(46 days)
The CEDIA® Tacrolimus Assay is an in vitro diagnostic medical device intended for the quantitative determination of tacrolimus in human whole blood using automated clinical chemistry analyzers as an aid in the management of kidney and liver transplant recipients receiving tacrolimus therapy.
CEDIA® Tacrolimus Calibrators are intended for calibration of the CEDIA® Tacrolimus Assay in whole blood.
The CEDIA® Tacrolimus Assay uses recombinant DNA technology (US Patent No. 4708929) to produce a unique homogeneous enzyme immunoassay system. The assay is based on the bacterial enzyme ß-galactosidase, which has been genetically engineered into two inactive fragments i.e., enzyme acceptor (EA) and enzyme donor (ED). These fragments spontaneously reassociate to form fully active enzyme that, in the assay format, cleaves a substrate, generating a color change that can be measured spectrophotometrically.
In the assay, analyte in the sample competes with analyte conjugated to one inactive fragment (ED) of ß-galactosidase for antibody binding site. If analyte is present in the sample, it binds to antibody, leaving the inactive enzyme fragments free to form active enzyme. If analyte is not present in the sample, antibody binds to analyte conjugated on the inactive fragment, inhibiting the reassociation of inactive ß-galactosidase fragments, and no active enzyme is formed. The amount of active enzyme formed and resultant absorbance change are directly proportional to the amount of analyte present in the sample.
The provided text describes the 510(k) summary for the CEDIA® Tacrolimus Assay, primarily focusing on its substantial equivalence to a predicate device rather than detailing specific acceptance criteria and a dedicated study proving its fulfillment. Therefore, some information, particularly regarding specific performance metrics and a standalone study to meet predefined acceptance criteria, is not explicitly present.
However, based on the context of a 510(k) submission and the information provided, we can infer and construct a response.
Here's a breakdown of the requested information based on the provided text:
Acceptance Criteria and Device Performance Study
The document states that the CEDIA® Tacrolimus Assay is substantially equivalent to the IMx® Tacrolimus II (MEIA). This equivalence is demonstrated by comparing device characteristics and, implicitly, performance, although specific performance acceptance criteria and direct comparative performance data against these criteria are not explicitly detailed in the provided summary. The guidance document "Class II Special Controls Guidance Document: Cyclosporine and Tacrolimus Assays; Guidance for Industry and FDA", dated September 16, 2002, was followed to demonstrate this equivalence.
Given the nature of diagnostic assays, "acceptance criteria" generally involve analytical performance characteristics like precision, accuracy, linearity, lower limit of detection (LoD), upper limit of quantification (LoQ), and potential interferences. While these specific criteria and the detailed results against them are not provided, the claim of "substantial equivalence" implies that these were assessed and found comparable to the predicate device.
1. Table of Acceptance Criteria and Reported Device Performance
As specific numerical acceptance criteria and direct performance metrics against them are not explicitly stated in the provided text, the table below will reflect the comparison made for "substantial equivalence" based on device characteristics. For a diagnostic assay, typical performance criteria would involve analytical accuracy, precision, and agreement with the predicate.
