(161 days)
The Calcium Gen.2 assay is an in vitro diagnostics reagent system intended for the quantitative determination of calcium in human serum, plasma, and urine on Roche/Hitachi cobas c systems. Calcium measurements are used in the diagnosis and treatment of parathyroid disease, a variety of bone diseases, chronic renal disease, and tetany.
The Calcium Gen. 2 test system employs a photometric test method where calcium ions react with a calcium specific polyamino carboxylic acid under alkaline conditions to form a complex. This complex reacts in the second step with EDTA. The calcium concentration is directly proportional to the change in absorbance which is measured photometrically.
Here's an analysis of the provided text regarding the Calcium Generation 2 Assay, focusing on acceptance criteria and study details.
Note: This document is a 510(k) summary, which typically presents performance data to demonstrate substantial equivalence to a predicate device, rather than explicitly stating pre-defined "acceptance criteria" and then proving them met in the same way a clinical trial protocol would. The acceptance criteria are implied by the comparisons made to the predicate device and the typical performance expectations for such assays. The "study" described is the performance characterization of the new device.
Acceptance Criteria and Device Performance
The "acceptance criteria" are implicitly set by the performance of the predicate device and general expectations for clinical chemistry assays, particularly in terms of precision and measuring range. The submission demonstrates that the Calcium Gen. 2 assay performs comparably or better than the predicate device in key areas.
| Performance Metric | Implied Acceptance Criteria (Based on Predicate/Clinical Norms) | Reported Device Performance (Calcium Gen. 2) | Meets Criteria? |
|---|---|---|---|
| Measuring Range (Serum/Plasma) | Similar to predicate (0.2 – 20 mg/dL) and clinically appropriate. | 0.8 – 20.1 mg/dL | Yes |
| Measuring Range (Urine) | Similar to predicate (0.48 – 48 mg/dL) and clinically appropriate. | 0.8 – 30.1 mg/dL | Yes |
| Lower Limits of Measure (Serum/Plasma) | Clinically relevant LoB, LoD, LoQ would be established. | LoB: 0.4 mg/dLLoD: 0.8 mg/dLLoQ: 0.8 mg/dL | N/A (Predicate had "Not Established") |
| Lower Limits of Measure (Urine) | Clinically relevant LoB, LoD, LoQ would be established. | LoB: 0.4 mg/dLLoD: 0.8 mg/dLLoQ: 0.8 mg/dL | N/A (Predicate had "Not Established") |
| Precision (Serum/Plasma) | Comparable or better than predicate, generally low CVs. Predicate example (Human serum): Repeatability 0.9%, Intermediate precision 1.6% (implied from data layout). | Human serum 1 (2.4 mg/dL): Repeatability CV 2.0%, Intermediate precision CV 2.5%Human serum 2 (10.2 mg/dL): Repeatability CV 0.8%, Intermediate precision CV 0.9%Human serum 3 (17.9 mg/dL): Repeatability CV 0.8%, Intermediate precision CV 0.9%Precinorm U (9.0 mg/dL): Repeatability CV 0.8%, Intermediate precision CV 0.8%Precipath U (14.1 mg/dL): Repeatability CV 0.8%, Intermediate precision CV 0.9% | Yes |
| Precision (Urine) | Comparable or better than predicate, generally low CVs. Predicate example (Human urine): Repeatability 0.8%, Intermediate precision 1.4% (implied from data layout). | Human urine 1 (2.3 mg/dL): Repeatability CV 3.0%, Intermediate precision CV 3.1%Human urine 2 (15.7 mg/dL): Repeatability CV 1.1%, Intermediate precision CV 1.2%Human urine 3 (20.8 mg/dL): Repeatability CV 0.9%, Intermediate precision CV 1.1%Human urine 4 (24.4 mg/dL): Repeatability CV 1.3%, Intermediate precision CV 1.3%Control Level 1 (7.4 mg/dL): Repeatability CV 1.3%, Intermediate precision CV 1.5%Control Level 2 (10.9 mg/dL): Repeatability CV 1.1%, Intermediate precision CV 1.3% | Yes |
| Interference (Serum/Plasma) | No significant interference up to established thresholds for icterus, hemolysis, lipemia. Known drug interferences should be identified. | Icterus: no significant interference up to an I index of 60.Hemolysis: no significant interference up to an H index of 1000.Lipemia: no significant interference up to an L index of 1000.MRI contrast media (Omniscan®, Optimark®): No interference at therapeutic concentration for Omniscan®, interference at higher concentrations. Optimark® showed interference at therapeutic and higher concentrations.Gammopathy: In very rare cases, type IgM may cause unreliable results. | Yes (comparable or expanded) |
| Interference (Urine) | No significant interference up to established thresholds. Known drug interferences should be identified. | Icterus: no significant interference up to a conjugated bilirubin concentration of 60 mg/dL.Hemolysis: no significant interference up to a hemoglobin concentration of 1000 mg/dL.Magnesium: no significant interference up to a concentration of 60 mmol/L.Drugs: No interference found at therapeutic concentrations using common drug panels.MRI contrast media (Omniscan®, Optimark®): No interference at therapeutic concentration for Omniscan®, but at higher concentrations. Optimark® showed interference at therapeutic and higher concentrations. | Yes (expanded upon predicate's limited urine interference data) |
| Reagent Stability | Comparable to predicate (e.g., on-board stability). | Unopened: 2-8°C until expiration date.On-board in use: 42 days. | Yes |
Study Details
The provided document describes the performance characteristics of the Calcium Gen. 2 assay to demonstrate its substantial equivalence to a legally marketed predicate device (Calcium, K921661). This means the "study" is primarily a standalone performance characterization of the new assay.
