-cytomegalovirus therapy.

The results from the Alinity m CMV test must be interpreted within the context of all relevant clinical and laboratory findings. The Alinity m CMV test is not intended as a screening test for the presence of CMV DNA in blood or blood products.

Alinity m CMV is an in vitro polymerase chain reaction (PCR) assay for the quantitation of CMV DNA in human EDTA plasma.

This device is similar to the predicate device originally approved (PMA P210022) with the exception that the subject device may use a new DNA Polymerase as an alternative to original DNA Polymerase in the reagent formulation of the assay. This formulation difference does not introduce any changes to sample processing, assay procedure, or data reduction.

Additional studies were initiated to support the formulation of the assay with alternative DNA Polymerase. Supplemental data from these studies were used with data previously obtained from the analytical and clinical testing studies submitted in P210022.

The steps of the Alinity m CMV consist of sample preparation, real-time PCR assembly, amplification/detection, result calculation, and reporting. All stages of the Alinity m CMV procedure are executed automatically by the Alinity m System. Manual dilutions may be performed for low-volume specimens to meet the minimum volume requirement.

The Alinity m System is designed to be a random-access analyzer that can perform the Alinity m CMV assay in parallel with other Alinity m assays on the same instrument.

Alinity m CMV requires three separate assay specific kits as follows:

• Alinity m CMV AMP Kit (List No. 09N46-095), consisting of 2 types of multi-well assay trays. The amplification trays (AMP TRAY 1) contain lyophilized, unit-dose PCR amplification/detection reagents and lyophilized, unit-dose IC in separate wells, and the activation trays (ACT TRAY 2) contain liquid unit-dose activation reagent. The intended storage condition for the Alinity m CMV AMP Kit is 2°C to 8°C.

• Alinity m CMV CTRL Kit (List No. 09N46-085), consisting of negative controls, low positive controls, and high positive controls, each supplied as liquid in single-use tubes. The intended storage condition for the Alinity m CMV CTRL Kit is –25°C to –15°C.

• Alinity m CMV CAL Kit (List No. 09N46-075), consisting of 2 calibrator levels, each supplied as liquid in single-use tubes. The intended storage condition for the Alinity m CMV CAL Kit is –25°C to –15°C.

CMV DNA from human plasma is extracted automatically on-board in the Alinity m System using the Alinity m Sample Prep Kit 2, Alinity m Lysis Solution, and Alinity m Diluent Solution. The Alinity m System employs magnetic microparticle technology to facilitate nucleic acid capture, wash, and elution. The resulting purified nucleic acids are then combined with liquid unit-dose Alinity m CMV activation reagent and lyophilized unit-dose Alinity m CMV amplification/detection reagents and transferred into a reaction vessel. Alinity m Vapor Barrier Solution is then added to the reaction vessel which is then transferred to an amplification/detection unit for PCR amplification, and real-time fluorescence detection of CMV targets.

At the beginning of the Alinity m CMV sample preparation process, a lyophilized unit-dose IC on the AMP Tray is rehydrated by the Alinity m System and delivered into each sample preparation reaction. The IC is then processed through the entire sample preparation and real-time PCR procedure along with the specimens, calibrators, and controls to demonstrate proper sample processing and validity.

The Alinity m CMV amplification/detection reagents consist of enzymes, primers, probes, and activation reagents that enable polymerization and detection.

A CMV calibration curve is required for determination of CMV DNA concentration. Two levels of calibrators are processed through sample preparation and PCR to generate the calibration curve. The concentration of CMV DNA in specimens and controls is then calculated from the stored calibration curve.

Assay controls are tested at or above an established minimum frequency to help ensure that instrument and reagent performance remains satisfactory. During each control event, a negative control, a low-positive control, and a high-positive control are processed through sample preparation and PCR procedures that are identical to those used for specimens.

The Alinity m CMV assay also utilizes the following:

• Alinity m CMV Application Specification File, (List No. 09N46-05B)
• Alinity m System and System Software (List No. 08N53)
• Alinity m Sample Prep Kit 2 (List No. 09N12-001)
• Alinity m Specimen Dilution Kit I (List No. 09N50-001)
• Alinity m System Solutions, (List No. 09N20):
  • Alinity m Lysis Solution (List No. 09N20-001)
  • Alinity m Diluent Solution (List No. 09N20-003)
  • Alinity m Vapor Barrier Solution, (List No. 09N20-004)
• Alinity m Tubes and Caps (List No. 09N49):
  • Alinity m LRV Tube (List No. 09N49-001)
  • Alinity m Transport Tubes Pierceable Capped (List No. 09N49-010)
  • Alinity m Transport Tube (List No. 09N49-011)
  • Alinity m Pierceable Cap (List No. 09N49-012)
  • Alinity m Aliquot Tube (List No. 09N49-013)

Here's a breakdown of the acceptance criteria and the study that proves the device meets them, based on the provided FDA 510(k) clearance letter for the Alinity m CMV assay:

The core of this submission is to demonstrate that a new formulation of the Alinity m CMV assay (using an "alternative DNA Polymerase") is substantially equivalent to the previously FDA-approved Alinity m CMV assay (using the "original DNA Polymerase"). Therefore, the acceptance criteria for the new formulation are implicitly that its performance characteristics (LoD, Linearity, Precision, Reproducibility, Method Comparison) are comparable to, and meet the established claims of, the original predicate device.

1. Table of Acceptance Criteria and Reported Device Performance

Since this is a submission demonstrating equivalence to an already approved device, the acceptance criteria are not explicitly stated as pass/fail thresholds in this document, but rather as meeting or being comparable to the performance of the predicate device (P210022). The reported performance shows that the new formulation did meet these implicit criteria.

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

The "test set" in this context refers to the samples used to evaluate the performance of the new formulation (alternative DNA Polymerase) against the established performance of the original formulation.

