(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.
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February 21, 2020
Roche Diagnostics Operations (RDO) Barbara McWhorter Regulatory Affairs Program Manager 9115 Hague Road Indianapolis, Indiana 46250
Re: K192072
Trade/Device Name: Tina-quant C-Reactive Protein IV Regulation Number: 21 CFR 866.5270 Regulation Name: C-reactive protein immunological test system Regulatory Class: Class II Product Code: DCN Dated: August 20, 2019 Received: August 22, 2019
Dear Barbara McWhorter:
We have reviewed your Section 510(k) premarket notification of intent to market the device referenced above and have determined the device is substantially equivalent (for the indications for use stated in the enclosure) to legally marketed predicate devices marketed in interstate commerce prior to May 28, 1976, the enactment date of the Medical Device Amendments, or to devices that have been reclassified in accordance with the provisions of the Federal Food, Drug, and Cosmetic Act (Act) that do not require approval of a premarket approval application (PMA). You may, therefore, market the device, subject to the general controls provisions of the Act. Although this letter refers to your product as a device, please be aware that some cleared products may instead be combination products. The 510(k) Premarket Notification Database located at https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfpmn/pmn.cfm identifies combination product submissions. The general controls provisions of the Act include requirements for annual registration, listing of devices, good manufacturing practice, labeling, and prohibitions against misbranding and adulteration. Please note: CDRH does not evaluate information related to contract liability warranties. We remind you, however, that device labeling must be truthful and not misleading.
If your device is classified (see above) into either class II (Special Controls) or class III (PMA), it may be subject to additional controls. Existing major regulations affecting your device can be found in the Code of Federal Regulations, Title 21, Parts 800 to 898. In addition, FDA may publish further announcements concerning your device in the Federal Register.
Please be advised that FDA's issuance of a substantial equivalence determination does not mean that FDA has made a determination that your device complies with other requirements of the Act or any Federal statutes and regulations administered by other Federal agencies. You must comply with all the Act's requirements, including, but not limited to: registration and listing (21 CFR Part 807); labeling (21 CFR Part
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801 and Part 809); medical device reporting of medical device-related adverse events) (21 CFR 803) for devices or postmarketing safety reporting (21 CFR 4, Subpart B) for combination products (see https://www.fda.gov/combination-products/guidance-regulatory-information/postmarketing-safety-reportingcombination-products); good manufacturing practice requirements as set forth in the quality systems (QS) regulation (21 CFR Part 820) for devices or current good manufacturing practices (21 CFR 4. Subpart A) for combination products; and, if applicable, the electronic product radiation control provisions (Sections 531-542 of the Act); 21 CFR 1000-1050.
Also, please note the regulation entitled, "Misbranding by reference to premarket notification" (21 CFR Part 807.97). For questions regarding the reporting of adverse events under the MDR regulation (21 CFR Part 803), please go to https://www.fda.gov/medical-device-safety/medical-device-reportingmdr-how-report-medical-device-problems.
For comprehensive regulatory information about medical devices and radiation-emitting products, including information about labeling regulations, please see Device Advice (https://www.fda.gov/medicaldevices/device-advice-comprehensive-regulatory-assistance) and CDRH Learn (https://www.fda.gov/training-and-continuing-education/cdrh-learn). Additionally, you may contact the Division of Industry and Consumer Education (DICE) to ask a question about a specific regulatory topic. See the DICE website (https://www.fda.gov/medical-device-advice-comprehensive-regulatoryassistance/contact-us-division-industry-and-consumer-education-dice) for more information or contact DICE by email (DICE@fda.hhs.gov) or phone (1-800-638-2041 or 301-796-7100).
Sincerely,
Carolina Kagan Acting Chief, IMFB Division of Immunology and Hematology Devices OHT7: Office of In Vitro Diagnostics and Radiological Health Office of Product Evaluation and Quality Center for Devices and Radiological Health
Enclosure
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Indications for Use
510(k) Number (if known) K192072
Device Name Tina-quant® C-Reactive Protein IV
Indications for Use (Describe)
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.
| Type of Use (Select one or both, as applicable) | |
|---|---|
| Prescription Use (Part 21 CFR 801 Subpart D) | Over-The-Counter Use (21 CFR 801 Subpart C) |
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Tina-quant® C-Reactive Protein IV 510(k) Summary
This summary of 510(k) safety and effectiveness information is being submitted in accordance with the requirements of 21 CFR 807.92.
