(68 days)
COBAS INTEGRA Gamma- Glutamyltransferase - IFCC: contains an in vitro diagnostic reagent system intended for use on COBAS INTEGRA for the quantitative determination of the catalytic activity of GGT, (EC 2.3.2.2, y-glutamyl peptide: amino acid y-glutamyltransferase) in serum and plasma (test GGTI, 0-562).
COBAS INTEGRA Lactate Dehydrogenase - IFCC: contains an in vitro diagnostic reagent system intended for use on COBAS INTEGRA for the quantitative determination of the catalytic activity of LDH (EC 1.1.1.27; L-lactate: NAD oxidoreductase ) in serum and plasma (test LDHI, 0-181).
COBAS INTEGRA Total Protein - urine and CSF: contains an in vitro diagnostic reagent system intended for use on COBAS INTEGRA for the quantitative determination of the total protein concentration in urine and cerebrospinal fluid (tests TPU, 0-123 and TPC, 0-223).
COBAS INTEGRA Lactate: contains an in vitro diagnostic reagent system intended for use on COBAS INTEGRA for the quantitative determination of the lactate concentration in plasma and cerebrospinal fluid (tests LACT, 0-22 and LACTC, 0-122).
COBAS INTEGRA Tobramycin: contains an in vitro diagnostic reagent system intended for use on COBAS INTEGRA for the quantitative determination of tobramycin in serum or heparinized plasma (test TOBR, 0-92).
COBAS INTEGRA Immunoglobulin A: contains an in vitro diagnostic reagent system intended for use on COBAS INTEGRA for the quantitative determination of the immunological determination of human immunoglobulin A in serum. In addition to the standard application (test IGA, 0-075), the sensitive application (test IGAP, 0-175) is designed for the quantitative determination of low IgA concentrations in e.g. pediatric samples.
COBAS INTEGRA Immunoglobulin G: contains an in vitro diagnostic reagent system intended for use on COBAS INTEGRA for the quantitative determination of the immunological determination of human immunoglobulin G in serum. In addition to the standard application (test IGG, 0-076), the sensitive application (test IGGP, 0-176) is designed for the quantitative determination of low IgG concentrations in e.g. pediatric samples.
COBAS INTEGRA Immunoglobulin M: contains an in vitro diagnostic reagent system intended for use on COBAS INTEGRA for the quantitative determination of the immunological determination of human immunoglobulin M in serum. In addition to the standard application (test IGM, 0-077), the sensitive application (test IGMP, 0-177) is designed for the quantitative determination of low IgM concentrations in e.g. pediatric samples.
Through this submission it is the intention of Roche to gain clearance of an additional 5 new COBAS INTEGRA Reagent Cassettes and a modified version of 3 previously cleared reagent cassettes. All of the COBAS INTEGRA Reagent Cassettes contained in this submission are intended for use with the COBAS INTEGRA Analyzer. The Analyzer provides quantitative measurement of these analytes via three measuring principles, i.e., absorbance, fluorescence polarization and ion-selective electrodes. The COBAS INTEGRA Reagent Cassettes are compact and preparation-free. Sixty-eight COBAS INTEGRA Reagent Cassettes can be stored on board, 24 hours a day at 2-8 °C. Each cassette is barcoded. This barcode label provides the analyzer with specific reagent information such as the lot number, the expiration date and the number of tests.
Here's an analysis of the provided text regarding acceptance criteria and device performance:
Overview of the Device:
The document describes several COBAS INTEGRA Reagent Cassettes, including 5 new ones and 3 modified versions of previously cleared reagent cassettes, all intended for use with the COBAS INTEGRA Analyzer for quantitative determination of various analytes (Gamma-Glutamyltransferase, Lactate Dehydrogenase, Total Protein, Lactate, Tobramycin, Immunoglobulin A, Immunoglobulin G, Immunoglobulin M).
The claims of substantial equivalence are based on comparisons to legally marketed predicate devices. The acceptance criteria are implicit in the performance characteristics and comparisons presented against these predicate devices. The study is a non-clinical in vitro diagnostic reagent system performance evaluation.
1. Table of Acceptance Criteria and Reported Device Performance
The acceptance criteria are not explicitly stated as distinct numerical targets (e.g., "Accuracy must be > 0.95"). Instead, the document presents comparative performance data against predicate devices or generally accepted analytical performance metrics (like precision and assay range). The implicit acceptance criterion is that the new or modified COBAS INTEGRA reagents perform equivalently to or better than the identified predicate devices, or demonstrate acceptable analytical performance for their intended use.