• Limit of Detection (LoD): 192 total replicates at 30 IU/mL (96 for Lot 1, 48 for Lot 2, 48 for Lot 3). CMV negative human plasma used as diluent.
• Linear Range: 17 panel members tested. Panel members were prepared from dilution of the 1st WHO International Standard, cultured virus, or clinical specimens.
• Precision: 8 panel members, 270 replicates per panel member (3 lots x 3 replicates x 2 runs/day x 15 days). Panel members prepared from CMV positive specimen, cultured virus, or CMV plasmid DNA diluted in human EDTA plasma.
• Lower Limit of Quantitation (LLoQ): Data from the LoD study was used. (Therefore, 192 replicates at 30 IU/mL etc. as per LoD). Prepared from 1st WHO International Standard diluted in CMV-negative plasma.
• Reproducibility: 9-member panel (8 positive, 1 negative). Tested at 3 clinical sites, over 5 non-consecutive days with 2 runs per day. 4 replicates of each panel member per day/run.
  • Positive Control: 111-119 total replicates per panel member.
  • Negative Control: 119 total replicates.
  • Panel members were prepared by spiking clinical specimen, cultured virus, or plasmid DNA into normal CMV negative K2EDTA plasma.
• Method Comparison: 141 samples. Source of these samples is not explicitly stated as clinical or contrived, but they are "samples with results that were within the common quantitation range of both [...] assays".

Data Provenance:

• The document implies the studies are part of the 510(k) submission, generally meaning prospective testing performed by the manufacturer.
• Country of Origin: Not explicitly stated for patient/specimen samples, but the study was conducted by Abbott Molecular Inc. in Des Plaines, Illinois, USA. The "3 clinical sites" for reproducibility are not named or localized.
• Retrospective or Prospective: All listed performance studies appear to be prospective analytical studies specifically designed to characterize the performance of the revised device. The P210022 PMA submission (predicate device) would have contained the primary clinical data, but this 510(k) focuses on analytical equivalence.

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

This device is an IVD (in vitro diagnostic) test for quantitating CMV DNA. The "ground truth" for quantitative nucleic acid tests is typically established using:

• Reference Materials: The 1st World Health Organization (WHO) International Standard for Human Cytomegalovirus for Nucleic Acid Amplification Techniques (NIBSC code 09/162) is repeatedly mentioned as the basis for quantitation and traceability. This is a highly standardized and globally recognized reference material, not expert consensus on individual patient samples.
• Analytical Methods: Dilutions of known concentrations (plasmids, cultured virus, clinical specimens) are used.

Therefore, for this type of quantitative IVD, the ground truth is established through analytical traceability to a well-characterized international standard and precise laboratory dilution/preparation methods, rather than by human rater consensus on individual cases. No human experts are reported as being used to establish a "ground truth" for the test set in the way a radiologist would for image analysis.

4. Adjudication Method for the Test Set

As the ground truth is established by analytical methods and reference standards, no adjudication method (like 2+1, 3+1) is relevant or mentioned for establishing the truth of the samples themselves. The studies measure the device's ability to consistently and accurately quantify CMV DNA relative to these known standards.

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

No MRMC comparative effectiveness study was done or is relevant for this device.

• This device is an in vitro diagnostic (IVD) assay, specifically a quantitative PCR test, not an AI-assisted diagnostic imaging tool.
• It provides a numerical output (CMV DNA concentration), not an interpretation that human readers would directly assist with or benefit from AI assistance.
• Therefore, the concept of "how much human readers improve with AI vs. without AI assistance" does not apply here.

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

This question is more applicable to AI/ML software as a medical device (SaMD). For a quantitative PCR assay:

• The device (Alinity m CMV) measures the quantity of CMV DNA independently and automatically on the Alinity m System.
• Its performance characteristics (LoD, linearity, precision, reproducibility) are inherently standalone (algorithm/device-only) measurements of its analytical capabilities, without human intervention in the result generation or analysis itself.
• Human interaction is primarily in sample loading, result review, and clinical interpretation in conjunction with other patient factors.

7. The Type of Ground Truth Used

The ground truth used for these analytical performance studies is based on:

• Reference Standards: Specifically, the 1st World Health Organization (WHO) International Standard for Human Cytomegalovirus for Nucleic Acid Amplification Techniques (NIBSC code 09/162).
• Contrived Samples: Highly characterized and precisely diluted samples using CMV positive clinical specimens, cultured virus, and plasmid DNA. The concentration of these contrived samples is "known" based on their preparation traceable to the WHO standard.

This is an analytical ground truth, not a clinical ground truth like pathology confirmation or patient outcomes data, nor is it expert consensus in the sense of a diagnostic interpretation.

8. The Sample Size for the Training Set

The provided document does not mention or describe a "training set" in the context of an AI/ML algorithm. This 510(k) is for a PCR assay, which is a chemical and enzymatic reaction-based test, not a machine learning model that undergoes a training phase.

If there were any internal optimization studies during the development of either the original or alternative polymerase formulations (e.g., to find optimal reagent concentrations), those might be analogous to "training" in a very broad sense, but they are not discussed in this 510(k) summary provided. The 510(k) focuses on the validation of the final product.

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

As there is no "training set" for an AI/ML algorithm for this PCR assay, this question is not applicable.

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Alinity m BKV is an in vitro nucleic acid amplification test for the quantitation of BK virus (BKV) DNA in human EDTA plasma (K2 EDTA, K3 EDTA, and PPT) and urine stabilized using the Alinity m Urine Transport Kit on the automated Alinity m System.

In EDTA plasma (K2 EDTA, K3 EDTA, and PPT) and urine stabilized using the Alinity m Urine Transport Kit, Alinity m BKV is intended for use as an aid in the diagnosis and management of BKV in transplant patients.

In patients undergoing monitoring of BKV in EDTA plasma, serial DNA measurements can be used to indicate the need for potential treatment changes and to assess viral response to treatment.

The results from Alinity m BKV must be interpreted in conjunction with clinical signs and other relevant laboratory findings. Alinity m BKV is not cleared as a screening test for blood or blood products or human cells, tissues, and cellular and tissue-based products.