In accordance with 21 CFR 807.87, Roche Diagnostics hereby submits official notification as required by Section 510(k) of the Federal Food, Drug and Cosmetics Act of our intention to market the device described in this Premarket Notification 510(k).
The purpose of this Traditional 510(k) Premarket Notification is to obtain FDA review and clearance for the Tina-quant® C-Reactive Protein IV.
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| Submitter Name | Roche Diagnostics |
|---|---|
| Address | 9115 Hague RoadP.O. Box 50416Indianapolis, IN 46250-0457 |
| Contact | Barbara Ann McWhorterPhone: (317) 521-2336FAX: (317) 521-2324Email: barbara.mcwhorter@roche.com |
| Date Prepared | January 10, 2020 |
| Proprietary Name | Tina-quant® C-Reactive Protein IV |
| Common Name | C-Reactive Protein |
| Classification Name | C-reactive protein immunological test system |
| Product Codes,Regulation Numbers | DCN, 21 CFR § 866.5270 |
| Predicate Devices | Roche Diagnostics C-Reactive Protein Gen.3 |
| Establishment Registration | Roche Diagnostics GmbH Mannheim, Germany: 9610126Roche Diagnostics GmbH in Penzberg, Germany: 9610529Roche Diagnostics Indianapolis IN, United States: 1823260 |
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1. DEVICE DESCRIPTION
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.
2. INDICATIONS FOR USE
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.
3. TECHNOLOGICAL CHARACTERISTICS
| Table 1: Tina-quant® C-Reactive Protein IV Technical Characteristics | ||||
|---|---|---|---|---|
| -- | -- | --------------------------------------------------------------------------- | -- | -- |
| Feature | Predicate C-Reactive ProteinGen.3K083444 | Candidate DeviceTina-quant® C-Reactive ProteinIV K192072 |
|---|---|---|
| Intended Use | Immunoturbidometric assay for the invitro quantitative determination of CRPin human serum and plasma on Rocheautomated clinical chemistry analyzers. | Tina-quant® C-Reactive Protein IV is animmunoturbidimetric assay for the in vitroquantitative determination of CRP inhuman serum and plasma on cobas csystems. |
| Feature | Predicate C-Reactive ProteinGen.3K083444 | Candidate DeviceTina-quant® C-Reactive ProteinIV K192072 |
| Indications for Use | Measurement of C-reactive protein aidsin evaluation of the amount of injury tobody tissues. | A C-reactive protein immunological testsystem is a device that consists of thereagents used to measure byimmunochemical techniques the C-reactive protein in serum and plasma.Measurement of C-reactive protein aids inevaluation of the amount of injury to bodytissues. |
| Assay Method | Particle enhanced immunoturbidimetricassay | Same |
| Detection Method | turbidimetric | Same |
| Instrument Platform | Roche automated clinical chemistryanalyzers | cobas c 501 analyzer |
| Sample Type/Matrix | SerumPlasma: K2- or K3-EDTA, lithiumheparin | Same |
| Calibrator | Calibrator f.a.s. Proteins | Same |
| Calibration Method | 6-point spline | Same |
| Calibration Interval | After reagent lot changeAs required following quality controlprocedures | - after reagent lot change- after 3 weeks on-board the analyzer- after 6 months when using a singlereagent lot- as required following quality controlprocedures |
| Controls | Precinorm ProteinPrecipath ProteinPreciControl ClinChem Multi 1PreciControl ClinChem Multi 2 | Precinorm ProteinPrecipath ProteinPreciControl ClinChem Multi 1PreciControl ClinChem Multi 2 |
| Traceability/Standardization | Standardized against an internal methodtraceable to CRM 470 (RPPHS -Reference Preparation for Proteins inHuman Serum). | Standardized against the certifiedreference material in human serum of theIRMM (Institute for Reference Materialsand Measurements) ERM-DA474/IFCC. |
