(475 days)
The ADVIA Centaur Cyclosporine assay is an in vitro diagnostic immunoassay for the quantitative determination of cyclosporine in human whole blood using the ADVIA Centaur systems. This assay is intended for use as an aid in the management of cyclosporine therapy in kidney, heart, and liver transplant patients.
The ADVIA Centaur® Cyclosporine assay is a competitive immunoassay using direct chemiluminescent technology. Cyclosporine in the patient sample competes with acridinium ester-labeled cyclosporine in the Lite Reagent for a limited amount of biotin-labeled monoclonal mouse anti-cyclosporine antibody. Biotinlabeled anti-cyclosporine binds to streptavidin that is covalently coupled to paramagnetic particles in the Solid Phase. In the ADVIA Centaur® Cyclosporine assay the sample is manually pretreated to lyse the cells and solubilize the cyclosporine. An inverse relationship exists between the amount of cyclosporine present in the patient sample and the amount of relative light units (RLUs) detected by the system.
Here's a breakdown of the acceptance criteria and study details for the ADVIA Centaur® Cyclosporine Assay, based on the provided text:
Acceptance Criteria and Reported Device Performance
The provided document describes comparison studies for the ADVIA Centaur® Cyclosporine assay against two reference methods: Tandem Mass Spectrometry (Tandem-MS) and the Abbott TDx®TDxFLx® Cyclosporine Monoclonal Whole Blood assay (and also Abbott AxSym). The "acceptance criteria" are implied by the ranges of statistical measures (slope, intercept, and correlation coefficient) that demonstrate substantial equivalence to the predicate devices and reference method. While explicit acceptance thresholds aren't stated as pass/fail criteria, the reported performance metrics indicate the device's acceptable agreement with established methods.
Here's a table summarizing the reported device performance, categorized by the comparative method and patient group/site:
Table 1: Acceptance Criteria (Implied) and Reported Device Performance for ADVIA Centaur® Cyclosporine Assay
| Comparative Method | Transplant Type | Patient Samples (n) | Slope (Desired: ~1.0) | Intercept (Desired: ~0.0) | Correlation Coefficient (Desired: ~1.0) | Interpretation of Performance |
|---|---|---|---|---|---|---|
| All Tandem-MS Comparisons | ||||||
| Tandem-MS | kidney | 108 | 1.11 | -8 | 0.962 | Strong correlation, slope close to 1, small intercept. |
| Tandem-MS | liver | 75 | 1.04 | -5 | 0.967 | Strong correlation, slope close to 1, small intercept. |
| Tandem-MS | heart | 67 | 0.89 | 20 | 0.966 | Strong correlation, slope slightly lower than 1, larger intercept. |
| Tandem-MS | all | 250 | 1.03 | -1 | 0.963 | Overall strong correlation, slope close to 1, very small intercept. |
| Tandem-MS | site 1 | 97 | 0.88 | 13 | 0.979 | Very strong correlation, slope slightly lower than 1, small intercept. |
| Tandem-MS | site 2 | 105 | 0.85 | 23 | 0.988 | Very strong correlation, slope lower than 1, somewhat larger intercept. |
| Tandem-MS | site 3 | 48 | 1.11 | 46 | 0.965 | Strong correlation, slope slightly higher than 1, larger intercept. |
| Tandem-MS | all (by site) | 250 | 0.94 | 19 | 0.960 | Overall strong correlation, slope close to 1, small intercept. |
| Tandem-MS | trough | 182 | 1.02 | 8 | 0.909 | Good correlation, slope close to 1, small intercept (slightly lower correlation). |
| Tandem-MS | peak | 68 | 1.15 | -104 | 0.898 | Good correlation, slope higher than 1, larger negative intercept (slightly lower correlation). |
| Tandem-MS | all (by trough/peak) | 250 | 1.03 | -1 | 0.963 | Overall strong correlation, slope close to 1, very small intercept. |
| Abbott TDx Comparisons | ||||||
| Abbott TDx | site 1 | 97 | 0.78 | 8 | 0.977 | Strong correlation, slope lower than 1, small intercept. |
| Abbott TDx | site 2 | 97 | 0.68 | -3 | 0.988 | Very strong correlation, significantly lower slope, small intercept. |
| Abbott TDx | site 3 | 48 | 0.71 | 22 | 0.977 | Strong correlation, significantly lower slope, small intercept. |
| Abbott TDx | all | 242 | 0.72 | 6 | 0.977 | Overall strong correlation, significantly lower slope, small intercept. |
| Abbott AxSym Comparisons | ||||||
| Abbott AxSym | site 1 | 219 | 0.68 | 18 | 0.960 | Strong correlation, significantly lower slope, small intercept. |
2. Sample Size and Data Provenance
-
Test Set Sample Size:
- Against Tandem-MS:
- Kidney transplant patients: 108 samples
- Liver transplant patients: 75 samples
- Heart transplant patients: 67 samples
- Total against Tandem-MS: 250 samples (across all transplant types)
- Total against Tandem-MS (by site): 250 samples (97 at site 1, 105 at site 2, 48 at site 3)
- Total against Tandem-MS (by trough/peak): 250 samples (182 trough, 68 peak)
- Against Abbott TDx: 242 samples (97 at site 1, 97 at site 2, 48 at site 3)
- Against Abbott AxSym: 219 samples (at site 1)
- Against Tandem-MS:
-
Data Provenance: The samples were from "three transplant patient groups (heart, kidney and liver)" and "three external sites." The text does not specify the country of origin, but given the submitter is Siemens Healthcare Diagnostics in Tarrytown, New York, USA, and the FDA submission, it's highly likely the data includes US patients. The study is retrospective, as it uses existing patient samples for comparison.