The Alinity m BKV assay utilizes real-time polymerase chain reaction (PCR) to amplify and detect BKV genomic DNA sequences that have been extracted from human EDTA plasma or urine specimens. The steps of the Alinity m BKV assay consist of sample preparation, real-time PCR assembly, amplification/detection, result calculation, and reporting. One transfer step of urine specimens into the Alinity m Urine Transport Kit by the user is required prior to placing urine specimens on the Alinity m System. Remaining steps of the Alinity m BKV assay procedure are executed automatically by the Alinity m System. Manual dilutions may be performed for low-volume plasma specimens to meet the minimum volume requirement. The Alinity m System is designed to be a randomaccess analyzer that can perform the Alinity m BKV assay in parallel with other Alinity m assays on the same instrument.

Alinity m BKV requires three separate assay specific kits as follows:

• . Alinity m BKV AMP Kit (List No. 09N85-095), consisting of 2 types of multi-well assay trays. The amplification tray (AMP TRAY 1) contains liquid, unit-dose PCR amplification/detection reagents and liquid, unit-dose Internal Control (IC) in separate wells; and the activation tray (ACT TRAY 2) contains liquid, unit-dose activation reagent. The intended storage condition for the Alinity m BKV AMP Kit is -25°C to -15°C.
• . Alinity m BKV CTRL Kit (List No. 09N85-085), consisting of negative controls, low positive controls, and high positive controls, each supplied as liquid in single-use tubes. The intended storage condition for the Alinity m BKV CTRL Kit is -25°C to -15°C.
• Alinity m BKV CAL Kit (List No. 09N85-075), consisting of 2 calibrator levels, . each supplied as liquid in single-use tubes. The intended storage condition for the Alinity m BKV CAL Kit is -25°C to -15°C.

The Alinity m BKV assay requires a transport kit for testing all urine specimens:

• Alinity m Urine Transport Kit (List No. 09N85-001) consisting of a transport tube . and transfer pipette. The transport tube contains transport buffer. The intended storage condition for the Alinity m Urine Transport Kit is 15℃ to 30℃.
  BKV DNA from human plasma or urine is extracted automatically on board the Alinity m System using the Alinity m Sample Prep Kit 2, Alinity m Lysis Solution, and Alinity m Diluent Solution. The Alinity m System employs magnetic microparticle technology to facilitate nucleic acid capture, wash, and elution. The resulting purified DNA is then combined with liquid unit-dose Alinity m BKV activation reagent and liquid unit-dose Alinity m BKV amplification/detection reagents and transferred into a reaction vessel. Alinity m Vapor Barrier Solution is then added to the reaction vessel which is then transferred to an amplification/detection unit for PCR amplification and real-time fluorescence detection of BKV DNA.

At the beginning of the Alinity m BKV sample preparation process, a liquid unit-dose IC on the AMP Tray is transferred by the Alinity m System and delivered into each sample preparation reaction. The IC is then processed through the entire sample preparation and real-time PCR procedure along with the specimens, calibrators, and controls to demonstrate proper sample processing and validity.

The Alinity m BKV amplification/detection reagents consist of enzymes, primers, probes, and activation reagents that enable amplification and detection of dual targets in the BKV genome. Amplification and detection of the two BKV targets ensures sensitive detection of the viral genome even at low levels. In addition to the BKV primers and probes, the assay utilizes an IC primer/probe set for amplification and detection of the IC target sequence, which is not related to BKV. The IC probe is labeled with a different fluorophore than the BKV probes. This allows for simultaneous detection and discrimination of both the BKV and IC amplified products within the same reaction vessel.

A BKV calibration curve is required for determination of BKV DNA concentration. Two levels of calibrators are processed through sample preparation and PCR to generate the calibration curve. The concentration of BKV DNA in specimens and controls is then calculated from the stored calibration curve.

Assay controls are tested at or above an established minimum frequency to help ensure that instrument and reagent performance remains satisfactory. During each control event, a negative control, a low-positive control, and a high positive control are processed through sample preparation and PCR procedures that are identical to those used for specimens.

The Alinity m BKV assay also utilizes the following:

• Alinity m BKV Application Specification File (List No. 09N85-05A) .
• Alinity m System and System Software (List No. 08N53-002)
• Alinity m Sample Prep Kit 2 (List No. 09N12-001)
• . Alinity m Specimen Dilution Kit I (List No. 09N50-001)
• . Alinity m System Solutions, (List No. 09N20):
  • o Alinity m Lysis Solution (List No. 09N20-001)
  • o Alinity m Diluent Solution (List No. 09N20-003)
  • o Alinity m Vapor Barrier Solution, (List No. 09N20-004)
• Alinity m Tubes and Caps (List No. 09N49): •
  • Alinity m LRV Tube (List No. 09N49-001) o
  • o Alinity m Transport Tubes Pierceable Capped (List No. 09N49-010)
  • o Alinity m Transport Tube (List No. 09N49-011)
  • o Alinity m Pierceable Cap (List No. 09N49-012)
  • o Alinity m Aliquot Tube (List No. 09N49-013)

1. Acceptance Criteria and Reported Device Performance

2. Sample Size for Test Set and Data Provenance

• Plasma Clinical Test Set: 579 EDTA plasma clinical specimens (555 neat and 24 diluted clinical specimens) from 556 subjects.
• Urine Clinical Test Set: 380 urine specimens (1 specimen per subject).
• Provenance: Clinical specimens were collected from solid organ transplant (SOT) and hematopoietic stem cell transplant (HSCT) subjects. The document does not specify the country of origin of the data or explicitly state if the studies were retrospective or prospective, but the nature of "clinical specimens" and "clinical sites" suggests they were likely collected in a clinical setting, potentially in a prospective or mixed fashion for evaluation. The "reproducibility" studies were performed at "3 clinical sites," indicating multi-center data collection.

3. Number of Experts and Qualifications for Ground Truth

• The document does not explicitly mention the use of experts to establish ground truth for the clinical test set. Instead, the device's performance is compared against an "FDA-cleared BKV nucleic acid test" (the predicate device, cobas® BKV (K203220)) to establish clinical agreement. This predicate device serves as the reference standard.

