(146 days)
In vitro test for the quantitative determination of the total protein concentration in urine and cerebral spinal fluid.
Protein measurements in urine are used in the diagnosis and treatment of disease conditions such as renal or heart diseases, or thyroid disorders.
CSF protein measurements are used in the diagnosis and treatment of conditions such as meningitis, brain tumors, and infections of the central nervous systems.
The Total Protein Urine/CSF assay provides quantitative measurement of total protein that is present in human urine and cerebral spinal fluid (CSF). Measurement is accomplished using a turbidimetric method.
Reagents for the COBAS Integra 400 plus analyzer are packaged in a cobas c pack with two bottles labeled with their instrument positioning, Reagent R1 in position B and Reagent SR in position C.
R1 contains Sodium Hydroxide: 677 mmol/L; EDTA-Na: 74 mmol/L
SR contains Benzethonium chloride: 32 mmol/L
Here's an analysis of the acceptance criteria and study findings for the TPUC3 Total Protein Urine/CSF Gen.3 device, based on the provided document:
1. Table of Acceptance Criteria and Reported Device Performance
| Test | Acceptance Criterion | Reported Device Performance |
|---|---|---|
| Interference by Radiopaque Media | Deviation ≤ ± 10% | At 6.4 g/L organically bound Iodine: - Deviation = 5.6% at level 1 (92.5 mg/L total protein) - Deviation = 9.7% at level 2 (961 mg/L total protein) Meets criterion. |
| Interference by Homogentisic Acid | Deviation ≤ ± 10% | At 1.2 mmol/L homogentisic acid: - Deviation = 6.8% at level 1 (107 mg/L total protein) - Deviation = 6.9% at level 2 (1180 mg/L total protein) Meets criterion. |
| High Dose Hook Effect | No false result reported up to a protein concentration of 100 g/L. All samples above the measuring range are flagged. | No false result reported up to a protein concentration of 100 g/L. All samples above the measuring range are flagged as either being above the measuring range or above the absorbance limit. Meets criterion. |
2. Sample Sizes Used for the Test Set and Data Provenance
- Interference by Radiopaque Media: The test used pooled human urine samples at two different total protein levels. Each level was spiked with 10 dilution steps of Hexabrix and tested in triplicate. The specific number of distinct pooled samples is not stated, but at least two unique pooled samples were used (referred to as "level 1" and "level 2").
- Interference by Homogentisic Acid: The test used the same protocol as for radiopaque media, meaning pooled human urine samples at two different total protein levels, spiked with homogentisic acid, and tested in triplicate at 10 dilution steps.
- High Dose Hook Effect: The test used one pooled human urine sample which was spiked with human Albumin up to 100 g/L, and a dilution series was prepared from this spiked sample. The samples were tested in triplicate.
Data Provenance: The document explicitly states "pooled human urine samples." While it doesn't specify the country of origin, the FDA submission context usually implies data relevant to the US regulatory environment. The studies appear to be prospective as they were specifically designed and conducted to evaluate the device's performance against the defined acceptance criteria.
3. Number of Experts Used to Establish Ground Truth for the Test Set and Qualifications of those Experts
This document describes performance studies for an in vitro diagnostic (IVD) device that quantifies total protein. The ground truth for such devices is typically established by:
- Reference methods/materials (e.g., traceable calibrators like NIST SRM-927 mentioned in the similarities section for calibration traceability)
- Known concentrations of interference substances (e.g., Hexabrix, homogentisic acid)
- Known concentrations of the analyte itself (e.g., human Albumin for the hook effect).
Therefore, the ground truth is based on analytical standards and precise spiking of known concentrations, not interpretation by medical experts. No human experts (like radiologists) were involved in establishing the ground truth for these specific performance tests.
4. Adjudication Method for the Test Set
Not applicable. The tests involve quantitative measurements against known spiked concentrations or defined analytical limits. There is no subjective interpretation requiring adjudication.
5. If a Multi-Reader Multi-Case (MRMC) Comparative Effectiveness Study Was Done
No. This document describes the performance of an IVD analyzer for quantitative protein measurement. MRMC studies are typically performed for diagnostic imaging devices where human readers interpret medical images. This is a standalone device performance study.
6. If a Standalone (i.e., algorithm only without human-in-the-loop performance) Was Done
Yes. The entire study described focuses on the standalone performance of the TPUC3 Total Protein Urine/CSF Gen.3 assay on the Roche COBAS Integra 400 plus analyzer. It evaluates the device's accuracy in the presence of specific interferents and its response to high analyte concentrations, without any human interpretation of the results being part of the performance evaluation.