Below is a combined table showing the reported device performance, with the implicit acceptance criteria being that these values are acceptable for the intended use and comparable to or better than the predicate devices' performance.
Note: "Acceptance Criteria" here refers to the desirable performance characteristics expected for such diagnostic assays, inferred from the general context and comparison with predicate devices. The document does not explicitly state quantitative "acceptance criteria" but rather presents the performance achieved by the device and a predicate for comparison.
| Analyte / Performance Characteristic | Acceptance Criteria (Inferred / Contextual) | COBAS INTEGRA Reagent Performance (Reported) | Predicate Device Performance (Reported) |
|---|---|---|---|
| Gamma-Glutamyltransferase - IFCC | |||
| Assay Range | Wide, clinically relevant | 0 - 1,200 U/L (0 - 12,000 U/L with post dilution) | 0 - 700 U/L (0 - 2,800 U/L with postdilution) |
| Precision (Within Run %CV) | Low %CV for reliability | Level 1: 1.0%, Level 2: 1.1% | Level 1: 0.67%, Level 2: 0.46% |
| Precision (Total %CV) | Low %CV for reliability | Level 1: 2.7%, Level 2: 2.5% | Level 1: 1.2%, Level 2: 1.4% |
| Accuracy (Correlation to Predicate) | High correlation (r > 0.95) | y = 1.27x - 0.9 U/L, r = 0.999 | y = 1.02x + 0 U/L, r = 0.998 |
| Lactate Dehydrogenase - IFCC | |||
| Assay Range | Wide, clinically relevant | 0 - 1,200 U/L (0 - 12,000 U/L with post dilution) | 0 - 1,000 U/L (0 - 10,000 U/L with postdilution) |
| Precision (Within Run %CV) | Low %CV for reliability | Level 1: 0.65%, Level 2: 0.65% | Level 1: 1.3%, Level 2: 0.99% |
| Precision (Total %CV) | Low %CV for reliability | Level 1: 2.6%, Level 2: 1.9% | Level 1: 2.8%, Level 2: 1.5% |
| Accuracy (Correlation to Predicate) | High correlation (r > 0.95) | y = 1.07x + 0.4 U/L, r = 0.999 | y = 0.95x - 14.3 U/L, r = 0.999 |
| Total Protein - Urine / CSF | |||
| Assay Range | Wide, clinically relevant | 1 - 250 mg/dL (1 - 250 mg/dL with post dilution) | 1 - 200 mg/dL |
| Precision (Urine Total %CV) | Low %CV for reliability | Level 1: 8.2%, Level 2: 2.9%, Level 3: 2.4% | Level 1: 9.37%, Level 2: 6.42%, Level 3: 2.57% |
| Precision (CSF Total %CV) | Low %CV for reliability | Level 1: 1.3%, Level 2: 0.80% | Level 1: 3.47%, Level 2: 2.65%, Level 3: 2.29% |
| Accuracy (Urine, Correlation to Predicate) | High correlation (r > 0.95) | y = 0.89x + 0 mg/L, r = 0.992 | y = 1.005x + 0.458, r = 0.997 |
| Lactate | |||
| Assay Range | Wide, clinically relevant | 0 - 180 mmol/L (0 - 1,800 mmol/L with post dilution) | Up to 100 mg/dL (Up to 199 mg/dL with postdilution) |
| Precision (Control Sera Within Run %CV) | Low %CV for reliability | Level 1: 0.92%, Level 2: 0.62% | Level 1: 2.7%, Level 2: 1.1%, Level 3: 0.7% |
| Precision (Control Sera Total %CV) | Low %CV for reliability | Level 1: 1.2%, Level 2: 1.1% | Level 1: 3.8%, Level 2: 1.3%, Level 3: 0.9% |
| Precision (CSF Within Run %CV) | Low %CV for reliability | Level 1: 0.90%, Level 2: 0.89% | Not specified |
| Accuracy (Correlation to Predicate) | High correlation (r > 0.95) | y = 1.00x - 0.1 mmol/L, r = 0.999 | y = 0.985x - 0.09, r = 0.999 |
| Tobramycin | |||
| Assay Range | Clinically relevant | 0.04 - 10 µg/mL | 0.18 - 10.0 µg/mL |
