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DiviTumTKa is an in vitro diagnostic device intended for the semi-quantitative measurement of thymidine kinase activity (TKa) in human serum. The assay is to be used as an aid in monitoring disease progression in previously diagnosed hormone receptor positive, metastatic postmenopausal female breast cancer patients. A TKa value of

Each DiviTum®TKa kit contains all necessary reagents, including calibrators and assay controls for analyses of 37 patient samples in duplicates. The kit components include Reagent A, Reagent B, Conjugate DiviTum®TKa, Control Low DiviTum®TKa, Control Medium DiviTum®TKa, Control High DiviTum®TKa, Calibrator 0 DiviTum®TKa through Calibrator 6 DiviTum®TKa, and Reaction Plate DiviTum®TKa. The Reaction Plate is a 96 well plate in sealed aluminum foil containing immobilized DNA strands, acting as a reaction chamber.

Here's an analysis of the DiviTum®TKa device based on the provided FDA 510(k) summary, structured to address your specific questions:

Acceptance Criteria and Device Performance for DiviTum®TKa

1. Table of Acceptance Criteria and the Reported Device Performance

The acceptance criteria for DiviTum®TKa are primarily focused on its clinical effectiveness as an aid in monitoring disease progression, along with analytical performance. The key clinical acceptance relates to its ability to identify progression within 30 or 60 days.

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

• Clinical Test Set:
  • Number of patients: 454 patients (subjects).
  • Total serum samples/test results: 1598 initially, with 52 excluded, resulting in 1546 test results for analysis (1164 during treatment, 382 from baseline).
  • Data Provenance: The study used "left-over banked serum samples from metastatic breast cancer patients undergoing treatment." The document does not explicitly state the country of origin, but the "U.S. Collected" healthy post-menopausal female specimens suggest at least some data might be from the US. The retrospective or prospective nature of the collection of these banked samples is not specified, but the analysis of these archived samples is retrospective.
• Analytical Test Sets:
  • Precision studies involved various samples (pooled breast cancer serum, healthy blood donor serum) with replicate measurements. For example, the multisite study used 75 measurements per sample, and the single-site study used 79-80 measurements per sample.
  • Linearity study used 10 intermediate concentrations with 4 replicates each.
  • Detection limit studies used unspecified numbers of replicates for LOB, LOD, and LOQ calculations.
  • Analytical specificity testing involved up to 55 substances.

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

The document does not specify the number or qualifications of experts used to establish the ground truth for disease progression in the clinical test set. It mentions that "clinical data on disease progression" was linked to the TKa measurements. This clinical data would typically be established by treating physicians using standard clinical methods (imaging, physician assessment, etc.), but the details of this process and the experts involved are not provided in this summary.

4. Adjudication Method for the Test Set

The document does not describe an explicit adjudication method (e.g., 2+1, 3+1) for establishing disease progression in the clinical test set. It relies on previously established "clinical data on disease progression."

5. If a Multi-Reader Multi-Case (MRMC) Comparative Effectiveness Study Was Done, If So, What Was the Effect Size of How Much Human Readers Improve with AI vs without AI Assistance

This device (DiviTum®TKa) is an in vitro diagnostic (IVD) test for measuring a biomarker (thymidine kinase activity) in serum. It is not an imaging AI device that assists human readers in interpreting images. Therefore, a Multi-Reader Multi-Case (MRMC) comparative effectiveness study focusing on human reader improvement with AI assistance is not applicable and was not performed or described in this summary.

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

Yes, the analytical and clinical performance studies presented describe the standalone performance of the DiviTum®TKa assay. The device measures TKa directly from serum samples and provides a quantitative result (DuA) which is then compared against a fixed cut-off of 250 DuA to aid in monitoring disease progression. There is no human-in-the-loop interpretation of the assay result itself described; the result is a direct measurement. However, the interpretation of what that result means for patient management requires a human clinician ("DiviTumTKa results should be used in conjunction with other clinical methods for monitoring breast cancer").

7. The Type of Ground Truth Used (Expert Consensus, Pathology, Outcomes Data, etc.)

The ground truth for the clinical study was outcomes data in the form of "disease progression." This was derived from "clinical data on disease progression" of breast cancer patients. While the specifics of how "disease progression" was defined (e.g., RECIST criteria, clinical signs, imaging changes) are not detailed in this summary, it represents an objective clinical outcome.

8. The Sample Size for the Training Set

The document refers to a "clinical validation study" but does not explicitly mention a separate "training set" for the clinical performance evaluation. The 454 patients (1546 samples) datasets were used for validation.

For the analytical performance, the device relies on a calibration curve for converting optical density readings to TKa units. Calibrators are included in each kit. The specific sample size for training the underlying algorithm if it involved machine learning beyond standard statistical models is not detailed, but given it's an enzyme immunoassay, it's unlikely to involve a large, separate machine learning "training set" in the common sense. The calibrators define the assay's conversion.

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

Given that DiviTum®TKa is an ELISA-based immunoassay, the "training set" more accurately refers to the development and calibration of the assay.

• Analytical Calibration: Calibrators with "predetermined nominal values" are included in the kit. These values are established during the development and manufacturing process by Biovica using established "in-house measurement procedures and calibrators to support values assigned to the product calibrators." The definition of 1 DuA is linked to the TK activity of 1 pg/mL of recombinant TK1 (MyBiosource).
• Clinical Reference Value ("Cut-off"): This was established by analyzing 123 serum samples from "apparently healthy post-menopausal females" in a reference study, with the ground truth being their healthy status. The 95th percentile of this healthy distribution (254 DuA) was used to set the initial clinical reference value. This was further "verified by published data" and evaluated using ROC analysis against the clinical outcomes (disease progression/no progression).

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