(263 days)
In vitro test for the quantitative determination of the total bilirubin concentration in human serum on COBAS Integra systems. Measurement of the level of bilirubin is used in the diagnosis and treatment of liver, hemolytic hematological, and metabolic disorders, including hepatitis and gall bladder block.
The Cobas Integra Bilirubin Total reagent is intended for use with the Cobas Integra systems for the quantitative determination of the total bilirubin concentration in human serum.
The provided text describes the 510(k) summary for the COBAS INTEGRA 400/800 Bilirubin Total device. This document is a premarket notification for an in vitro diagnostic (IVD) device, which are typically assessed for analytical performance characteristics rather than clinical performance based on ground truth established by experts.
Therefore, many of the requested categories (e.g., number of experts, adjudication method, MRMC study, sample size for training set, how ground truth for training set was established) are not applicable to this type of device submission. The study focuses on demonstrating analytical performance metrics like precision, accuracy (method comparison), measuring range, and sensitivity.
Here's the breakdown of the available information:
1. Table of Acceptance Criteria and Reported Device Performance:
The document doesn't explicitly state "acceptance criteria" in a separate section with pass/fail thresholds. Instead, it presents the performance characteristics of the modified device and compares them to the predicate device, implying that equivalence to the predicate's performance or standard analytical performance is the "acceptance criteria."
| Characteristic | Acceptance Criteria (Implied / Predicate Performance) | Reported Device Performance (Modified COBAS Integra Bilirubin Total) |
|---|---|---|
| Measuring Range | Test range: 0-340 umol/L (0-20 mg/dL) w/ postdilution: 0-1020 umol/L (0-60 mg/dL) Postdilution factor: 3 | 1.7-340 umol/L (0.099-20 mg/dL). Samples with higher concentrations can be determined via rerun function (1:3 dilution), results automatically multiplied by 3. |
| Lower Detection Limit | Sensitivity: 2.9 x 10-3 ΔA per umol/L (5.0 x 10-2 ΔA per mg/dL) total bilirubin | 1.7 umol/L (0.099 mg/dL). Calculated as zero sample + 3 SD (within-run precision, n=30). |
| Precision (Reproducibility) | Level 1: Mean: 24.2 umol/L (1.4 mg/dL); CV w/in run: 0.46%; CV day/day: 0.48%; CV total: 0.78%Level 2: Mean: 72.5 umol/L (4.2 mg/dL); CV w/in run: 0.45%; CV day/day: 0.53%; CV total: 0.80% | Level 1: Mean: 24.2 umol/L (1.4 mg/dL); CV w/in run: 0.45%; CV total: 0.78%Level 2: Mean: 72.5 umol/L (4.2 mg/dL); CV w/in run: 0.53%; CV total: 0.80%(Note: Table format is slightly different, but values are very similar) |
| Accuracy (Method Comparison) | Cobas Mira vs. Predicate: Sample size (n) 208, Values 1.7 to 350.6 umol/L (0.1 to 20.5 mg/dL), Corr Coefficient (r) 0.999, Lin Regression y = 1.00x + 1.2 umol/L, Passing Bablock y = 1.00x + 0.6 umol/LAlternative System vs. Predicate: Sample size (n) 210, Values 1.7 to 350.6 umol/L (0.1 to 20.5 mg/dL), Corr Coefficient (r) 0.999, Lin Regression y = 0.93x + 0.8 umol/L, Passing Bablock y = 0.93x + 0.4 umol/L | Modified vs. Cobas Integra Total Bilirubin Special (Cobas Integra 800): Sample size (n) = 49, Values 5.49 to 317 umol/L (0.321 to 18.5 mg/dL), Passing/Bablok y = 0.956x + 2.113 umol/L, r = 0.999Modified vs. Roche/Hitachi 911 (Cobas Integra 400): Sample size (n) = 104, Values 3.29 to 282 umol/L (0.192 to 16.5 mg/dL), Linear regression y = 0.989x - 0.520 umol/L, Passing/Bablok y = 0.991x + 0.219 umol/L, r = 0.999 |
| Limitations – Interference (Hemolysis) | Avoid hemolyzed specimens. Even slight hemolysis interferes with the test. | No significant interference up to an H index of 10 (approximate hemoglobin concentration 6 umol/L or 10 mg/dL). |
| Limitations – Interference (Lipemia) | Avoid lipemic specimens. Even slight lipemia interferes with the test. | No significant interference up to an L index of 9. |
| Limitations – Interference (Drugs) | Propranolol and theophylline cause artificially low total bilirubin values. | No interference found except for Propranolol and theophylline (causing artificially low values). Hydroxocobalamin (Cyanokit) may cause false-high results. In very rare cases, gammopathy (Type IgM / Waldenstrom's macroglobulinemia) may cause unreliable results. |
2. Sample Size Used for the Test Set and Data Provenance:
- Precision (Reproducibility):
- Within-run: n=20
- Between-run: n=20 (These likely refer to replicates per sample/control, not unique patient samples. The NCCLS manual EP5-T2, referenced for the predicate, typically involves multiple days/runs.)