| Reagent Stability | Shelf life at 2-8 °C: See expiration dateon cobas c pack label.On-board in use and refrigerated on theanalyzer: 12 weeks | Same |
| Measuring Range | 0.3 to 350 mg/L | 3 to 350 mg/L |
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| Feature | Predicate C-Reactive ProteinGen.3K083444 | Candidate DeviceTina-quant® C-Reactive ProteinIV K192072 | ||||||
|---|---|---|---|---|---|---|---|---|
| Repeatability | Repeatability | |||||||
| Mean(mg/L) | SD(mg/L) | CV% | Mean(mg/L) | SD(mg/L) | CV% | |||
| CRP TControl N | 3.35 | 0.04 | 1.2 | PrecinormProtein | 9.69 | 0.128 | 1.3 | |
| PrecipathProtein | 44.4 | 0.6 | 1.3 | PrecipathProtein | 55.2 | 0.859 | 1.6 | |
| HumanSerum 1 | 0.57 | 0.02 | 3.6 | HumanSerum 2 | 4.55 | 0.0702 | 1.5 | |
| HumanSerum 2 | 1.56 | 0.03 | 1.6 | HumanSerum 3 | 10.6 | 0.167 | 1.6 | |
| HumanSerum 3 | 43.2 | 0.5 | 1.2 | HumanSerum 4 | 82.4 | 1.82 | 2.2 | |
| HumanSerum 5 | 186 | 3.76 | 2.0 | |||||
| Precision | HumanSerum 6 | 331 | 4.40 | 1.3 | ||||
| Intermediate Precision | Intermediate Precision | |||||||
| Mean(mg/L) | SD(mg/L) | CV% | Mean(mg/L) | SD(mg/L) | CV% | |||
| CRP TControl N | 3.06 | 0.09 | 2.9 | PrecinormProtein | 9.69 | 0.142 | 1.5 | |
| PrecipathProtein | 43.6 | 0.8 | 1.9 | PrecipathProtein | 55.2 | 1.04 | 1.9 | |
| HumanSerum 1 | 0.51 | 0.06 | 11.1 | HumanSerum 2 | 4.55 | 0.0735 | 1.6 | |
| HumanSerum 2 | 1.44 | 0.06 | 3.9 | HumanSerum 3 | 10.6 | 0.206 | 1.9 | |
| HumanSerum 3 | 41.3 | 0.7 | 1.7 | HumanSerum 4 | 82.4 | 1.97 | 2.4 | |
| HumanSerum 5 | 186 | 4.39 | 2.4 | |||||
| HumanSerum 6 | 331 | 5.80 | 1.8 | |||||
| LoB | 0.2 mg/L | Same | ||||||
| LoD | 0.3 mg/L | Same | ||||||
| LoQ | 0.6 mg/L | 3 mg/L |
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| Feature | Predicate C-Reactive ProteinGen.3K083444 | Candidate DeviceTina-quant® C-Reactive ProteinIV K192072 |
|---|---|---|
| Method Comparison:Predicate vs Candidate | Passing Bablok: | |
| $Y=0.985x+0.278$ | ||
| $R=0.999$ | ||
| N=110Min=3.06/Max=347 mg/L | ||
| Interferences: | Serum Index:I=60 mg/dLH=1000 mg/dLL=1000RH: no interference up to 1200 IU/mLImmunoglobulins: no interference up to50 g/L | Same |
4. NON-CLINICAL PERFORMANCE EVALUATION
The following performance data were provided in support of the substantial equivalence determination:
Precision according to CLSI EP5-A3
Detection Limit: LoB, LoD and LoQ according to CLSI EP17-A2
Linearity according to CLSI EP6-A
Interferences- L, H and I Indices
Interferences – Albumin, Immunoglobulin (IgG) and Rheumatoid Factors
Interference - Drugs
Matrix Comparison - Anticoagulants
Method Comparison to Predicate
All performance specifications were met.
4.1. Precision: Repeatability and Intermediate Precision (CLSI EP05-A3)
Precision measurements were conducted to evaluate repeatability (within-run precision) and the intermediate precision (within-laboratory precision) according the CLSI guideline EP05-A3.
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The Tina-quant® C-Reactive Protein IV reagent was evaluated on a single cobas c 501 analyzer according to CLSI guideline EP05-A3. The protocol consisted of 4 human serum samples along with 2 controls (Precinorm Protein and Precipath Protein) which were analyzed in 2 parts for 21 days. Two aliquots of each sample were randomized and then analyzed on 3 lots of reagents. One operator performed all analysis along with utilizing 1 calibration throughout the 21-day study period.