4. Adjudication Method for the Test Set

• As the ground truth for clinical performance was established by comparison to an FDA-cleared predicate device, "adjudication" in the sense of expert consensus on individual cases is not directly applicable. The FDA-cleared predicate device's results were considered the reference for comparison. Discordant results were analyzed but not adjudicated by an independent panel of experts. Instead, results more than one box away from the diagonal in the agreement tables were defined as "discordant."

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

• No MRMC comparative effectiveness study was done. This device is a quantitative viral nucleic acid test (an in vitro diagnostic medical device), not an imaging device or AI-assisted diagnostic tool that would typically involve human readers. Therefore, the concept of "how much human readers improve with AI vs without AI assistance" is not relevant to this type of device.

6. Standalone Performance

• Yes, a standalone (algorithm only) performance study was conducted. The entire analytical and clinical performance evaluation of the Alinity m BKV assay, as described in the document, represents the standalone performance of the device without human-in-the-loop assistance for result generation. The system is automated, performing sample preparation, PCR, detection, calculation, and reporting.

7. Type of Ground Truth Used

• Analytical Performance Studies (LoD, Linearity, Precision, Specificity, Carryover):
  • External Standard: The 1st World Health Organization (WHO) International Standard for BK virus for Nucleic Acid Amplification Techniques (NIBSC code: 14/212) was used as the primary reference for quantitation and traceability.
  • Defined Samples: BKV-negative human EDTA plasma and BKV-negative stabilized urine were used as matrices, spiked with known concentrations of BKV (WHO standard, armored DNA, or clinical specimens).
• Clinical Performance Studies (Plasma and Urine):
  • Comparative Reference: An "FDA-cleared BKV nucleic acid test" (the predicate device) was used as the comparative reference for clinical agreement. This implies that the results from the predicate device served as the de-facto "ground truth" for the comparison of clinical performance.
  • Clinical Specimens: Actual patient samples from transplant subjects were used.

8. Sample Size for the Training Set

• The document describes performance studies, not the development of a machine learning model that would typically have a distinct "training set." Therefore, a specific sample size for a training set in that context is not provided. The development and optimization of the assay itself would involve internal studies, but these are not explicitly termed "training sets" in the context of AI/ML.

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

• As no specific "training set" for an AI/ML model is described, this question is not directly applicable. The development and validation of the BKV assay would have relied on a combination of:
  • Scientific principles of nucleic acid amplification and detection.
  • Characterization of BKV strains and their genomic sequences.
  • Internal R&D experimentation and optimization using known concentrations of BKV and control samples, often traceable to international standards (like the WHO standard mentioned).
  • Extensive analytical studies to define assay characteristics like sensitivity, specificity, and linearity before clinical validation.

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Alinity m Resp-4-Plex is a multiplexed real-time in vitro reverse transcription polymerase chain reaction (RT-PCR) assay for use with the automated Alinity m System for the qualitative detection and differentiation of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), influenza A virus, influenza B virus and Respiratory Syncytial Virus (RSV) in nasopharyngeal swab specimens collected from patients 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 Alinity m Resp-4-Plex assay is intended for use in the differential detection of SARS-CoV-2, 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 B and RSV viral RNA are generally detectable in nasopharyngeal swab specimens during the acute phase of infection. This test is not intended to detect influenza C virus infections.

Positive results are indication 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 Alinity m Resp-4-Plex assay may not be the definite cause of disease.

Negative results do not preclude SARS-CoV-2, influenza B and/or RSV infections and should not be used as the sole basis for diagnosis, treatment or other patient management decisions.

The Alinity m Resp-4-Plex assay requires two separate assay-specific kits: Alinity m Resp-4-Plex AMP Kit and Alinity m Resp-4-Plex CTRL Kit. The assay utilizes real-time PCR to amplify and detect genomic RNA sequences of influenza A (flu A), influenza B (flu B), RSV, and/or SARS-CoV-2 from nasopharyngeal (NP) swab specimens. The assay targets 2 different genes within the SARS-CoV-2 genome. Fluorescently labeled probes allow for simultaneous detection and differentiation of amplified products of all 4 viruses and Internal Control (IC) in a single reaction vessel. All steps of the assay procedure are executed automatically by the Alinity m System, which is a continuous random-access analyzer. The system performs automated sample preparation using magnetic microparticle technology. The IC is introduced into each specimen at the beginning of sample preparation. Purified RNA is combined with activation and amplification/detection reagents and transferred to a reaction vessel for reverse transcription, PCR amplification, and real-time fluorescence detection. A positive and negative control are tested to ensure performance. Patient results are automatically reported. The assay also utilizes the Alinity m Resp-4-Plex Assay Application Specification File, Alinity m System and System Software, Alinity m Sample Prep Kit 2, Alinity m Tubes and Caps, and Alinity m System Solutions.

The provided text is a 510(k) Summary for the Abbott Molecular Inc. Alinity m Resp-4-Plex assay, a multiplexed real-time RT-PCR assay for the qualitative detection and differentiation of SARS-CoV-2, influenza A, influenza B, and RSV.

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

Acceptance Criteria and Reported Device Performance

The acceptance criteria for this device are demonstrated through various analytical and clinical studies, primarily focusing on analytical sensitivity (Limit of Detection), inclusivity, precision, reproducibility, analytical specificity (interfering substances and cross-reactants), competitive interference, carryover, and clinical performance (Positive Percent Agreement - PPA, and Negative Percent Agreement - NPA).

The document implicitly defines the acceptance criteria as the successful demonstration of performance metrics that are typically expected for such in vitro diagnostic devices, often compared to highly sensitive FDA-cleared or EUA assays. While specific numerical acceptance criteria (e.g., PPA > X%, NPA > Y%) are not explicitly stated as "acceptance criteria," they are demonstrated by the reported results. The conclusion statement (Section 5.0) explicitly states that the "analytical and clinical study results demonstrate that the Alinity m Resp-4-Plex assay... performs comparably to the predicate device... the results support a substantial equivalence decision." This implies that the demonstrated performance values met the FDA's criteria for substantial equivalence to the predicate device.

