(158 days)
Rx ONLY
For in vitro diagnostic use only.
For the quantitative measurement of CK-MB in human serum and plasma (EDTA or heparin) using the VITROS 3600 Immunodiagnostic System.
Measurements of creatine phosphokinase and its isoenzymes are used in the diagnosis and treatment of myocardial infarction and muscle diseases such as progressive, Duchenne-type muscular dystrophy.
The VITROS Immunodiagnostic Products CK-MB assay is performed using the VITROS CK-MB Reagent Pack and the VITROS CK-MB Calibrators on the VITROS Systems.
The current VITROS Immunodiagnostic Products CK-MB assay is susceptible to interference from biotin. Ortho has made a modification to the manufacturing process to allow the biotinylated antibody capture conjugate to be pre-bound to the well, thus mitigating the risk of biotin interference.
The modified product utilizes all the same antibodies and raw materials with the exception of the addition of 0.7% Tween 20 and an increase in EDTA concentration from 0.001M to 0.030M, both of these modifications are to improve serum/plasma agreement which required a conversion factor in the previously cleared product.
An immunometric immunoassay technique is used, which involves the reaction of CK-MB present in the sample with a microwell coated with biotinylated Antibody (Mouse monoclonal anti-CK-BB bound to Streptavidin), and a Horseradish Peroxidase (HRP)-labeled antibody conjugate (Mouse monoclonal anti-CK-MB). Unbound (HRP)-labeled anti-CK-MB antibody conjugate is removed by washing.
The bound HRP conjugate is measured by a luminescent reaction. A reagent containing luminogenic substrates (a luminol derivative and a peracid salt) and an electron transfer agent, is added to the wells. The HRP in the bound conjugate catalyzes the oxidation of the luminol derivative, producing light. The electron transfer agent (a substituted acetanilide) increases the level of light produced and prolongs its emission. The light signals are read by the system. The amount of CK-MB conjugate bound is directly proportional to the concentration of CK-MB present in the sample.
The provided document describes the 510(k) premarket notification for the VITROS Immunodiagnostic Products CK-MB Reagent Pack. This is an in vitro diagnostic device, not an AI/ML-based medical device. Therefore, many of the requested criteria related to AI/ML device testing (e.g., number of experts for ground truth, adjudication methods, MRMC studies, sample sizes for training sets) are not applicable to this document.
The document focuses on demonstrating the substantial equivalence of a modified CK-MB assay to a legally marketed predicate device, primarily through non-clinical performance studies.
Here's an analysis based on the provided text, addressing the applicable criteria for an in vitro diagnostic device:
1. Table of Acceptance Criteria and Reported Device Performance
For an in vitro diagnostic device like this, acceptance criteria typically revolve around analytical performance characteristics such as precision, linearity, detection limits, and method comparison to a predicate. The document doesn't explicitly state "acceptance criteria" as a pass/fail threshold, but rather presents the results of various validation studies.
| Performance Characteristic | Acceptance Criteria (Implied/Standard) | Reported Device Performance (VITROS CK-MB Reagent Pack) |
|---|---|---|
| Precision | Repeatability & Within-Lab CV% within acceptable ranges for diagnostic assays. | Repeatability: |
| 1.8 ng/mL: 2.7% CV | ||
| 16.90 ng/mL: 2.4% CV | ||
| 46.3 ng/mL: 1.7% CV | ||
| 256 ng/mL: 1.7% CV | ||
| Within Lab: | ||
| 1.8 ng/mL: 7.1% CV | ||
| 16.90 ng/mL: 5.0% CV | ||
| 46.3 ng/mL: 5.5% CV | ||
| 256 ng/mL: 5.0% CV | ||
| Limit of Detection (LoD) | LoD clinically sensitive enough for intended use. | LoD: 0.22 ng/mL (µg/L) |
| Limit of Quantitation (LoQ) | LoQ clinically relevant for intended use. | LoQ: 0.22 ng/mL (µg/L) |
| Limit of Blank (LoB) | LoB sufficiently low to detect absent analyte. | LoB: 0.07 ng/mL (µg/L) |
| Linearity/Measuring Range | Range should cover clinically relevant concentrations. | Measuring Range: 0.22–400 ng/mL (µg/L) |
| Analytical Specificity (Interferences) | Bias from common interferents should be minimal (10% bias noted:** |
- Cefoxitin (at 521 mg/dL): -27.7% bias at 3.00 ng/mL CK-MB
- Dextran 40 (at 2400 mg/dL): -15.0% bias at 3.00 ng/mL CK-MB; -44.9% bias at 50.0 ng/mL CK-MB |
| Cross-Reactivity | Minimal or no cross-reactivity with structurally similar substances. | CK-BB (50 µg/dL): Not Detectable
CK-MM (4 mg/dL): Not Detectable |
| Method Comparison to Predicate Device (Accuracy) | Strong correlation and minimal bias compared to the predicate device, with slope close to 1 and intercept close to 0. | System (3600 vs. Comparative Method): - n: 149 patient samples
- Slope: 0.99 (95% CI: 0.9812 to 0.9950)
- Correlation Coefficient: 0.999
- Intercept: 0.112 ng/mL (95% CI: 0.05080 to 0.1723) |
| High Dose Hook Effect | No significant hook effect within relevant supraphysiological concentrations. | No high dose hook effect up to 44,200 ng/mL (µg/L). |
2. Sample Sizes Used for the Test Set and Data Provenance
- Precision:
- Sample Size: 80 observations (likely meaning replicates across runs and days, as per CLSI EP05 methodology) for each of 4 patient pools.
