(203 days)
Tina-quant® C-Reactive Protein IV is an immunoturbidimetric assay for the in vitro quantitative determination of CRP in human serum and plasma on cobas c systems.
A C-reactive protein immunological test system is a device that consists of the reagents used to measure by immunochemical techniques the C-reactive protein in serum and plasma. Measurement of C-reactive protein aids in evaluation of the amount of injury to body tissues.
The Tina-quant® C-Reactive Protein IV reagent will be a liquid ready to use 2 component particle enhanced immunoturbidimetric assay.
Reagents - working solutions
R1: TRIS* buffer with bovine serum albumin; preservatives
R2 Latex particles coated with anti-CRP (mouse) in glycine buffer; immunoglobulins (mouse); preservative
- TRIS= Tris(hydroxymethyl)-aminomethane
The Tina-quant® C-Reactive Protein IV assay will be based on the DUREL technology (dual radius enhanced latex - technology) which is also used in C-Reactive Protein Gen.3 predicate method. Human CRP agglutinates with latex particles coated with monoclonal anti-CRP antibodies. The aggregates are determined turbidimetrically.
The document describes the non-clinical performance evaluation of the Tina-quant® C-Reactive Protein IV device. Here's a summary of the acceptance criteria and the study that proves the device meets them:
1. A table of acceptance criteria and the reported device performance
| Performance Characteristic | Acceptance Criteria or Expected Outcome (or Predicate Performance) | Reported Device Performance (Tina-quant® C-Reactive Protein IV) |
|---|---|---|
| Precision | Repeatability (CV%) | Repeatability (CV%) |
| Precinorm Protein | Predicate: 1.2% | 1.3% |
| Precipath Protein | Predicate: 1.3% | 1.6% |
| Human Serum Samples | Predicate: 3.6%, 1.6%, 1.2% (for different samples) | 1.5% (Serum 2), 1.6% (Serum 3), 2.2% (Serum 4), 2.0% (Serum 5), 1.3% (Serum 6) |
| Intermediate Precision (CV%) | Intermediate Precision (CV%) | Intermediate Precision (CV%) |
| Precinorm Protein | Predicate: 2.9% | 1.5% |
| Precipath Protein | Predicate: 1.9% | 1.9% |
| Human Serum Samples | Predicate: 11.1%, 3.9%, 1.7% (for different samples) | 1.6% (Serum 2), 1.9% (Serum 3), 2.4% (Serum 4), 2.4% (Serum 5), 1.8% (Serum 6) |
| Analytical Sensitivity | ||
| Limit of Blank (LoB) | Claimed LoB: 0.2 mg/L | Observed LoB: 0.0700 mg/L (Meets criterion: Observed is less than claimed) |
| Limit of Detection (LoD) | Claimed LoD: 0.3 mg/L | Observed LoD: 0.137 mg/L (Meets criterion: Observed is less than claimed) |
| Limit of Quantitation (LoQ) | Claimed LoQ: 3 mg/L (Predicate was 0.6 mg/L, but 3 mg/L is claimed for the candidate device. The study shows the device is capable of quantifying lower.) | Observed LoQ: 0.313 mg/L (Exceeds criterion as it is much lower than the claimed 3 mg/L, indicating better performance. The claimed measuring range for Tina-quant® C-Reactive Protein IV starts at 3 mg/L, so the LoQ of 0.313 mg/L is well below the lowest reportable value, which is acceptable.) |
| Linearity/Assay Reportable Range | Consistent with predicate, good correlation (R > 0.999), and linearity across the intended measuring range. | Linear Regression: y=1.002x-0.0169; Pearson correlation coefficient (R)=0.9994. Claimed Measuring Range: 3 to 350 mg/L. (Meets criterion) |