Here's a table summarizing the reported device performance, which implicitly met the acceptance criteria:

Table 1: Acceptance Criteria (as Demonstrated Performance) and Reported Device Performance

Study Details

Here's the breakdown of the study details as requested:

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

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

   • Analytical Studies (Test Set):

     • LoD: For each virus (Flu A, Flu B, RSV, SARS-CoV-2), preliminary LoD involved testing a minimum of 3 levels, each in a minimum of 3 replicates. Final LoD confirmation involved testing a minimum of 3 panel members with target concentrations bracketing the preliminary LoD, each panel member in a minimum of 20 replicates. (Total specific sample numbers not provided per virus, but this describes the method and minimums). Specimens were pooled negative NP clinical specimens.
     • Inclusivity: Each individual virus isolate or strain was tested in replicates of 5. (Total specific sample numbers not provided per virus, but 16 Flu A strains, 9 Flu B, 6 RSV, 9 SARS-CoV-2). Specimens were pooled negative clinical NP swab matrix.
     • Precision: 5 panel members (1 negative, 4 positive) tested with 4 replicates twice each day for 5 days, on 3 Alinity m Systems operated by 3 operators using 3 reagent lots. This leads to:
       • Flu A: 120 positive replicates for each level, 360 negative replicates.
       • Flu B: 120 positive replicates for each level, 357 negative replicates.
       • RSV: 120 positive replicates for moderate, 117 for low, 360 negative.
       • SARS-CoV-2: 120 positive replicates for each level, 357 negative.
     • Reproducibility: 5 panel members tested at 3 external clinical testing sites. Each site tested 2 Alinity m Resp-4-Plex AMP Kit lots, on 5 non-consecutive days for each lot. Four replicates of each panel member were tested on each of 5 days. This leads to:
       • Flu A: 120 positive replicates for each level, 360 negative replicates.
       • Flu B: 120 positive replicates for each level, 359 negative replicates.
       • RSV: 120 positive replicates for moderate, 119 for low, 360 negative.
       • SARS-CoV-2: 120 positive replicates for moderate, 117 for low, 359 negative.
     • Analytical Specificity (Interfering Substances): 34 substances evaluated in 2 different positive panel members (PM1 & PM2), each containing multiple analytes at 3xLoD. (Replicate number not specified).
     • Analytical Specificity (Cross-Reactants): 74 microorganisms added to pooled negative clinical NP swab matrix (replicate number not specified) and also to positive samples (replicate number not specified).
     • Competitive Interference: 4 panel members, each containing 3 viruses at low concentrations and one at high concentration. (Replicate number not specified).
     • Carryover: Negative and high positive samples tested in alternating positions, across 3 Alinity m Systems. 360 negative samples total.

   • Clinical Performance (Test Set):

     • Prospective Clinical Study:
       • Flu A/B, RSV: 2,753 valid results initially, 2,504 (Flu A), 2,710 (Flu B), 2,700 (RSV) used in analysis.
         • Data Provenance: Multicenter study using prospectively collected nasopharyngeal swab specimens. 4 US clinical sites for testing. Specimens collected during 2021-2022 flu season at 7 geographically distributed locations in the US and during the 2020 flu season at 1 location in the Southern Hemisphere.
       • SARS-CoV-2: 826 valid results initially, 698 used in analysis.
         • Data Provenance: Specimens collected at 10 geographically distributed locations in the US over 2 time periods (Dec 2020 - Feb 2021 and May 2023).
     • Retrospective Clinical Study:
       • Flu A/B, RSV: 515 valid results initially, 506 (Flu A), 504 (Flu B), 505 (RSV) used in analysis.
         • Data Provenance: Preselected archived flu B positive NP swab specimens in UVT or UTM collected during the 2017-2018 and 2019-2020 flu seasons. Randomly mixed with known negative specimens.

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 test sets (both prospective and retrospective) was established using a Composite Comparator (CC). This CC was based on results from "2 to 3 FDA cleared assays for flu A, flu B, and RSV" and "2 to 3 highly sensitive EUA SARS-CoV-2 molecular assays."
   • The document does not specify the number or qualifications of human experts (e.g., radiologists, pathologists) involved in establishing this ground truth. The ground truth method described is entirely based on laboratory comparator assays, not expert human interpretation of results.

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

   • The ground truth was established by a Composite Comparator (CC) method:
     • A specimen was categorized as CC positive if a minimum of 2 comparator positive results were reported.
     • A specimen was categorized as CC negative if a minimum of 2 comparator negative results were reported.
     • A specimen was categorized CC indeterminate if a CC could not be determined due to missing results from the comparator assays.
   • This functions as a type of "majority rule" adjudication or consensus, but strictly between other molecular assays, not human experts.

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, an MRMC comparative effectiveness study was not done.
   • This device is an in vitro diagnostic (RT-PCR assay) that provides a qualitative (positive/negative) result directly. It does not involve human "readers" interpreting images or other complex data that would typically benefit from AI assistance or an MRMC study design. Therefore, there's no data on human reader improvement with or without AI assistance.

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

   • Yes, the primary performance evaluation is a standalone algorithm-only performance.
   • The Alinity m Resp-4-Plex assay is an automated RT-PCR system. Its performance (PPA, NPA) in both analytical and clinical studies is the performance of the "algorithm only" in generating positive/negative results from the sample. Human intervention is limited to sample collection and system operation, not interpretation of the primary diagnostic output.

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

   • The ground truth for the clinical studies was established using a Composite Comparator (CC) method based on the results of other FDA-cleared molecular diagnostic assays (or EUA high-sensitivity molecular assays for SARS-CoV-2).
   • It was not based on expert consensus, pathology, or outcomes data directly.

8. The sample size for the training set:

   • The document describes a de novo device, or a device for which substantial equivalence is being sought, not an AI/ML device that requires a distinct "training set" and "test set" in the context of model development.
   • The studies presented are primarily verification and validation studies to demonstrate the device's analytical and clinical performance after its development.
   • Therefore, the concept of a separate "training set" as understood in machine learning (where data is used to train a model) is not applicable to this RT-PCR assay. The assay's "knowledge" is embedded in its reagents, primers, probes, and system parameters, which were likely optimized during development using various analytical samples, but these are not typically referred to as a "training set" in the context of a 510(k) for an RT-PCR assay.