7. The Type of Ground Truth Used
The ground truth used for these studies is based on:
- Known (spiked) concentrations of interferents (organically bound iodine from Radiopaque media, homogentisic acid) in pooled human urine.
- Known (spiked) concentrations of the analyte (human Albumin) to assess the high dose hook effect.
- The concentrations of these substances were precisely controlled and quantified.
8. The Sample Size for the Training Set
The document does not provide information on the training set size. This submission is for modifications to an existing device (TPUC3 Total Protein Urine/CSF Gen.3). The described studies are validation/verification tests for these specific modifications related to interference claims and hook effect, not for initial model development or training. IVD devices like this are typically developed through iterative analytical and clinical studies, but information about the "training set" for the underlying chemistry/method is not detailed here.
9. How the Ground Truth for the Training Set Was Established
As no training set information is provided, there is no information on how its ground truth was established. For IVD devices, the initial ground truth for method development (analogous to a training set) would generally involve:
- Certified reference materials.
- Patient samples characterized by established reference methods.
- Spiking studies with known concentrations of analytes and interferents.
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Food and Drug Administration 10903 New Hampshire Avenue Document Control Center - WO66-G609 Silver Spring, MD 20993-0002
ROCHE DIAGNOSTICS OPERATIONS (RDO) PATRICK STIMART REGULATORY AFFAIRS CONSULTANT 9115 HAGUE ROAD INDIANAPOLIS IN 46250
December 9, 2014
Re: K141925
Trade/Device Name: TPUC3 Total Protein Urine/CSF Gen.3 Regulation Number: 21 CFR 862.1645 Regulation Name: Urinary protein or albumin (nonquantitative) test system Regulatory Class: I exempt, meets limitations of exemptions per 862.9 (c)(1)(4) Product Code: JIO Dated: November 7, 2014 Received: November 10, 2014
Dear Mr. Patrick Stimart:
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. 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 Parts 801 and 809); medical device reporting (reporting of medical device-related adverse events) (21 CFR 803); good manufacturing practice requirements as set forth in the quality systems (QS) regulation (21 CFR Part 820); and if applicable, the electronic product radiation control provisions (Sections 531-542 of the Act); 21 CFR 1000-1050.
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If you desire specific advice for your device on our labeling regulations (21 CFR Parts 801 and 809), please contact the Division of Industry and Consumer Education at its toll-free number (800) 638 2041 or (301) 796-7100 or at its Internet address
http://www.fda.gov/MedicalDevices/Resourcesfor You/Industry/default.htm. 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
http://www.fda.gov/MedicalDevices/Safety/ReportaProblem/default.htm for the CDRH's Office of Surveillance and Biometrics/Division of Postmarket Surveillance.
You may obtain other general information on your responsibilities under the Act from the Division of Industry and Consumer Education at its toll-free number (800) 638-2041 or (301) 796-7100 or at its Internet address
http://www.fda.gov/MedicalDevices/ResourcesforYou/Industry/default.htm.
Sincerely yours,
Katherine Serrano -S
For : Courtney H. Lias, Ph.D. Director Division of Chemistry and Toxicology Devices Office of In Vitro Diagnostics and Radiological Health Center for Devices and Radiological Health
Enclosure
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Indications for Use
510(k) Number (if known) K141925
Device Name Total Protein Urine/CSF Gen.3
Indications for Use (Describe)
In vitro test for the quantitative determination of the total protein concentration in urine and cerebral spinal fluid.
Protein measurements in urine are used in the diagnosis and treatment of disease conditions such as renal or heart diseases, or thyroid disorders.
CSF protein measurements are used in the diagnosis and treatment of conditions such as meningitis, brain tumors, and infections of the central nervous systems.