- Accuracy (Method Comparison):
- Cobas Integra 800 Analyzer (comparison against Cobas Integra Total Bilirubin Special): n = 49 human serum samples.
- Cobas Integra 400 Analyzer (comparison against Roche/Hitachi 911 analyzer): n = 104 human serum samples.
- Lower Detection Limit: n=30 (for within-run precision of a zero sample).
Data Provenance: The method comparison studies used "human serum samples." The document does not specify the country of origin. Given Roche Diagnostics is listed with an Indianapolis, IN address, it's reasonable to infer a US-based study, but this is not explicitly stated. The studies appear to be retrospective in the sense that they tested samples to evaluate device performance post-development.
3. Number of Experts Used to Establish the Ground Truth for the Test Set and Qualifications of Those Experts:
Not applicable. For IVD devices like this bilirubin assay, "ground truth" is established by reference methods or validated comparative methods (other commercially available or predicate devices), not by expert human interpretation.
4. Adjudication Method for the Test Set:
Not applicable. There is no expert adjudication for chemical assays.
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:
Not applicable. This is an automated analytical device, not an imaging device requiring human readers or AI assistance in interpretation.
6. If a Standalone (i.e. algorithm only without human-in-the-loop performance) was done:
Yes, the studies described (precision, accuracy, sensitivity, linearity, interference) are all standalone performance evaluations of the analytical device. The "algorithm" here is the chemical assay and the instrument's processing of the spectrophotometric readings.
7. The Type of Ground Truth Used:
For analytical devices, "ground truth" is typically established by:
- Reference methods: Highly accurate and precise methods often used in specialized laboratories for validation.
- Comparative methods: Established, legally marketed devices (predicate devices or other commercially available, validated assays) that serve as a comparative standard.
In this submission, the ground truth for the accuracy studies was established by comparison with other established bilirubin measurement systems:
- Cobas Integra Total Bilirubin Special reagent on a Cobas Integra 800 analyzer.
- Commercially available reagents for total bilirubin on a Roche/Hitachi 911 analyzer.
8. The Sample Size for the Training Set:
Not applicable. This is not a machine learning or AI device that undergoes a discrete "training" phase with a specific dataset. Its performance is based on the chemical reactions and optical detection system.
9. How the Ground Truth for the Training Set Was Established:
Not applicable. See point 8.