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

   • As explained in point 8, there isn't a "training set" in the AI/ML sense for this RT-PCR assay. The ground truth for any samples used during the development or optimization phases would similarly be established using well-characterized samples (e.g., cultured viruses, positive clinical samples confirmed by reference methods, synthetic nucleic acids, negative clinical samples).

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The Alinity m HSV 1 & 2 / VZV assay is an in vitro real-time polymerase chain reaction (PCR) assay for the qualitative detection and differentiation of Herpes Simplex Virus 1 (HSV-1), Herpes Simplex Virus 2 (HSV-2) and Varicella Zoster Virus (VZV) DNA from clinician-collected cutaneous or mucocutaneous lesion swab specimens from symptomatic patients suspected of active herpes simplex virus 2 and/or varicella-zoster infection. The Alinity m HSV 1 & 2 / VZV assay is intended to aid in the diagnosis of herpes simplex virus 1, herpes simplex virus 2 and/or varicella-zoster active cutaneous or mucocutaneous infections. Negative results do not preclude herpes virus type 1, herpes simplex virus type 2 or varicella-zoster virus infections and should not be used as the sole basis for diagnosis, treatment or other management decisions.

The Alinity m HSV 1 & 2 / VZV assay is not intended for use with cerebrospinal fluid (CSF) or to aid in the diagnosis of HSV or VZV infections of the central nervous system (CNS). The Alinity m HSV 1 & 2 / VZV assay is not intended for use in prenatal screening.

The Alinity m HSV 1 & 2 / VZV assay is an in vitro real-time polymerase chain reaction (PCR) assay for the qualitative detection and differentiation of Herpes Simplex Virus 1 (HSV-1), Herpes Simplex Virus 2 (HSV-2) and Varicella Zoster Virus (VZV) DNA from clinician--collected cutaneous or mucocutaneous lesion swab specimens from symptomatic patients suspected of active herpes simplex virus 1, herpes simplex virus 2 and/or varicella-zoster infection. This assay is intended for use with the automated Alinity m System.

The steps of the Alinity m HSV 1 & 2 / VZV assay consist of sample preparation, PCR assembly, amplification/detection, and result calculation and reporting. The steps involved in all stages of the Alinity m HSV 1 & 2 / VZV assay procedure are executed automatically by the Alinity m System. No intermediate processing or transfer steps are performed by the user. The Alinity m System is designed to be a random access analyzer that can perform the Alinity m HSV 1 & 2 / VZV assay in parallel with other Alinity assays on the same instrument.

The Alinity m HSV 1 & 2 / VZV assay requires two separate assay specific kits as follows:

1. The Alinity m HSV 1 & 2 / VZV AMP Kit (List No. 09N61-095) is comprised of 2 types of multi-well trays:

TRAY 1: Alinity m HSV 1 & 2 / VZV AMP TRAY 1 TRAY 2: Alinity m HSV 1 & 2 / VZV ACT TRAY 2.

TRAY 1 - Alinity m HSV 1 & 2 / VZV AMP is individually packed in a foil pouch and contains 48 unit-dose liquid amplification reagent wells and 48 unitdose liquid IC wells. One well of each is used per test.

· Amplification reagent wells consist of synthetic oligonucleotides, DNA Polymerase, dNTPs, and 0.15% ProClin® 950 in a buffered solution with a reference dye. IC wells consist of plasmid DNA with unrelated IC sequences and poly dA:dT in a TE buffer containing 0.15% ProClin 950 as a preservative.

TRAY 2 - Alinity m HSV 1 & 2 / VZV ACT is individually packed in a foil pouch and contains 48 unit-dose liquid activation reagent wells. One reagent well is used per test.

· Activation reagent wells consist of magnesium chloride, potassium chloride, and tetramethylammonium chloride. Preservative: 0.15% ProClin 950.

2. The Alinity m HSV 1 & 2 / VZV CTRL Kit (09N61-085) consists of negative controls and positive controls, each supplied as liquid in single-use tubes.

Alinity m HSV 1 & 2 / VZV Negative CTRL (List No. 9N61Z) consists of Negative Diluent / TE buffer (containing 0.085% Sodium Azide and 0.087% ProClin 950).

Alinity m HSV 1 & 2 / VZV Positive CTRL (List No. 9N61W) consists of linearized plasmid DNA containing HSV-1, HSV-2 and VZV DNA sequences in Negative Diluent / TE buffer (containing 0.085% Sodium Azide and 0.087% ProClin 950).

The Alinity m HSV 1 & 2 / VZV assay is to be run on the Alinity m System which is a fully integrated, sample to result automated system that performs real-time PCR test using the Alinity m HSV 1 & 2 / VZV AMP Kit along with the Alinity m HSV 1 & 2 / VZV CTRL Kit.

The provided text describes the performance of the "Alinity m HSV 1 & 2 / VZV" assay, which is an in vitro real-time PCR assay for detecting and differentiating Herpes Simplex Virus 1 (HSV-1), Herpes Simplex Virus 2 (HSV-2), and Varicella Zoster Virus (VZV) DNA.

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

1. Table of Acceptance Criteria and Reported Device Performance

The acceptance criteria are implicitly defined by the clinical agreement and analytical performance values demonstrated to establish substantial equivalence to a predicate device. For clinical agreement, the performance is measured by Positive Percent Agreement (PPA) and Negative Percent Agreement (NPA) compared to a commercially available NAAT comparator method.

The acceptance criteria typically would be pre-defined statistical thresholds for PPA and NPA (e.g., PPA ≥ 95% and NPA ≥ 95%). Based on the reported results, the device successfully meets high performance metrics, suggesting that the implicit acceptance criteria were met for substantial equivalence.