- Data Provenance: Not explicitly stated, but typically from internal lab testing.
- Limit of Detection/Quantitation: Not explicitly stated, but derived from experiments consistent with CLSI document EP17.
- Analytical Specificity (Interference) & Cross-Reactivity: Not explicitly stated, but involves testing at specific concentrations of CK-MB and interferents.
- Method Comparison to Predicate Device:
- Sample Size: 149 patient (serum) samples.
- Data Provenance: Not explicitly stated regarding country of origin, but described as "patient (serum) samples," implying collected clinical samples. The study is an analytical/non-clinical study, not a clinical trial, so it's prospective in the sense of testing the new device on these samples.
3. Number of Experts Used to Establish Ground Truth for the Test Set and Qualifications of Those Experts
- Not Applicable. This is an in vitro diagnostic device measuring a biomarker concentration. The "ground truth" for method comparison is the measurement obtained by the predicate device and the analytical properties of the reference materials. Expertise is in laboratory medicine and analytical chemistry, not interpretation of images for diagnosis by human experts.
4. Adjudication Method for the Test Set
- Not Applicable. As above, no human expert adjudication is involved in establishing the "ground truth" for quantitative assay validation.
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
- Not Applicable. This is not an AI/ML device, nor does it involve human readers interpreting images.
6. If a Standalone (i.e. algorithm only without human-in-the-loop performance) was done
- Not Applicable. While the device operates standalone (human performs the test, the system provides a result), the concept of an "algorithm only" performance study typically refers to AI/ML models. For an IVD, the "standalone performance" is exactly what is described in the precision, linearity, and detection limit sections.
7. The Type of Ground Truth Used
- For precision, linearity, and detection limits: Analyte concentrations of reference materials or patient pools. The "truth" is established by highly controlled laboratory methods.
- For method comparison: Results obtained from the legally marketed predicate device (VITROS Immunodiagnostic CK-MB Reagent Pack, K993068). The predicate serves as the "true" or gold standard against which the modified device is compared. This is a common "ground truth" for demonstrating substantial equivalence for IVDs. While not explicitly stated, these predicate measurements would have been established through a similar robust validation process.
8. The Sample Size for the Training Set
- Not Applicable. This is not an AI/ML device, so there is no "training set" in the sense of machine learning. The device's performance characteristics are inherent to its chemical and biological components and manufacturing process, validated through the non-clinical studies detailed.
9. How the Ground Truth for the Training Set Was Established
- Not Applicable. As there is no training set for an AI/ML model, this question is not relevant. The device development involved standard IVD R&D and manufacturing, not machine learning training.
§ 862.1215 Creatine phosphokinase/creatine kinase or isoenzymes test system.
(a)
Identification. A creatine phosphokinase/creatine kinase or isoenzymes test system is a device intended to measure the activity of the enzyme creatine phosphokinase or its isoenzymes (a group of enzymes with similar biological activity) in plasma and serum. Measurements of creatine phosphokinase and its isoenzymes are used in the diagnosis and treatment of myocardial infarction and muscle diseases such as progressive, Duchenne-type muscular dystrophy.(b)
Classification. Class II.