| Specimen | Mean (mg/L) | SD (mg/L) | CV % |
|---|---|---|---|
| Precinorm Protein | 9.69 | 0.128 | 1.3 |
| Precipath Protein | 55.2 | 0.859 | 1.6 |
| Serum 2 | 4.55 | 0.0702 | 1.5 |
| Serum 3 | 10.6 | 0.167 | 1.6 |
| Serum 4 | 82.4 | 1.82 | 2.2 |
| Serum 5 | 186 | 3.76 | 2.0 |
| Serum 6 | 331 | 4.40 | 1.3 |
Table 2: Repeatability Summary
Table 3: Intermediate/Within Lab Precision Summary
| Specimen | Mean (mg/L) | SD (mg/L) | CV % |
|---|---|---|---|
| Precinorm Protein | 9.69 | 0.142 | 1.5 |
| Precipath Protein | 55.2 | 1.04 | 1.9 |
| Serum 2 | 4.55 | 0.0735 | 1.6 |
| Serum 3 | 10.6 | 0.206 | 1.9 |
| Serum 4 | 82.4 | 1.97 | 2.4 |
| Serum 5 | 186 | 4.39 | 2.4 |
| Serum 6 | 331 | 5.80 | 1.8 |
4.2. Analytical Sensitivity (CLSI EP17-A2)
4.2.1. Limit of Blank (LoB)
LoB of the Tina-quant® C-Reactive Protein IV assay was tested on 3 reagent lots. Ten aliquots of analyte free saline were analyzed on 1 Roche cobas c 501 analyzer in 6 runs over 3 days, for a total of N=60 determinations per lot.
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Table 4: LoB
| Claimed LoB [mg/L] | Observed LoB [mg/L] |
|---|---|
| 0.2 | 0.0700 |
4.2.2. Limit of Detection (LoD)
LoD of the Tina-quant® C-Reactive Protein IV assay was tested on 3 reagent lots. Five samples of low analyte level human serum were analyzed, each with 2 aliquots, on 1 Roche cobas c 501 analyzer, in 6 runs, over 3 days, for a total of N=60 determinations per lot.
Table 5: LoD
| Claimed LoD [mg/L] | Observed LoD [mg/L] |
|---|---|
| 0.3 | 0.137 |
Limit of Quantitation (LoQ) 4.2.3.
The LoQ of Tina-quant® C-Reactive Protein IV assay was tested on 3 reagent lots. Nine low concentration human serum samples (in the range from LoB up to approximately 2 times the specified LoQ) were analyzed on 1 Roche cobas c 501 analyzer, in 5 runs, with 5 aliquots of each sample for a total of N=25 determinations per sample per lot.
Table 6: LoQ
| Claimed LoQ [mg/L] | Observed LoQ [mg/L] |
|---|---|
| 3 | 0.313 |
Linearity/Assay Reportable Range (CLSI EP06-A) 4.3.
The dilution series was prepared from native unmodified human serum sample pools and then analyzed on using Tina-quant® C-Reactive Protein IV reagent. The dilution series was prepared resulting in 15 levels (including the high and low concentration pools). The diluted samples spanned the measuring range including a non-zero sample below the low end of measuring range and a sample over the high end of measuring range. Each dilution level was measured in triplicate (n ≥ 3).
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Table 7: Linearity
| Sample type / | Linear Regression | Claimed Measuring Range |
|---|---|---|
| Serum | y=1.002x-0.0169Pearson correlation coefficient(R)=0.9994 | 3 to 350 mg/L |
4.4. Endogenous Interference
4.4.1. L, H, and I Indices
The effect on quantitation of Tina-quant® C-Reactive Protein IV in the presence of lipemia, hemolysis and bilirubin were determined at 2 levels, 5-10 mg/L and 35-100 mg/L c-reactive protein, utilizing a dilution set of the added interfering substances. Eleven level serial dilution sets were prepared. Each of the 11 interferent levels were measured in triplicate from low to high concentration. All dilution levels for each interferent were measured in 1 run. The mean concentration of the 3 replicates at each level was used to calculate recovery to the known creactive protein concentration.
Table 8: Interference - L, H and I Indices
| Interferent | ClaimNo interference up to |
|---|---|
| Lipemia | 1000 L Index |
| Hemolysis | 1000 H Index |
| Bilirubin | 60 I Index |
| Ditauro Bilirubin | 60 I Index |
Albumin, Immunoglobulin (IgG) and Rheumatoid Factors Interference 4.4.2.