| 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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| Introduction | The following information provides sufficient detail to understand the basis for adetermination of substantial equivalence according to the requirements of 21 CFR807.92.Note: There were no prior submissions for this device for which FDA providedfeedback related to the data or information needed to support substantialequivalence. | |||
|---|---|---|---|---|
| Applicant | This Special 510(k) premarket notification was prepared by Patrick Stimart fromRoche Professional Diagnostics Regulatory Affairs and submitted on July 15, 2014. | |||
| Roche Diagnostics Operationsc/o Patrick Stimart, Regulatory AffairsPO Box 50416Indianapolis IN 46250-0416 | ||||
| Phone: 317-521-3954Fax: 317-521-2324e-mail: patrick.stimart(@roche.com | ||||
| Candidatedevice | Proprietary name: TPUC3 Total Protein Urine/CSF Gen.3Common name: Total Protein Urine/CSF | |||
| Measurand | Total Protein | |||
| Predicatedevice | The candidate device is a modification of the predicate device. The device name,TPUC3 Total Protein Urine/CSF Gen.3, is unchanged from how it was cleared in510(k) K071239. | |||
| Regulatory | Table 1: Regulatory Classification of Candidate Device | |||
| classification of | Device Classification Name | Urinary protein or albumin test system | ||
| device | Produce Code | JIQ | ||
| Device Class | ]* | |||
| Regulation | 862.1645 | |||
| Panel | Clinical Chemistry | |||
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Continued
| Regulatoryclassification ofdevice(Continued) | * Although the regulation for this assay lists it as Class I, exempt from 510(k)requirements, a 510(k) submission is required because the Total Protein Urine/CSFGen.3 assay meets the limitations for exemption found in 21 CFR 862.9 (c) 1 and 4. |
|---|---|
| Devicedescription | The Total Protein Urine/CSF assay provides quantitative measurement of totalprotein that is present in human urine and cerebral spinal fluid (CSF). Measurementis accomplished using a turbidimetric method.Reagents for the COBAS Integra 400 plus analyzer are packaged in a cobas c packwith two bottles labeled with their instrument positioning, Reagent R1 in position Band Reagent SR in position C.R1 contains Sodium Hydroxide: 677 mmol/L; EDTA-Na: 74 mmol/LSR contains Benzethonium chloride: 32 mmol/L |
| Intendeduse/indicationsfor use | In vitro test for the quantitative determination of the total protein concentration inurine and cerebral spinal fluid.Protein measurements in urine are used in the diagnosis and treatment of diseaseconditions such as renal or heart diseases, or thyroid disorders.CSF protein measurements are used in the diagnosis and treatment of conditionssuch as meningitis, brain tumors and infections of the central nervous systems.Note: The intended use of the modified device, as described in its labeling, has notchanged as a result of the modification. |
| Specialconditions foruse | For prescription use only |
| Specialinstrumentsrequired | For use on the Roche COBAS Integra 400 plus analyzer |
| Continued on next page |
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| Devicemodification | The candidate device, Total Protein Urine/CSF Gen.3, has been modified from thepredicate device with the addition of the following information to the Limitations-interferences section of the labeling:Patient samples containing greater than 6.4 g/L of organically bound iodinefrom Radiopaque media (e.g. Hexabrix) may have falsely elevated results. High levels of homogentisic acid can be found in the urine of patients withthe rare genetic disorder Alkaptonuria10. Homogentisic acid in urinesamples at concentration greater than 1.2 mmol/L can cause falsely elevatedresults. There is no high dose hook effect at protein concentrations up to 100 g/L. |
|---|---|
| ------------------------ | ------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------- |
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Continued
| Feature | Predicate Device | Candidate Device | |
|---|---|---|---|
| Total Protein Urine/CSFGen.3 | Total Protein Urine/CSFGen.3 | ||
| In vitro test for thequantitative determination ofthe total protein concentrationin urine and cerebrospinalfluid on COBAS INTEGRAsystems. | same | ||
| Intendeduse/indications foruse | Protein measurements inurine are used in thediagnosis and treatment ofdisease conditions such asrenal or heart diseases, orthyroid disorders, which arecharacterized by proteinuriaor albuminuria.CSF protein measurementsare used in the diagnosis andtreatment of conditions suchas meningitis, brain tumorsand infections of the centralnervous systems. | same | |
| Test principle | Turbidimetric method | same | |
| Sample volume | 10 µL | same | |
| Sample types | Urine and cerebral spinalfluid (CSF) | same | |
| Reagents | R1: Sodium hydroxide 677mmol/L; EDTA-Na 74mmol/LSR: Benzethonium chloride32 mmol/L | same | |
| Similarities,continued | Feature | Predicate Device | Candidate Device |
| Table 4: Similarities between Predicate and Candidate Devices | |||
| Total Protein Urine/CSFGen.3 | Total Protein Urine/CSFGen.3 | ||
| Calibrationinterval | COBAS INTEGRA 400 plussystem:• each cobas c pack• every 43 days• as required followingquality controlprocedures | same | |