| Characteristic | Acceptance Criterion (Implicitly based on Predicate) | Reported Device Performance (CEDIA® Tacrolimus Assay) |
|---|---|---|
| Intended Use | Quantitative determination of tacrolimus in human whole blood as an aid in managing kidney and liver transplant patients receiving tacrolimus therapy with automated clinical chemistry analyzers. | Quantitative determination of tacrolimus in human whole blood using automated clinical chemistry analyzers as an aid in the management of kidney and liver transplant recipients receiving tacrolimus therapy. (Equivalent to Predicate) |
| Analyte | Tacrolimus | Tacrolimus |
| Matrix | Whole blood extract | Whole blood extract |
| Calibrator Form | Liquid | Liquid |
| Calibrator Levels | Not explicitly stated as acceptance criteria, but predicate has 6 levels (0, 3, 6, 12, 20, and 30 ng/mL). | Two (2) Levels (0 and 30 ng/mL) - Note: This is a difference compared to the predicate, but implied to be acceptable for substantial equivalence. |
| Storage (Reagents) | 2°C to 8°C until expiration. | Reagents are stored at 2°C to 8°C until expiration date. (Equivalent to Predicate) |
| Storage (Calibrators) | Frozen until expiration. | Calibrators are stored at -20°C until expiration date. (Equivalent to Predicate type of storage, though specific temperature differs: frozen vs. -20°C) |
| Stability | Until expiration date noted on vial label. | Until expiration date noted on vial label and Package Insert. (Equivalent to Predicate) |
| Accuracy / Agreement (Inferred) | Clinical agreement and correlation with the predicate device (IMx® Tacrolimus II). | "Data and results amply demonstrate that the CEDIA® Tacrolimus Assay is substantially equivalent to the IMx® Tacrolimus II assay for the quantitative determination of tacrolimus..." (Specific statistical metrics or performance data are not provided in the summary). |
| Precision (Inferred) | Acceptable within-run, between-run, and total precision for tacrolimus quantification. | Implied to be acceptable for substantial equivalence, but specific data not provided. |
| Linearity (Inferred) | Linear response across the claimed assay range. | Implied to be acceptable for substantial equivalence, but specific data not provided. |
2. Sample size used for the test set and the data provenance
The document does not specify the sample size used for the test set or the data provenance (e.g., country of origin, retrospective or prospective). It broadly mentions that "Data and results provided in this premarket notification were collected and prepared, respectively, in accordance with the established guideline, 'Class II Special Controls Guidance Document: Cyclosporine and Tacrolimus Assays; Guidance for Industry and FDA'". This guideline is likely to define the requirements for such studies, but the specific details are absent from this summary.
3. Number of experts used to establish the ground truth for the test set and the qualifications of those experts
This information is not applicable and hence not provided. For an in vitro diagnostic (IVD) quantitative assay like the CEDIA® Tacrolimus Assay, ground truth is typically established through reference methods, certified calibrators, or established analytical techniques directly measuring tacrolimus concentration, rather than human expert interpretation of images or clinical assessments.
4. Adjudication method for the test set
This information is not applicable and hence not provided for a quantitative IVD assay. Adjudication methods like "2+1" or "3+1" are relevant for subjective interpretations, often in imaging or pathology, where human experts might disagree.
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 information is not applicable. The CEDIA® Tacrolimus Assay is an in vitro diagnostic (IVD) device for quantitative biochemical analysis, not an AI-assisted diagnostic tool that aids human readers (e.g., radiologists interpreting images). Therefore, an MRMC study with human readers and AI assistance is not relevant to this device.
6. If a standalone (i.e. algorithm only without human-in-the-loop performance) was done
Yes, a standalone performance assessment was implicitly done. The CEDIA® Tacrolimus Assay is an automated enzyme immunoassay system. Its performance evaluation would have been conducted as an "algorithm only" (or assay-only) study to determine its analytical characteristics (accuracy, precision, linearity) and compare them to the predicate device. The claim of "substantial equivalence" is based on the standalone performance of the assay. The summary does not detail the specifics of this standalone study, but it is integral to the submission.
7. The type of ground truth used (expert consensus, pathology, outcomes data, etc.)
For this type of quantitative diagnostic assay, the "ground truth" would be established by:
- Reference materials/calibrators: Tacrolimus concentrations would be measured against highly pure, certified reference standards.
- Comparison to a legally marketed predicate device: The submitted study directly aims to show substantial equivalence to the IMx® Tacrolimus II, implying the predicate device's results serve as a comparative standard or "ground truth" for evaluating the novel assay's performance.
8. The sample size for the training set
The document does not provide details on a "training set." The development of an IVD assay typically involves internal development and validation, which might use various samples (clinical, spiked, controls) for optimization and preliminary testing. However, the term "training set" is more commonly used in machine learning and AI contexts. For an immunoassay, the samples used for validating performance are usually referred to as "validation sets" or "test sets" as outlined in question 2.
9. How the ground truth for the training set was established
As there is no explicit mention of a "training set" in the context of machine learning for this IVD device, this question is not directly applicable in the sense of establishing ground truth for AI model training. The ground truth for assay development and validation (if considered broadly analogous to "training/validation" in an AI sense) would be established as described in point 7 (reference materials/calibrators, comparison to predicate).
§ 862.1678 Tacrolimus test system.
(a)
Identification. A tacrolimus test system is a device intended to quantitatively determine tacrolimus 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 tacrolimus.(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.