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KC81193
Attachment 5
JAN 1 6 2009
510(k) Summary - COBAS INTEGRA 400/800 Bilirubin Total
| Introduction | According to the requirements of 21 CFR 807 92, the following information provides sufficient detail to understand the basis for a determination of substantial equivalence |
|---|---|
| Submitter name, address, contact | Roche Diagnostics9115 Hague RdIndianapolis IN 46250(317) 521-4569 |
| Contact person Jennifer TribbettDate prepared April 23, 2008 | |
| Device Name | Proprietary name Cobas Integra 400/800 Bilirubin TotalCommon name Bilirubin (total or direct) test systemClassification name Bilirubin (total or direct) test system |
| Device Description | The Cobas Integra Bilirubin Total reagent is intended for use with the Cobas Integra systems for the quantitative determination of the total bilirubin concentration in human serum |
| Intended use | In vitro test for the quantitative determination of the total bilirubin concentration in human serum on Cobas Integra Bilirubin is formed in the reticuloendothelial system during the degradation of aged erythrocytes The heme portion from hemoglobin and from other heme-containing proteins is removed, metabolized to bilirubin and transported as a complex with serum albumin to the liver In the liver, bilirubin is conjugated with glucuronic acid for solubilization and subsequent transport through the bile duct and elimination via the digestive tract Diseases or conditions which, through hemolytic processes, produce bilirubin faster than the liver can metabolize it, cause the levels of unconjugated (indirect) bilirubin to increase in the circulation Liver immaturity and several other diseases in which the bilirubin conjugation mechanism is impaired cause similar elevations of circulating unconjugated bilirubin Bile duct obstruction or damage to hepatocellular structure causes increases in the levels of both conjugated (direct) and unconjugated (indirect) bilirubin in the circulation |
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| Predicate Device | We claim substantial equivalence to the Cobas Integra Bilirubin Total (K951595) |
|---|---|
| Substantial equivalency - device comparison | The table below indicates the similarities and differences between the modified Bilirubin Total and the predicate Bilirubin Total (K951595) |
| Characteristic | Predicate Cobas Integra Bilirubin Total(K951595) | Modified Cobas IntegraBilirubin Total |
|---|---|---|
| Intended Use | The Cobas Integra Cassette Bilirubin Total(BIL-T) contains an in vitro diagnostic reagentsystem intended for use on Cobas Integra forthe quantitative determination of the totalbilirubin concentration in serum and plasma(test BIL-T, 0-048) | In vitro test for thequantitative determinationof the total bilirubinconcentration in humanserum (test BIL-T, 0-048)on Cobas Integra |
| Indications for Use | Bilirubin is formed in the reticuloendothelialsystem during the degradation of agederythrocytes The heme portion fromhemoglobin and from other heme-containingproteins is removed, metabolized to bilirubinand transported as a complex with serumalbumin to the liver In the liver, bilirubin isconjugated with glucuronic acid forsolubilization and subsequent transport throughthe bile duct and elimination via the digestivetract Diseases or conditions which, throughhemolytic processes, produce bilirubin fasterthan the liver can metabolize it, cause the levelsof unconjugated (indirect) bilirubin to increasein the circulation Liver immaturity and severalother diseases in which the bilirubinconjugation mechanism is impaired causesimilar elevations of circulating unconjugatedbilirubin Bile duct obstruction or damage tohepatocellular structure causes increases in thelevels of both conjugated (direct) andunconjugated (indirect) bilirubin in thecirculation | Same |
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| Characteristic | Predicate Cobas Integra Bilirubin Total(K951595) | Modified Cobas Integra BilirubinTotal | |
|---|---|---|---|
| Assay principle | Diazo method | Same | |
| Active Ingredients | R1 | R2 Test | Same |
| Sulfanilic AcidOxalic AcidHEDTAMyristytrimethyl-ammonium bromideDodecyltrimethyl-ammonium bromideSodium nitritepH | 354042524.511 | 13.5 mmol/L15.4 mmol/L1.5 mmol/L0.8 %1.9 %3.1 mmol/L1.4 | |
| Measuring range | Test range 0-340 umol/L (0-20 mg/dL)w/postdilution 0-1020 umol/L (0-60 mg/dL)Postdilution factor 3 | 17-340 umol/L (0.099-20 mg/dL)Determine samples having higherconcentrations via the rerunfunction. Dilution of samples viathe rerun function is a 1:3 dilution.Results from samples diluted by thererun function are automaticallymultiplied by a factor of 3. | |
| Sensitivity: The sensitivity is defined as thechange of analytical response (ΔA) per unitchange in analyte concentration at apathlength of 1 cm. The sensitivity is 2.9 x103 ΔA per umol/L of total bilirubin (5.0 x10-2 ΔA per mg/dL of bilirubin) | Lower Detection Limit: 1.7 umol/L(0.099 mg/dL). The detection limitrepresents the lowest measurableanalyte level that can bedistinguished from zero. It iscalculated as the value lying threestandard deviations above that of azero sample (zero sample + 3 SD,within-run precision, n=30). | ||