The effect on quantitation of Tina-quant® C-Reactive Protein IV in the presence of albumin, IgG and rheumatoid factors were determined at 2 levels, 5-10 mg/L and 35-100 mg/L c-reactive protein, utilizing a dilution set of the added interfering substances. Eleven level serial dilution sets were prepared. Each of the eleven interferent levels were measured in triplicate from low to high concentration. All dilution levels for each interferent were measured in 1 run. The median
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concentration of the 3 replicates at each level was used to calculate recovery to the known creactive protein concentration.
| Interferent | ClaimNo interference up to |
|---|---|
| Albumin | 60 g/L |
| IgG | 50 g/L |
| RF Factor | 1200 IU/mL |
| Table 9: Interference - Albumin, Immunoglobulin (IgG) and Rheumatoid Factors | |||||
|---|---|---|---|---|---|
| ------------------------------------------------------------------------------ | -- | -- | -- | -- | -- |
4.5. Exogenous Interferences - Drugs
The effect on quantitation of Tina-quant® C-Reactive Protein IV in the presence of potentially interfering drugs were determined at 2 levels, 5-10 mg/L and 35-100 mg/L c-reactive protein. One portion of each pool was spiked with the respective amount of drug and the other portion of the pool with solvent used to dissolve the drug, which was used for the baseline reference creactive protein concentration. The c-reactive protein mean concentration of both portions was determined in N=5 results. The mean % Recovery was calculated when comparing the drug spiked portions to the c-reactive protein baseline reference mean concentration.
| Drug | Tested Up To With NoInterference (mg/L) |
|---|---|
| N-Acetylcysteine | 1660 |
| Ampicillin-Na | 1000 |
| Ascorbic acid | 300 |
| Cefoxitin | 6600 |
| Heparin | 5000 IU/L |
| Levodopa | 20 |
| Methyldopa + 1.5 | 22.5 |
| Metronidazole | 200 |
| Doxycyclin | 50 |
| Acetylsalicylic acid | 1000 |
| Rifampicin | 60 |
| Ticarcillin | 225 |
| Penicillamin | 24 |
| Table 10: Exogenous Interference - Drugs | |||
|---|---|---|---|
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| Phenylbutazone | 400 |
|---|---|
| Cyclosporine | 5 |
| Acetaminophen | 200 |
| Ibuprofen | 500 |
| Theophylline | 100 |
Sample Matrix Comparison 4.6.
The effect on quantitation of c-reactive protein in the presence of anticoagulants with the Tinaquant® C-Reactive Protein IV reagent was determined on the cobas c 501 analyzer by comparing values obtained from native samples (single donors) drawn into serum, Li-Heparin, K2- and K3-EDTA plasma primary tubes.
Table 11: Sample Matrix Comparison
| Anticoagulant | Linear Regression | Range Tested [mg/L] |
|---|---|---|
| Serum vs. Li-Heparin | $y = 1.029x - 0.192, r = 0.999$ | 3.34 to 344 |
| Serum vs. K2-EDTA | $y = 1.024x - 0.201, r = 0.999$ | 3.34 to 344 |
| Serum vs. K3-EDTA | $y = 1.024x - 0.258, r = 0.999$ | 3.34 to 344 |
Method Comparison to Predicate 4.7.
A method comparison of the Tina-quant® C-Reactive Protein IV on the cobas c 501 analyzer versus the predicate device, Roche Diagnostics C-Reactive Protein Gen.3 was completed. One hundred ten native, unaltered serum samples, were tested in 1 run on 1 cobas c 501 analyzer in singlet using 1 lot of reagent. All samples were also testing for icteric, lipemic and hemolytic interference via analyzer serum indices. Statistics were created using Passing/Bablok and weighted Deming regression analysis.
| Passing/BablokRegression | Weighted DemingRegression | |
|---|---|---|
| Slope | 0.985 | 0.979 |
| Intercept | +0.278 | +0.296 |
| Correlation (Pearson) | 0.999 | 0.999 |
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4.8. Stability
The stability studies and acceptance criteria have been reviewed and found to be acceptable. The stability data supports Roche Diagnostic's claims as reported on the package labeling.
5. FDA GUIDANCE
FDA Guidance for Industry and FDA Staff: Review Criteria for Assessment of C-Reactive Protein (CRP), High Sensitivity C-Reactive Protein (hsCRP) and Cardiac C-Reactive Protein (cCRP) Assays was followed in this 510(k) submission.
6. ADDITIONAL INFORMATION
Other Devices Required But Not Provided:
- Calibrator f.a.s Proteins, K133330 ●
- . Precinorm Protein, K133330
- . Precipath Protein, K133330
- . PreciControl ClinChem Multi 1, K133330
- . PreciControl ClinChem Multi 2, K133330
There have been no changes to these items marketed with the new Tina-quant® C-Reactive Protein IV.
§ 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).