| Precision (Total %CV) | Low %CV for reliability | Level 1: 6.0%, Level 2: 4.5%, Level 3: 4.0% | Level 1: 5.18%, Level 2: 4.45%, Level 3: 4.62% |
| Accuracy (Correlation to Predicate) | High correlation (r > 0.95) | y = 0.854 + 0.015, r = 0.996 | y = 0.934 + 0.248 µg/mL, r = 0.951 |
| Sensitivity | Clinically appropriate | 0.04 µg/mL | 0.18 µg/mL |
| Immunoglobulin A (Modified) | |||
| Assay Range (Standard) | Wide, clinically relevant | 0.11 - 3.54 g/L (0.04 - 10.6 g/L with rerun) | 0.95 - 15.2 g/L (0.32 - 36.5 g/L with rerun) |
| Precision (Standard, Total %CV) | Low %CV for reliability | Level 1: 2.8%, Level 2: 1.8% | Level 1: 2.8%, Level 2: 1.8% |
| Precision (Pediatric, Total %CV) | Low %CV for reliability | Level 1: 3.0%, Level 2: 1.0% | Not applicable |
| Accuracy (Standard, Correlation to Predicate) | High correlation (r > 0.95) | y = 0.97x - 0.05 g/L, r = 0.989 | Not specified |
| Accuracy (Pediatric, Correlation to Predicate) | High correlation (r > 0.95) | y = 1.01x + 0.01 g/L, r = 0.996 | Not applicable |
| Immunoglobulin G (Modified) | |||
| Assay Range (Standard) | Wide, clinically relevant | 4.0 - 63.8 g/L (1.0 - 153 g/L with rerun) | 4.7 - 75 g/L (1.2 - 180 g/L with rerun) |
| Precision (Standard, Total %CV) | Low %CV for reliability | Level 1: 2.9%, Level 2: 1.9% | Similar to modified IgA |
| Precision (Pediatric, Total %CV) | Low %CV for reliability | Level 1: 3.0%, Level 2: 1.3% | Not applicable |
| Accuracy (Standard, Correlation to Predicate) | High correlation (r > 0.95) | y = 1.02x - 0.9 g/L, r = 0.996 | Not specified |
| Accuracy (Pediatric, Correlation to Predicate) | High correlation (r > 0.95) | y = 0.93x + 0.30 g/L, r = 0.986 | Not applicable |
| Immunoglobulin M (Modified) | |||
| Assay Range (Standard) | Wide, clinically relevant | 0.31 - 5.0 g/L (0.11 - 12.1 g/L with rerun) | 0.47 - 7.5 g/L (0.16 - 18 g/L with rerun) |
| Precision (Standard, Total %CV) | Low %CV for reliability | Level 1: 3.1%, Level 2: 2.2% | Similar to modified IgM |
| Precision (Pediatric, Total %CV) | Low %CV for reliability | Level 1: 4.9%, Level 2: 2.1% | Not applicable |
| Accuracy (Standard, Correlation to Predicate) | High correlation (r > 0.95) | y = 1.12x - 0.06 g/L, r = 0.994 | Not specified |
| Accuracy (Pediatric, Correlation to Predicate) | High correlation (r > 0.95) | y = 1.17x - 0.03 g/L, r = 0.984 | Not applicable |
2. Sample Size Used for the Test Set and Data Provenance
The sample sizes for the studies are provided in the "Accuracy" section for each analyte, indicating the number of samples ($n$) used for method correlation. The data provenance is generally implied as clinical and non-clinical studies for in vitro diagnostic assays. No specific countries of origin are mentioned, nor is it explicitly stated whether the studies were retrospective or prospective, though the nature of these tests (evaluating analytical performance) typically involves prospective or controlled laboratory studies.
- Gamma-Glutamyltransferase - IFCC: n = 202
- Lactate Dehydrogenase - IFCC: n = 106
- Total Protein - urine and CSF: n = 274 (for urine accuracy), no specific n for CSF accuracy is given separately though precision data is provided for CSF.