| Characteristic | Predicate Cobas Integra Bilirubin Total(K951595) | Modified Cobas Integra Bilirubin Total | |
| Precision | Precision was evaluated on Cobas Integrausing two human serum pools and followingthe guidelines of the NCCLS Manual EP5-T2 | Reproducibility was determined using humansamples and controls in an internal protocol(within-run n=20, between-run n=20) Thefollowing results were obtained | |
| Level 1Level 2 | Level 1Level 2 | ||
| Mean$24.2$ umol/L( $1.4$ mg/dL) | Mean$24.2$ umol/L( $1.4$ mg/dL) | ||
| $72.5$ umol/L( $4.2$ mg/dL) | $72.5$ umol/L( $4.2$ mg/dL) | ||
| CV w/in run$0.46$ % | CV w/in run$0.45$ % | ||
| CV day/day$0.48$ % | $0.53$ % | ||
| CV total$0.78$ % | CV total$0.80$ % | ||
| Accuracy | Accuracy Total bilirubin values for humansera and plasma samples obtained on CobasIntegra with the cassette bilirubin total werecompared to those determined with reagentsfor total bilirubin on Cobas Mira and thecommercially available alternative clinicalchemistry system Samples were measuredin duplicate Sample size (n) represents allreplicates Values ranged from $1.7$ to $350.6$umol/L ( $0.1$ to $20.5$ mg/dL)Cobas MiraSample size (n) $208$Corr Coefficient (r) $0.999$( $r_s$ ) $0.985$Lin Regression $y = 1.00x + 1.2$ umol/LPassing Bablock $y = 1.00x + 0.6$ umol/LAlternative SystemSample size (n) $210$Corr Coefficient (r) $0.999$( $r_s$ ) $0.972$Lin Regression $y = 0.93x + 0.8$ umol/LPassing Bablock $y = 0.93x + 0.4$ umol/L | Method Comparison Total bilirubin values forhuman serum samples obtained on a CobasIntegra 800 analyzer using the Cobas IntegraBilirubin Total reagent (y) were compared tothose determined using Cobas Integra TotalBilirubin Special reagent on a Cobas Integra 800analyzer (x)Cobas Integra 800 analyzerSample size (n) = $49$Passing/Bablok$y = 0.956x + 2.113$ umol/L$r = 0.999$Values ranged from $5.49$ to $317$ umol/L ( $0.321$to $18.5$ mg/dL)Total bilirubin values for human serum samplesobtained on a Cobas Integra 400 analyzer usingthe Cobas Integra Bilirubin Total reagent (y)were compared to those determined withcommercially available reagents for totalbilirubin on a Roche/Hitachi 911 analyzer (x)Roche/Hitachi 911 analyzerSample size (n) = $104$Linear regression$y = 0.989x - 0.520$ umol/L$r = 0.999$Passing/Bablok$y = 0.991x + 0.219$ umol/LValues ranged from $3.29$ to $282$ umol/L ( $0.192$to $16.5$ mg/dL) | |
| Characteristic | Predicate Cobas Integra Bilirubin Total(K951595) | Modified Cobas Integra Bılırubın Total | |
| ExpectedValues | Adults and infants >1month3 4–17 umol/L (0 2–1 0 mg/dL) | Same | |
| Newborns (up to 24 h)34-103 umol/L (2 0 – 6 0 mg/dL) | |||
| Newborns (up to 48 h)103-171 umol/L (6 0 –10 0 mg/dL) | |||
| Newborns (3 to 5 days)68 – 137 umol/L (4 0 – 8 0 mg/dL) | |||
| Note It is recommended that eachlaboratory establishes and maintains itsown reference ranges and that the valuesgiven here are used as a guideline only | Each laboratory should investigate thetransferability of the expected values to itsown patient population and if necessarydetermine its own reference range |
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| Characteristic | Predicate Cobas Integra BilirubinTotal (K951595) | Modified Cobas Integra BilirubinTotal |
|---|---|---|
| Limitations –interference | Hemolysis Avoid hemolyzedspecimens Even slight hemolysisinterferes with the testLipemia Avoid lipemic specimensEven slight lipemia interferes with thetestDrugs Of the drugs tested in vitro,propranolol and theophyline causeartificially low total bilirubin valuesat the tested drug level | Hemolysis No significantinterference up to an H index of 10(approximate hemoglobinconcentration 6 umol/L or 10mg/dL)Lipemia (Intralipid): No significantinterference up to an L index of 9There is a poor correlation betweenthe L index (corresponds toturbidity) and triglyceridesconcentrationDrugs Therapeutic druginterference was tested according tothe recommendations of VDGHNo interference was foundException Propranolol andtheophylline cause artificially lowtotal bilirubin values at the testeddrug level Hydroxocobalamin(Cyanokit) may cause false-highresultsOther In very rare casesgammopathy, in particular typeIgM (Waldenstromsmacroglobulinemia) may causeunreliable results |
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Image /page/6/Picture/1 description: The image is a seal for the Department of Health & Human Services USA. The seal is circular, with the words "DEPARTMENT OF HEALTH & HUMAN SERVICES USA" arranged around the perimeter of the circle. In the center of the seal is an emblem that resembles a stylized bird or eagle with three wing-like shapes. The emblem is black, and the text is also black against a white background.
