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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.

• ≤ 0.25 Log IU/mL for 500-100,000,000 IU/mL
• ≤ 0.50 Log IU/mL for 50-

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The Aptima® CMV Quant Assay is an in vitro nucleic acid amplification test for the quantitation of human cytomegalovirus (CMV) DNA in human EDTA plasma on the fully automated Panther® system.

The Aptima CMV Quant Assay is intended for use to aid in the management of solid-organ transplant patients and hematopoietic stem cell transplant patients receiving anti-CMV therapy, serial DNA measurements can be used to assess viral response to treatment. The results from Aptima CMV Quant assay must be interpreted within the context of all relevant clinical and laboratory findings.

The Aptima CMV Quant Assay is not intended for use as a screening assay for the presence of CMV in blood or blood products.

The Aptima CMV Quant Assay is an in vitro nucleic acid amplification test that uses real-time transcription mediated amplification (TMA) technology on the Panther Fusion system to quantify CMV DNA, genotypes 1, 2, 3, and 4. The primer design targets the highly conserved UL56 gene to ensure accurate quantitation of the CMV DNA. The assay is standardized to the WHO International Standard for human cytomegalovirus. The Aptima CMV Quant Assay is intended for use to aid in the management of solid-organ transplant patients and hematopoietic stem cell transplant patients.

The addition of a protocol to treat specific plasma samples with proteinase K in the assay package insert will allow the retesting of those samples to obtain a valid result.

The provided text describes a 510(k) premarket notification for the "Aptima CMV Quant Assay" and specifically details an update to the assay's package insert to include a protocol for retesting plasma samples that initially yield an "ML2 flag" invalid result. This retesting involves a manual pretreatment with proteinase K. The information provided is for a diagnostic assay, not an AI/ML-based device. Therefore, many of the requested elements pertaining to AI/ML development, such as training sets, ground truth establishment for AI/ML, expert consensus for imaging, MRMC studies, and effect sizes of AI assistance, are not applicable.

However, I can extract information related to the acceptance criteria and the study that proves the device (specifically, the proteinase K pretreatment protocol) meets the acceptance criteria within the context of a diagnostic assay's performance and validation.

Acceptance Criteria and Study for the Proteinase K Pretreatment Protocol

The primary acceptance criterion for this change is to demonstrate that the proteinase K pretreatment protocol effectively resolves the "ML2 flag" invalid results and does not negatively impact the accuracy of the CMV quantification.

1. Table of Acceptance Criteria and the Reported Device Performance:

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

• Test Set Sample Sizes:
  • Without Proteinase K: 1039 plasma specimens
  • With Proteinase K: 4098 plasma specimens
• Data Provenance: The plasma specimens were collected from the transplant patient population by the National Institute of Health (NIH). This suggests a retrospective analysis of archived samples or a prospective study conducted at the NIH. The location is the USA.

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

• Not applicable as this is a quantitative diagnostic assay for DNA detection, not an image-based AI/ML device requiring expert interpretation of images for ground truth. The "ground truth" here is the actual CMV DNA concentration, which the assay is designed to measure.

4. Adjudication Method for the Test Set:

• Not applicable for a quantitative diagnostic assay. The performance is assessed against the ability to produce a valid quantitative result for CMV DNA and maintain accuracy, not against human consensus.

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

• No, this is not an MRMC study. MRMC studies are typically performed for visual diagnostic aids (e.g., medical imaging AI) to compare human reader performance with and without AI assistance. This device is a direct quantitative assay.

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

• Yes, in a sense. The study validates the protocol (which includes a manual pretreatment step) and its effect on the automated assay system's ability to produce a valid result. The "performance" refers to the assay's output after the sample preparation, not an AI algorithm's independent decision. The core assay itself operates in a "standalone" fashion once the sample is loaded onto the Panther system.

7. The type of ground truth used:

• The implicit ground truth is the actual CMV DNA concentration in patient samples (or spiked controls used in accuracy assessments), as determined by a reference method or known concentrations. The study's focus, however, is on resolving an assay technical issue (ML2 flag) and demonstrating that the resolution method maintains the accuracy of CMV quantification. The reference to the NIH demonstrating that "using proteinase K for pretreatment of specimens did not impact the accuracy of CMV quantification" confirms that accurate quantitation (the ground truth outcome) was assessed.

8. The Sample Size for the Training Set:

• Not applicable. This is not an AI/ML device that requires a training set in the conventional sense. The "training" for such an assay would be its initial development and optimization, which isn't described in terms of a specific "training set" size for this modification. The data provided refers to validation/test sets for the new protocol.

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

• Not applicable, as it's not an AI/ML device with a training set for model development.

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