3. Number of Experts and Qualifications for Ground Truth
The study does not involve human readers/experts in the traditional sense of interpreting images or clinical data. Instead, it compares the performance of the ADVIA Centaur® Cyclosporine assay against established analytical methods. Therefore, the concept of "experts establishing ground truth" as it applies to subjective assessments is not directly relevant here.
The "ground truth" is established by:
- Tandem Mass Spectrometry (Tandem-MS): This is a highly accurate and precise analytical method often considered a gold standard for quantifying small molecules like cyclosporine. The operators of these machines are typically highly trained laboratory professionals.
- Abbott TDx®TDxFLx® Cyclosporine Monoclonal Whole Blood assay: This is a legally marketed predicate device, representing an established and accepted method for cyclosporine measurement.
- Abbott AxSym: Another legally marketed device for comparison.
4. Adjudication Method for the Test Set
No adjudication method is described, as the "test set" involves analytical measurements rather than subjective interpretations requiring consensus. The "comparison" is statistical (Deming regression) between the new device and established reference methods.
5. Multi-Reader Multi-Case (MRMC) Comparative Effectiveness Study
No, an MRMC comparative effectiveness study was not done. This type of study is typically used for diagnostic imaging or subjective clinical assessments where multiple human readers interpret cases. The ADVIA Centaur® Cyclosporine assay is an in vitro diagnostic assay that produces a quantitative numerical result; its performance is evaluated by comparison to other quantitative methods, not by improvements in human reader performance.
6. Standalone (Algorithm Only) Performance
Yes, this entire study is a standalone performance study. The ADVIA Centaur® Cyclosporine assay itself (the "algorithm" in this context, albeit a chemical immunoassay) is being tested for its direct, unassisted performance in quantifying cyclosporine. There is no human-in-the-loop component being evaluated for its direct impact on the assay's result.
7. Type of Ground Truth Used
The ground truth used is based on:
- Analytical Reference Method: Tandem Mass Spectrometry (Tandem-MS), which is typically considered a highly accurate and precise reference method for cyclosporine quantification.
- Predicate Device Performance: The results from the legally marketed Abbott TDx®TDxFLx® Cyclosporine Monoclonal Whole Blood assay and Abbott AxSym are used as a comparative "truth" to establish substantial equivalence.
8. Sample Size for the Training Set
The document does not provide information about a separate "training set" for the assay. Immunoassays like the ADVIA Centaur® Cyclosporine assay are developed and optimized through laboratory procedures, reagent formulation, and calibration curves, rather than being "trained" on a dataset in the way a machine learning algorithm would be. The data presented in the tables are for performance validation (the "test set" in an ML context).
9. How Ground Truth for the Training Set Was Established
As noted above, the concept of a "training set" and its "ground truth" doesn't directly apply here in the way it would for a machine learning model. The assay's internal calibration and performance characteristics would have been established during its development and manufacturing process, likely using characterized reference materials and calibrators, not through a "ground truth" dataset in the clinical study sense. The reference calibrators themselves (ADVIA Centaur® Cyclosporine Calibrator) have their own manufacturing and quality control processes to establish their known concentrations.
§ 862.1235 Cyclosporine test system.
(a)
Identification. A cyclosporine test system is a device intended to quantitatively determine cyclosporine concentrations as an aid in the management of transplant patients receiving therapy with this drug. This generic type of device includes immunoassays and chromatographic assays for cyclosporine.(b)
Classification. Class II (special controls). The special control is “Class II Special Controls Guidance Document: Cyclosporine and Tacrolimus Assays; Guidance for Industry and FDA.” See § 862.1(d) for the availability of this guidance document.