Food and Drug Administration 2098 Gaither Road Rockville MD 20850
JAN 1 6 2009
Roche Diagnostics c/o Jennifer Tribbett Regulatory Affairs Principal 9115 Hague Road Indianapolis, IN 46250
Re K081193
Trade/Device Name Roche COBAS Integra Bılırubın Total (BIL-T) Regulation Number 21 CFR 862 1110 Regulatıon Name Bılırubın (total or dırect) test system Regulatory Class Class II Product Code CIG Dated December 18, 2008 Received December 19, 2008
Dear Ms Tribbett
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
If your device is classified (see above) into either class II (Special Controls) or class III (PMA), it may be subject to such additional controls Existing major regulations affecting your device can be found in Title 21, Code of Federal Regulations (CFR), Parts 800 to 895 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 lımıted to registration and lıstıng (21 CFR Part 807), labeling (21 CFR Parts 801 and 809), and good manufacturing practice requirements as set forth in the quality systems (QS) regulation (21 CFR Part 820)
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This letter will allow you to begin marketing your device as described in your Section 510(k) premarket notification The FDA finding of substantial equivalence of your device to a legally marketed predicate device results in a classification for your device and thus, permits your device to proceed to the market
If you desire specific information about the application of labeling requirements to your device, or questions on the promotion and advertising of your device, please contact the Office of In Vitro Diagnostic Device Evaluation and Safety at (301) 594-3084 Also, please note the regulation entitled, "Misbranding by reference to premarket notification" (21CFR Part 807 97) You may obtain other general information on your responsibilities under the Act from the 1900 of Small Manufacturers, International and Consumer Assistance at tts tolli-free number (800) 638-2041 or (301) 443-6597 or at its Internet address http //www fda gov/cdrh/dsma/dsmamam html
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Sincerely yours,
Coy C. He
Courtney C Harper, Ph D Acting Director Division of Chemistry and Toxicology Office of In Vitro Diagnostic Device Evaluation and Safety Center for Devices and Radiological Health
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Indication for Use
510(k) Number (if known) K081193
Device Name Roche COBAS Integra Bilirubin Total (BIL-T)
Indication For Use
In vitro test for the quantitative determination of the total bilirubin concentration in human serum on COBAS Integra systems
Measurement of the level of bilirubin is used in the diagnosis and treatment of liver, hemolytic hematological, and metabolic disorders, including hepatitis and gall bladder block
Prescription Use _XXX (21 CFR Part 801 Subpart D) And/Or
Over the Counter Use (21 CFR Part 801 Subpart C)
(PLEASE DO NOT WRITE BELOW THIS LINE, CONTINUE ON ANOTHER PAGE IF NEEDED)
Concurrence of CDRH, Office of In Vitro Diagnostic Device Evaluation and Safety (OIVD)
Carol C. Benson
Division Sign-Off
Office of In Vitro Diagnostic Device Evaluation and Safety
510(k) K081193
Page 1 of 1
§ 862.1110 Bilirubin (total or direct) test system.
(a)
Identification. A bilirubin (total or direct) test system is a device intended to measure the levels of bilirubin (total or direct) in plasma or serum. Measurements of the levels of bilirubin, an organic compound formed during the normal and abnormal distruction of red blood cells, if used in the diagnosis and treatment of liver, hemolytic hematological, and metabolic disorders, including hepatitis and gall bladder block.(b)
Classification. Class II.