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

• Prospective Study Test Set:
  • Sample Size: 1,258 results (1,257 for HSV-1, 1,257 for HSV-2, and 1,257 for VZV) from unique specimens.
  • Data Provenance: Multicenter, prospective clinical study conducted in the United States. Specimens were clinician-collected from symptomatic individuals.
• Retrospective Study Test Set:
  • Sample Size: 411 specimens (410 for HSV-1, 410 for HSV-2, and 411 for VZV).
  • Data Provenance: Retrospective study using archived, leftover lesion swab specimens from routine clinical testing. The location is not explicitly stated, but given it follows a prospective US study and is for US FDA clearance, it is highly likely to be from the US.

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

• The document does not specify the number or qualifications of experts used to establish the ground truth.
• The ground truth was established by comparison to a "commercially available NAAT comparator method (NAAT 1)". For discordant results, a "second commercially available RT-PCR comparator method (NAAT 2)" was used for informational purposes only (not for the primary analysis of device performance). This means the ground truth is essentially defined by the predicate/comparator device(s).

4. Adjudication Method for the Test Set

• The primary ground truth was established by a single comparator method (NAAT 1).
• For specimens with discordant results between the Alinity m assay and NAAT 1, a second NAAT method (NAAT 2) was used. However, the results of this second test were "not included in the analysis of device performance and are considered for information purposes only." This implies that the primary PPA/NPA calculations are based solely on the agreement with NAAT 1, and there was no formal 2+1 or 3+1 adjudication to establish a "resolved" ground truth for discordant cases that would then be used in the performance calculations.

5. If a Multi-Reader Multi-Case (MRMC) Comparative Effectiveness Study was done, and what was the effect size of how much human readers improve with AI vs without AI assistance

• This is not applicable as the device is an in vitro diagnostic (IVD) assay detecting viral DNA, not an AI-assisted diagnostic imaging device requiring human reader interpretation. There are no "human readers" in the context of this device.

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

• Yes, this is a standalone device performance study. The Alinity m HSV 1 & 2 / VZV assay is an automated system described as "fully integrated, sample to result." The performance data presented (clinical agreement, analytical sensitivity, specificity, precision, reproducibility, carryover) represent the performance of the algorithm/assay system without direct human interpretation of raw data being a variable. The "results are calculated and reported" automatically by the Alinity m System.

7. The Type of Ground Truth Used

• The ground truth was established by comparison to a "commercially available NAAT comparator method (NAAT 1)." For discordant cases, a second NAAT (NAAT 2) was used, but its results were for informational purposes only. This is a form of clinical surrogate ground truth, relying on an established and legally marketed diagnostic method. It is not pathology, expert consensus (in the traditional sense of multiple human interpretations), or outcomes data.

8. The Sample Size for the Training Set

• The document does not provide information regarding a specific training set size or how the device's algorithms (if any, beyond PCR signal processing) were trained. Regulatory submissions for IVD assays primarily focus on analytical and clinical validation of the final, locked-down device performance, rather than algorithm development specifics. The device seems to be a PCR assay, where the "training" would be more akin to assay design and optimization, not machine learning model training on large datasets in the way an AI imaging model is.

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

• As the document does not mention a training set in the context of machine learning, there is no information on how a ground truth for such a set would have been established. For a PCR assay, the development process involves extensive analytical characterization, optimization, and verification using characterized samples (e.g., known positive/negative samples, spiked samples, reference strains) to establish assay parameters and thresholds. This is distinct from establishing ground truth for a machine learning training dataset.

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The Alinity m STI Assay is an in vitro polymerase chain reaction (PCR) assay for use with the automated Alinity m System for the direct, qualitative detection and differentiation of ribosomal RNA from Chlamydia trachomatis (CT), DNA from Neisseria gonorrhoeae (NG), ribosomal RNA from Trichomonas vaginalis (TV), and ribosomal RNA from Mycoplasma genitalium (MG), to aid in the diagnosis of disease(s) caused by infection from these organisms. The assay may be used to test the following specimens from symptomatic and asymptomatic individuals for the following analytes:

• . CT: vaginal swabs (clinician-collected and self-collected in a clinical setting). endocervical swabs, gynecological specimens in ThinPrep PreservCyt Solution, female urine, male urine, oropharyngeal swabs, and rectal swabs
• . NG: vaginal swabs (clinician-collected and self-collected in a clinical setting), endocervical swabs, gynecological specimens in ThinPrep PreservCyt Solution, female urine, male urine, oropharyngeal swabs, and rectal swabs
• . TV: vaginal swabs (clinician-collected and self-collected in a clinical setting). endocervical swabs, gynecological specimens in ThinPrep PreservCyt Solution, female urine, and male urine
• . MG: vaginal swabs (clinician-collected and self-collected in a clinical setting), endocervical swabs, and male urine

A vaginal swab (self-collected or clinician-collected) is the preferred specimen type for MG testing in females due to the higher clinical sensitivity compared to endocervical swabs. If endocervical swab specimens test negative, testing with a vaginal swab may be indicated if M. genitalium infection is suspected.

The Alinity m STI Assay utilizes real time PCR to amplify and detect Chlamydia trachomatis (CT) ribosomal RNA sequences, Neisseria gonorrhoeae (NG) genomic DNA sequences, Trichomonas vaginalis (TV) ribosomal RNA sequences, Mycoplasma genitalium (MG) ribosomal RNA sequences, and human genomic DNA sequences that have been extracted from endocervical swab specimens, vaginal swab specimens, oropharyngeal swab specimens, rectal swab specimens, male and female urine specimens, and gynecological specimens preserved in PreservCyt Solution. Endocervical swab, vaginal swab, oropharyngeal swab, rectal swab, and urine specimens are collected with the Alinity m multi-Collect Specimen Transport Kit. PreservCyt specimens are transferred to a transport tube for processing on the Alinity m System.

This device is similar to the predicate device originally cleared (K202977). It does not introduce any changes to the Alinity m STI Assay reagents, sample processing, assay procedure, and data reduction. This device is updating the previous FDA-cleared Intended Use (K202977) to include claims for the following specimens for the following analytes:

• CT: Gynecological specimens in ThinPrep PreservCyt Solution, female urine .
• NG: Female urine

Two studies were initiated to support these claims (refer to Section 1.7.2.) This supplemental data was used with data previously obtained from the Alinity m STI Assay clinical testing studies submitted in K202977.