| Endogenous Interference | No interference up to specified levels for lipemia, hemolysis, bilirubin, ditauro bilirubin, albumin, IgG, and RF Factor. | No interference up to: Lipemia: 1000 L Index; Hemolysis: 1000 H Index; Bilirubin: 60 I Index; Ditauro Bilirubin: 60 I Index; Albumin: 60 g/L; IgG: 50 g/L; RF Factor: 1200 IU/mL. (Meets criterion) |
| Exogenous Interference (Drugs) | No interference up to specified drug concentrations. | No interference up to: N-Acetylcysteine: 1660 mg/L; Ampicillin-Na: 1000 mg/L; Ascorbic acid: 300 mg/L; Cefoxitin: 6600 mg/L; Heparin: 5000 IU/L; Levodopa: 20 mg/L; Methyldopa: 22.5 mg/L; Metronidazole: 200 mg/L; Doxycyclin: 50 mg/L; Acetylsalicylic acid: 1000 mg/L; Rifampicin: 60 mg/L; Ticarcillin: 225 mg/L; Penicillamin: 24 mg/L; Phenylbutazone: 400 mg/L; Cyclosporine: 5 mg/L; Acetaminophen: 200 mg/L; Ibuprofen: 500 mg/L; Theophylline: 100 mg/L. (Meets criterion) |
| Sample Matrix Comparison | Good agreement between serum and plasma types (Li-Heparin, K2-EDTA, K3-EDTA) with correlation (r) close to 1 and slope near 1, intercept near 0. | Linear Regression: Serum vs. Li-Heparin: y = 1.029x - 0.192, r = 0.999; Serum vs. K2-EDTA: y = 1.024x - 0.201, r = 0.999; Serum vs. K3-EDTA: y = 1.024x - 0.258, r = 0.999. (Meets criterion) |
| Method Comparison to Predicate | Strong correlation with the predicate device (R > 0.999) and slope near 1, intercept near 0. | Passing/Bablok Regression: Slope = 0.985, Intercept = +0.278, Correlation (Pearson) = 0.999. Weighted Deming Regression: Slope = 0.979, Intercept = +0.296, Correlation = 0.999. (Meets criterion for substantial equivalence) |
| Stability | Meet Roche Diagnostic's claims on package labeling. | Data supports Roche Diagnostic's claims. (Meets criterion) |
Study Details:
The performance studies were designed in accordance with CLSI guidelines (EP5-A3, EP17-A2, EP6-A) and FDA guidance for CRP assays.
2. Sample sized used for the test set and the data provenance:
- Precision (Repeatability & Intermediate Precision):
- Controls: Precinorm Protein and Precipath Protein.
- Human Serum Samples: 4 human serum samples were used to evaluate repeatability and intermediate precision, plus 6 human serum samples for the specific results documented in the table. Each sample/control was analyzed with multiple aliquots (e.g., 2 aliquots for 21 days for precision).
- Data Provenance: Not explicitly stated (e.g., country of origin), but it's noted as "human serum samples." The studies are prospective for the device evaluation.
- Analytical Sensitivity (LoB, LoD, LoQ):
- LoB: Ten aliquots of analyte-free saline (N=60 determinations per lot).
- LoD: Five samples of low analyte level human serum (N=60 determinations per lot).
- LoQ: Nine low concentration human serum samples (N=25 determinations per sample per lot).
- Data Provenance: Not explicitly stated for specific origin, but uses "analyte free saline" and "human serum."
- Linearity/Assay Reportable Range:
- Samples: Dilution series prepared from native unmodified human serum sample pools, resulting in 15 levels. Each level measured in triplicate (n ≥ 3).
- Data Provenance: "native unmodified human serum sample pools."
- Endogenous Interference:
- Samples: Effects determined at 2 CRP levels (5-10 mg/L and 35-100 mg/L) utilizing 11-level serial dilution sets of interfering substances. Each level measured in triplicate.
- Data Provenance: Not explicitly stated, likely lab-prepared samples with added interferents.
- Exogenous Interference (Drugs):
- Samples: Effects determined at 2 CRP levels (5-10 mg/L and 35-100 mg/L) using pooled samples spiked with drugs. N=5 results per drug.
