(86 days)
Creatine Kinase is an in vitro test for the quantitative determination of creatine kinase (CK) in human serum and plasma on Roche/Hitachi cobas c systems. The determination of CK and CK isoenzyme activities is utilized in the diagnosis and monitoring of myocardial infarction and myopathies such as the progressive Duchenne muscular dystrophy.
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 Creatine Kinase assay is a two reagent assay for the quantitative determination of creatine kinase (CK) in human serum and plasma on automated clinical chemistry analyzers. Photometrically measured NAPDP formation is directly proportional to CK activity in a human sample.
Here's a breakdown of the acceptance criteria and study information based on the provided document:
Creatine Kinase Device Performance Study Summary
1. Acceptance Criteria and Reported Device Performance
| Feature / Metric | Acceptance Criteria (Claim in Document) | Reported Device Performance |
|---|---|---|
| Limit of Blank (LoB) | Claim: 7 U/L | 0.3 U/L |
| Limit of Detection (LoD) | Claim: 7 U/L | 1.0 U/L |
| Limit of Quantitation (LoQ) | Claim: 7 U/L | 3.3 U/L |
| Precision (Repeatability) | Achieved with Human Serum samples and PreciControl ClinChem Multi controls. Specific acceptance limits for CV/SD are not explicitly stated as "acceptance criteria" but implied by the presentation of successful results. For example: Human Serum 1 (18.7 U/L) CV = 0.998) and slope close to 1, intercept close to 0 implied for substantial equivalence. | Serum vs. Serum Gel Separation: y = 0.998x + 0.010, r = 0.999 |
| Serum vs. Li-heparin: y = 1.00x - 1.994, r = 0.998 | ||
| Serum vs. K2-EDTA: y = 0.993x - 2.016, r = 0.998 | ||
| Serum vs. K3-EDTA: y = 0.981x - 2.671, r = 0.999 | ||
| Interference (Hemolysis) | No significant interference up to an H index of 100 (approx. 62.1 µmol/L or 100 mg/dL). | No interference up to Level 1: 103 H Index, Level 2: 130 H Index. |
| Interference (Lipemia) | No significant interference up to an L index of 1000. | No interference up to Level 1: 1356 L Index, Level 2: 1143 L Index. |
| Interference (Unconjugated Bilirubin) | No significant interference up to an I index of 60 for conjugated and unconjugated bilirubin (approx. 1026 µmol/L or 60 mg/dL). | No interference up to Level 1: 67 I Index, Level 2: 67 I Index. |
| Interference (Conjugated Bilirubin) | No significant interference up to an I index of 60 for conjugated and unconjugated bilirubin (approx. 1026 µmol/L or 60 mg/dL). | No interference up to Level 1: 68 I Index, Level 2: 76 I Index. |
| Interference (Drugs) | No interference at therapeutic concentrations using common drug panels. (Exception noted for Cyanokit). | No interference found at therapeutic concentrations using common drug panels. (Cyanokit (Hydroxocobalamin) at therapeutic concentrations interferes with the test). |
| Method Comparison (Predicate) | The objective is for results to demonstrate substantial equivalence to the predicate device (COBAS INTEGRA Creatine Kinase, K951595) via Passing Bablok Regression where the slope is close to 1 and the intercept close to 0, and a high correlation coefficient (r). | y = 1.021x + 5.88 U/L, r = 0.999 |
2. Sample Sizes Used for the Test Set and Data Provenance
- Detection Limits (LoB, LoD):
- LoB: One analyte-free sample, measured with three lots, 10-fold determination in 6 runs (total 60 measurements per lot).
- LoD: Five low-analyte concentration samples, measured with three lots, two-fold determination in 6 runs (total 60 measurements per lot).
- Limit of Quantitation (LoQ):
- Five human serum samples, tested in 5 replicates per sample on 5 days.
- Precision (Repeatability & Intermediate):
- Not explicitly stated as a single number, but experiments conducted with multiple human serum samples (5) and control materials (2), with two aliquots per run, two runs per day for ≥ 21 days on the same analyzer using 3 lots of reagent.