| Traceability | Traceability: This method hasbeen standardized against theNational Bureau of StandardsReference Material SRM-927using the biuret method forthe quantitation of protein. | same | |
| Reagent stability | Shelf life at 15-25 °CSee expiration date on cobasc pack labelCOBAS INTEGRA 400 plussystemOn-board in use at 10-15 °C12 weeks | same | |
| Measuring range | 40-2000 mg/L (4-200mg/dL) | same | |
| Lower detectionlimit | 40 mg/L (4 mg/dL) | same | |
| Expected values | Urine: 24h: < 150 mg/24 hCSF: 150-450 mg/L(15-45 mg/dL)Each laboratory shouldinvestigate the transferabilityof the expected values to itsown patient population and ifnecessary determine its ownreference ranges. | same | |
| Feature | Predicate Device | Candidate Device | |
| Total Protein Urine/CSFGen.3 | Total Protein Urine/CSFGen.3 | ||
| Instrumentplatform | COBAS Integra400/400+/700/800 | COBAS Integra 400+ | |
| Calibrator | C.f.a.s. TPUC 200 | C.f.a.s. PUC | |
| Controls | Use commercially availableurine and CSF proteincontrols or other suitablecontrol material.See predicate method sheet | Precinorm PUC, PrecipathPUCIn addition, other suitablecontrol material can be used. | |
| Limitations –interference | Same as predicate except forthe following additions:Patient samples containinggreater than 6.4 g/L oforganically bound iodinefrom Radiopaque media (e.g.Hexabrix) may have falselyelevated results.High levels of homogentisicacid can be found in the urineof patients with the raregenetic disorderAlkaptonuria10.Homogentisic acid in urinesamples at concentrationgreater than 1.2 mmol/L cancause falsely elevated results.There is no high dose hookeffect at proteinconcentrations up to 100 g/L. |
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Continued
Differences
Table 5: Differences between Predicate and Candidate Devices
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Continued
| Summary ofperformancedata | Based on the risk analysis, the modifications to the Total Protein Urine/CSF Gen.3did not introduce any new risks to the performance of the assay.To address the modifications, performance data from verification and validationtesting demonstrated that all of the acceptance criteria were met. |
|---|---|
| Testing ofinterference byradiopaquemedia | Testing is performed in pooled human urine samples at two different total proteinlevels on the Integra 400 plus analyzer. Each level is spiked with varying levels ofthe radiopaque media Hexabrix containing organically bound iodine (10 dilutionsteps per level) which were tested in triplicate and the median value was used tocalculate % deviation from expected concentration. |
| Acceptance criterion: Deviation $≤ ± 10 %$ | |
| Results: At an organically bound Iodine concentration of 6.4 g/L;Deviation = 5.6 % at level 1 (92.5 mg/L total protein)Deviation = 9.7 % at level 2 (961 mg/L total protein) | |
| The results meet the criterion of $≤ ± 10 %$ deviation at all concentrations tested up toand including 6.4 g/L of organically bound iodine, and thus support the claim of nointerference up to 6.4 g/L of organically bound iodine from Radiopaque media. | |
| Testing ofinterference byHomogentisicacid | The same protocol as described for radiopaque media above except that human urinesamples were spiked with homogentisic acid instead of Hexabrix.Acceptance criterion: Deviation $≤ ± 10 %$ |
| Results: At a homogentisic acid concentration of 1.2 mmol/L;Deviation = 6.8 % at level 1 (107 mg/L total protein)Deviation = 6.9 % at level 2 (1180 mg/L total protein) | |
| The results meet the criterion of $≤± 10 %$ deviation at all concentrations tested up toand including 1.2 mmol/L of homogentisic acid, and thus support the claim of nointerference up to 1.2 mmol/L of homogentisic acid. |
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Continued
| Testing for highdose hook effect | A pooled human urine sample was spiked with human Albumin up to a total proteinconcentration of 100 g/L. A dilution series was prepared by diluting the sample withun-spiked pooled human urine sample. The samples were tested in triplicate. Themedian was calculated. |
|---|---|
| Acceptance criterion:No false result reported up to a protein concentration 100 g/L.All samples above the measuring range are flagged. | |
| Results: No false result reported up to a protein concentration up to 100 g/L.All samples above the measuring range are flagged as either being above themeasuring range or above the absorbance limit. | |
| The results meet the criterion of no false result reported up to a protein concentration100 g/L, and thus support the claim that there is no high dose hook effect at proteinconcentrations up to 100 g/L. | |
| Conclusion | The submitted information in this premarket notification supports a substantialequivalence decision. The differences between predicate and candidate do notimpact the indications for use or technological characteristics. |
§ 862.1645 Urinary protein or albumin (nonquantitative) test system.
(a)
Identification. A urinary protein or albumin (nonquantitative) test system is a device intended to identify proteins or albumin in urine. Identification of urinary protein or albumin (nonquantitative) is used in the diagnosis and treatment of disease conditions such as renal or heart diseases or thyroid disorders, which are characterized by proteinuria or albuminuria.(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.