- Lactate: n = 224
- Tobramycin: n = 196
- Immunoglobulin A (Modified): n = 400 (standard application), n = 204 (pediatric application)
- Immunoglobulin G (Modified): n = 244 (standard application), n = 212 (pediatric application)
- Immunoglobulin M (Modified): n = 400 (standard application), n = 214 (pediatric application)
Data Provenance: "Clinical and nonclinical studies performed using the COBAS INTEGRA Reagent Cassettes." (Page 3). No further detail on country or retrospective/prospective nature.
3. Number of Experts Used to Establish the Ground Truth and Qualifications
This type of submission (510(k) for an in vitro diagnostic reagent cassette) does not typically involve human experts establishing ground truth in the way described for imaging or clinical decision support AI systems. The "ground truth" for these comparative studies is established by the predicate devices and well-established analytical methods. The performance of the new device is compared to these existing, legally marketed and validated methods. Therefore, the concept of "number of experts" and "qualifications of experts" like radiologists is not applicable here.
4. Adjudication Method for the Test Set
Since this is an in vitro diagnostic assay comparing quantitative measurements, adjudication methods like 2+1 or 3+1 (common in medical imaging for clinical endpoints) are not relevant. The "adjudication" is inherent in the analytical methods themselves, where the results from the new device are mathematically compared (e.g., using correlation coefficients and regression equations) against a reference method (the predicate device) or established laboratory standards.
5. Multi Reader Multi Case (MRMC) Comparative Effectiveness Study
No, an MRMC comparative effectiveness study was not done. This type of study is typically performed for AI-assisted diagnostic tools that involve human interpretation of medical images or other complex data where reader variability is a factor. The COBAS INTEGRA Reagent Cassettes are automated in vitro diagnostic tests, where the result is a quantitative analytical value from an instrument, not a human interpretation. Therefore, the concept of "how much human readers improve with AI vs without AI assistance" is not applicable.
6. Standalone (Algorithm Only Without Human-in-the-Loop Performance) Study
Yes, in a sense, the entire performance evaluation presented for each reagent cassette is a "standalone" study of the algorithm (i.e., the reagent's analytical method) without human intervention. The COBAS INTEGRA Analyzer is an automated system, and the reported precision and accuracy directly reflect the performance of the reagent and instrument system, which is analogous to an "algorithm only" performance. The device provides a quantitative result without a human interpreting an image or complex patterns.
7. Type of Ground Truth Used
The ground truth for these studies is established by comparison with legally marketed predicate devices using established analytical methodologies. For each assay:
- Gamma-Glutamyltransferase - IFCC: Compared against Roche COBAS INTEGRA, GGT (TRIS)
- Lactate Dehydrogenase - IFCC: Compared against Roche COBAS INTEGRA, LD (Lactate - Pyruvate)
- Total Protein - urine and CSF: Compared against SIGMA Diagnostics, Microprotein-PR
- Lactate: Compared against Boehringer Mannheim, Lactate
- Tobramycin: Compared against Abbott Diagnostics, TDX / TDX Flex Tobramycin
- Immunoglobulin A, G, M (Modified): Compared against Behring Diagnostics, N and NA Reagents (and implicitly, the previously marketed COBAS INTEGRA versions).
This approach relies on the well-established performance of predicate devices as the "ground truth" or reference standard for analytical accuracy.
8. Sample Size for the Training Set
The document does not specify a separate "training set" or "training set size." This is characteristic of traditional in vitro diagnostic device submissions, which do not typically employ machine learning or AI models that require distinct training and test data sets. The studies described are performance validation studies for the finished reagent product.
9. How the Ground Truth for the Training Set Was Established
As there is no explicitly mentioned "training set" in the context of machine learning, this question is not directly applicable. The performance characteristics of these reagents are validated using standard analytical chemistry and immunoassay principles, with reference to the performance of predicate devices established through similar rigorous analytical validation.
§ 862.1360 Gamma-glutamyl transpeptidase and isoenzymes test system.
(a)
Identification. A gamma-glutamyl transpeptidase and isoenzymes test system is a device intended to measure the activity of the enzyme gamma-glutamyl transpeptidase (GGTP) in plasma and serum. Gamma-glutamyl transpeptidase and isoenzymes measurements are used in the diagnosis and treatment of liver diseases such as alcoholic cirrhosis and primary and secondary liver tumors.(b)
Classification. Class I (general controls). The device is exempt from the premarket notification procedures in subpart E of part 807 of this chapter subject to § 862.9.