- Data Provenance: Lab-prepared samples with added drugs.
- Sample Matrix Comparison:
- Samples: Native samples from single donors drawn into serum, Li-Heparin, K2-EDTA, and K3-EDTA plasma primary tubes.
- Range Tested: 3.34 to 344 mg/L.
- Data Provenance: "native samples (single donors)."
- Method Comparison to Predicate:
- Samples: One hundred ten (N=110) native, unaltered serum samples.
- Data Provenance: "native, unaltered serum samples."
3. Number of experts used to establish the ground truth for the test set and the qualifications of those experts (e.g., radiologist with 10 years of experience)
This device is an in-vitro diagnostic (IVD) assay for quantitative determination of C-Reactive Protein (CRP). The "ground truth" for such devices is established by reference methods, certified reference materials, and accepted analytical techniques, not by expert interpretation in the same way imaging studies might use radiologists. The measurements for the test set samples (e.g., CRP concentrations) are determined by the analytical methods themselves, often verified against established standards or predicate devices. There is no mention of human experts establishing ground truth for the test set in the context of interpretation.
4. Adjudication method (e.g., 2+1, 3+1, none) for the test set
For IVD assays, ground truth is typically analytical, not based on expert adjudication of observations. The "truth" is the measured concentration, often confirmed by multiple replicates or comparative methods, as opposed to a consensus reading process found in clinical imaging studies. Therefore, no adjudication method (like 2+1 or 3+1) is applicable or described here.
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
No, an MRMC comparative effectiveness study was not performed. This device is an in-vitro diagnostic instrument for measuring a biomarker (CRP). It does not involve human readers interpreting images or results that would be "assisted" by AI. The device directly produces quantitative results.
6. If a standalone (i.e., algorithm only without human-in-the-loop performance) was done
Yes, the performance studies described are for the device (Tina-quant® C-Reactive Protein IV on a cobas c 501 analyzer) operating in a standalone capacity. It measures CRP in samples without human intervention in the interpretive output. The studies evaluate the analytical performance of the instrument and reagents themselves.
7. The type of ground truth used (expert consensus, pathology, outcomes data, etc.)
The ground truth for this IVD device is based on:
- Analytical Standards: For LoB, LoD, LoQ, and Linearity, ground truth is established through statistical derivation from measurements of samples with known low or varying concentrations, or through the use of analyte-free samples or reference materials.
- Predicate Device Comparison: The "Method Comparison to Predicate" establishes the ground truth by comparing the device's results against a legally marketed and established predicate device (Roche Diagnostics C-Reactive Protein Gen.3), assuming the predicate provides the accepted reference values.
- Spiked Samples/Known Concentrations: For interference studies (endogenous and exogenous), ground truth is established by adding known amounts of interfering substances or drugs to samples with known CRP concentrations and observing the recovery of the expected CRP value.
- Certified Reference Materials (CRM): The "Traceability/Standardization" indicates that the candidate device is standardized against the certified reference material of IRMM (Institute for Reference Materials and Measurements) ERM-DA474/IFCC. This is a primary source of analytical ground truth.
8. The sample size for the training set
This document describes a premarket notification (510(k)) submission for a medical device. The "training set" concept is typically associated with machine learning or AI models. This device is an immunoturbidimetric assay, which is a traditional analytical chemistry method, not an AI/ML system. Therefore, there is no "training set" in the context of machine learning. The studies described are performance evaluations to demonstrate that the device meets its analytical specifications.
9. How the ground truth for the training set was established
As there is no "training set" for an AI/ML model for this traditional IVD assay, this question is not applicable. The device's performance is validated against analytical performance criteria as described above in point 7.
§ 866.5270 C-reactive protein immunological test system.
(a)
Identification. A C-reactive protein immunological test system is a device that consists of the reagents used to measure by immunochemical techniques the C-reactive protein in serum and other body fluids. Measurement of C-reactive protein aids in evaluation of the amount of injury to body tissues.(b)
Classification. Class II (performance standards).