The steps of the Alinity m STI Assay consist of sample preparation. RT-PCR assembly, amplification/detection, and result calculation and reporting. All stages of the Alinity m STI Assay procedure are executed automatically by the Alinity m System. No intermediate processing or transfer steps are performed by the user. The Alinity m System is designed to be a random-access analyzer that can perform the Alinity m STI Assay in parallel with other Alinity m assays on the same instrument.

The Alinity m STI Assay is an in vitro diagnostic device for the qualitative detection and differentiation of nucleic acids from Chlamydia trachomatis (CT), Neisseria gonorrhoeae (NG), Trichomonas vaginalis (TV), and Mycoplasma genitalium (MG) in various human specimen types. The device operates on the automated Alinity m System and utilizes real-time Polymerase Chain Reaction (PCR) technology. This submission primarily focuses on supporting expanded claims for specific analytes and specimen types: CT in gynecological specimens in ThinPrep PreservCyt Solution and female urine, and NG in female urine.

Here's a breakdown of the acceptance criteria and study details:

1. Table of Acceptance Criteria and Reported Device Performance:

The document doesn't explicitly state "acceptance criteria" for the clinical performance in terms of specific thresholds (e.g., minimum PPA/NPA). Instead, it presents the Positive Percent Agreement (PPA) and Negative Percent Agreement (NPA) values with 95% Confidence Intervals (CI) as the primary performance metrics, demonstrating the device's accuracy against a Composite Comparator Algorithm (CCA).

Note: The table is constructed based on the "specimen-specific positive and negative agreement" data. The document does not provide specific acceptance thresholds, but the presented performance metrics are high, demonstrating the device's effectiveness.

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

• CT and NG in Female Urine:
  • Sample Size: A total of 2,798 female subjects were enrolled. 2,785 CT results and 2,784 NG results were used in the analysis after exclusions due to missing/indeterminate CCA results.
  • Data Provenance: The study was a multicenter clinical study conducted in the United States. Subjects provided urine specimens. The data includes both symptomatic and asymptomatic individuals.
• CT in PreservCyt Specimens:
  • Sample Size: 1,939 specimens from a multicenter clinical study were included in the analysis.
  • Data Provenance: The study was a multicenter clinical study conducted in the United States. Female subjects provided gynecological specimens collected in PreservCyt Solution.

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

The ground truth was established using a clinical comparator method, not individual experts.

• Ground Truth Method: A Composite Comparator Algorithm (CCA) was used.
• Details: For each subject, a CCA was determined for each analyte based on the combined results from commercially available nucleic acid amplification tests (NAATs).
  • For the female urine study (CT and NG), comparator assays included 3 commercially available NAATs. Specimens were initially tested with 2 NAATs. If they disagreed or a result was missing/indeterminate, a third tiebreaker NAAT was used.
  • For the PreservCyt study (CT), specimens were tested with up to 3 comparator NAATs. Similar to the urine study, specimens were initially tested with 2 NAATs, and a third was used as a tiebreaker if needed.
• Qualifications of Experts: The document does not mention the use of human experts or their qualifications for establishing ground truth. The ground truth is effectively an "expert panel of assays" (the comparator NAATs).

4. Adjudication Method for the Test Set:

• Method: A 2+1 adjudication method was employed for establishing the Composite Comparator Algorithm (CCA).
  • Description: Specimens were initially tested with two comparator NAATs.
  • If the two initial NAATs agreed (both positive or both negative), that result formed the CCA.
  • If the two initial NAATs disagreed, or if one result was missing or indeterminate, a third "tiebreaker" NAAT was used to resolve the discrepancy and establish the CCA.
  • A subject was categorized as "Positive" if at least 2 comparator assay results were positive and "Negative" if at least 2 comparator assay results were negative.

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

No, an MRMC comparative effectiveness study was not done. The Alinity m STI Assay is an in vitro diagnostic device (IVD) that provides a qualitative result directly. Its performance is compared against a composite reference standard (CCA) derived from other NAATs, not against human readers. Therefore, the concept of human readers improving with AI assistance is not applicable in this context.

6. If a Standalone (Algorithm Only Without Human-in-the-Loop Performance) Was Done:

Yes, a standalone performance study was done. The reported performance metrics (PPA and NPA) reflect the accuracy of the Alinity m STI Assay (algorithm and reagents performed on the automated Alinity m System) operating independently against the established ground truth (CCA). The device provides a direct, qualitative result without human interpretation of the algorithm's output for diagnosis.

7. The Type of Ground Truth Used:

The ground truth used was a Composite Comparator Algorithm (CCA), which is an expert consensus based on multiple FDA-cleared nucleic acid amplification tests (NAATs). These NAATs are considered the gold standard for detecting these pathogens. The CCA essentially serves as the "best available truth" when a true clinical outcome or pathological confirmation for all cases is not feasible or practical in a large-scale clinical trial.

8. The Sample Size for the Training Set:

The document does not explicitly describe a separate "training set" for the Alinity m STI Assay in the context of this 510(k) submission. This is typical for IVD devices, where the assay's design, reagent formulation, and analytical parameters are developed through internal R&D, rather than a machine learning training paradigm with a distinct training dataset for an "algorithm." The clinical studies mentioned (both the original K202977 studies and the supplemental studies) serve as validation/test sets to demonstrate the performance of the already developed assay.

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

Since a distinct "training set" in the machine learning sense is not described, the question of how its ground truth was established is not directly applicable. The Alinity m STI Assay's underlying technology (real-time PCR) and design would have been established and optimized based on known genetic sequences, analytical performance studies (e.g., analytical sensitivity, specificity), and prior knowledge of the target organisms, where ground truth sources for these developmental phases would likely include:

• Well-characterized isolates/strains: Known positive and negative biological samples.
• Synthetic nucleic acid targets: Designed to validate primer and probe performance.
• Spiked matrix samples: To assess analytical performance in relevant specimen types.

These developmental activities would precede the clinical validation studies that are the focus of this 510(k) submission.

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