- Linearity (Serum & Plasma):
- Two separate dilution series (serum and plasma), each with 14 concentrations, measured in triplicate.
- Matrix Comparison - Anticoagulants:
- For each of the four tube types (Serum Gel Separation, Li-heparin, K2-EDTA, K3-EDTA), 30 tubes were filled completely. This implies 30 samples for each comparison.
- Interferences - H, L, I Indices:
- Pooled human serum samples spiked with varying levels of interferent. The resulting sample series (10 dilution steps per sample) were tested in triplicate.
- Interferences - Drugs:
- Two sample pools (low and high CK concentrations), divided into aliquots. Each spiked aliquot measured in triplicate.
- Method Comparison to Predicate:
- 132 human serum samples (9 of which were spiked with human recombinant CK MB). Samples tested in singlicate.
Data Provenance: The document explicitly mentions "human serum samples" and "pooled human serum samples." The manufacturer is Roche Diagnostics Operations, located in Indianapolis, IN, USA. Based on the context of FDA submission for a device to be marketed in the USA, it is highly probable the data is retrospective and likely collected in a clinical laboratory setting (possibly in the USA or aligned with international standards like CLSI), but the specific country of origin for the patient samples is not stated.
3. Number of Experts Used to Establish the Ground Truth for the Test Set and Qualifications
N/A. This is a submission for an in vitro diagnostic device that quantitatively measures a biomarker (Creatine Kinase). The "ground truth" for the test set is established by the reference measurement procedure or the known concentration of the analyte in calibrators/controls, not by expert interpretation of images or clinical data. Therefore, human experts for ground truth adjudication are not applicable in this context.
4. Adjudication Method for the Test Set
N/A. See explanation above. The measurements are quantitative chemical analyses against instrument-derived values and established reference methods/materials, not subjective interpretations.
5. Multi-Reader Multi-Case (MRMC) Comparative Effectiveness Study
No. This is an in vitro diagnostic device for quantitative measurement of a biomarker in biological samples. MRMC studies are typically performed for imaging devices or other diagnostic tools where human interpretation plays a significant role, to evaluate how AI assistance impacts human reader performance. This is not applicable here.
6. Standalone (Algorithm Only) Performance Study
Yes, the entire submission is a standalone performance study of the Creatine Kinase assay on the Roche/Hitachi cobas c systems. The device itself is an "algorithm only" in the sense that it is an automated analytical system (reagent + instrument) that produces quantitative results without human intervention in the measurement process itself, beyond sample loading and system maintenance. The studies described (Detection Limits, Precision, Linearity, Interference, Method Comparison) directly assess the performance of this standalone analytical system.
7. Type of Ground Truth Used
The ground truth for the performance studies relies on:
- Reference Materials/Methods: For calibration and verification of accuracy, the method is stated to be traceable to IFCC (International Federation of Clinical Chemistry and Laboratory Medicine) Method for Creatine Kinase.
- Known Concentrations: For studies like LoB, LoD, LoQ, linearity, and interference, samples are either analyte-free, spiked with known concentrations of analyte or interferents, or diluted from samples with established reference values. This essentially uses calibrated reference standards and materials as the ground truth.
- Predicate Device Measurements: For method comparison, the predicate device's results (COBAS INTEGRA Creatine Kinase cleared in K951595 on the COBAS INTEGRA analyzer) serve as a comparative ground truth to establish substantial equivalence.
8. Sample Size for the Training Set
N/A. This is not a machine learning or AI-based diagnostic device in the modern sense that requires a "training set" of data to learn from. It is a traditional in vitro diagnostic assay based on a defined enzymatic chemical reaction and photometric measurement. The development of such assays involves extensive research and development to optimize reagents and instrument parameters, but not in the framework of a "training set" as understood in AI/ML.
9. How the Ground Truth for the Training Set Was Established
N/A. As explained above, there is no "training set" in the context of an AI/ML device for this product. The development of the assay involves chemical and enzymatic principles, optimized through laboratory experimentation and knowledge of biochemistry, rather than learning from a dataset via a specified ground truth.
§ 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.