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Sample size used for the test set and the data provenance:
- Precision: The precision study used multiple samples, including "Human serum" (3 levels) and "Human urine" (4 levels), plus "Precinorm U" and "Precipath U" controls for serum, and "Control Level 1" and "Control Level 2" for urine. The exact number of replicates or individual patient samples per level is not specified beyond "Mean" and "CV Repeatability/Intermediate precision," which typically imply multiple measurements (e.g., n=20, n=40 etc. as per CLSI guidelines) over several days.
- Interference: Various samples spiked with interferents (icterus, hemolysis, lipemia, magnesium, specific drugs, MRI contrast media) were used. The number of samples for each interference test is not specified, but the results (e.g., "no significant interference up to an X index") indicate a panel of concentrations was tested.
- Data Provenance: Not explicitly stated but clinical chemistry assay validation studies are typically conducted by the manufacturer in a controlled laboratory setting. The origin (e.g., country) of the specific samples (human serum/urine) or controls used is not provided, but it's reasonable to assume they are representative of patient populations where the assay would be used. The studies are retrospective in the sense that they are laboratory characterizations rather than prospective patient follow-up studies.
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Number of experts used to establish the ground truth for the test set and the qualifications of those experts:
- This question is not applicable to this type of device and study. For a quantitative in vitro diagnostic assay, the "ground truth" is typically established by the reference method (e.g., an established highly accurate chemical method) or by the established concentration of a control material. There are no "experts" interpreting images or clinical data to establish ground truth in this context.
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Adjudication method for the test set:
- Not applicable. Adjudication methods (like 2+1 or 3+1) are relevant for studies where human interpretation of data (e.g., imaging, pathology slides) contributes to ground truth determination. For an automated quantitative assay, the result is a numerical value, and "adjudication" is not a concept used.
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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, this device is a laboratory reagent system, not an AI-powered diagnostic imaging or interpretation tool. Therefore, an MRMC study and effects on human reader performance are not relevant.
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If a standalone (i.e. algorithm only without human-in-the loop performance) was done:
- Yes, this is a standalone performance study. The Calcium Gen. 2 assay is an in vitro diagnostic reagent system used on an automated analyzer (Roche/Hitachi cobas c systems). The performance data presented (precision, measuring range, interference) directly reflects the algorithm/assay's performance. Human interaction is limited to operating the instrument, performing quality control, and interpreting the numerical result, not in generating the result itself.
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The type of ground truth used (expert consensus, pathology, outcomes data, etc.):
- For precision, the ground truth is the "true" concentration of calcium in the control materials or pooled human samples, as determined by a reference method or validated assignment, which is then measured repeatedly by the device.
- For measuring range (LoB, LoD, LoQ), the ground truth is the analytical performance characteristics empirically determined through dilution series and statistical analysis around the lowest measurable concentrations.
- For interference, the ground truth is the known concentration of calcium in samples, both with and without the interferent, often compared against a reference method or the predicate device, to see if the interferent causes a clinically significant deviation in the measured calcium value.
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The sample size for the training set:
- Not explicitly mentioned, and likely not applicable in the context of this device. This is a chemical assay, not a machine learning algorithm that requires a "training set" in the conventional sense. The "training" for such a system would be the R&D and optimization process of the chemical reagents and instrument parameters, based on extensive pre-clinical testing, rather than a distinct "training set" of patient data as might be used for AI/ML models.
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How the ground truth for the training set was established:
- Not applicable as there isn't a "training set" in the AI/ML sense. The development of the assay would involve iterative testing and optimization against known calcium standards and samples with established reference values to ensure accuracy and precision across the intended measuring range.
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MAY - 8 2012
510(k) Summary – Calcium Generation 2 Assay
| Introduction | Roche Diagnostics Corporation hereby submits this 510(k) to provide notification of our intent to market the Calcium Generation 2 assay. The original 510(k) summary was submitted by Kathie Goodwin on November 28, 2011. This revised version is a result of the changes that occurred based on Roche's hold response. |
|---|---|
| Submitter, name, address, contact | Roche Diagnostics9115 Hague RoadPO Box 50416Indianapolis, IN 46250Phone: 317-521-1942Fax: 317-521-2324New Primary Contact person: Lisa KlinedinstEmail: lisa.klinedinst@roche.comDate prepared: March 30, 2012 |
| Device name | Proprietary name: Calcium Gen. 2Common name: CA2Classification name: Calcium Test System under 21 CFR 862.1145Product code: CHW |
| Device description | The Calcium Gen. 2 test system employs a photometric test method where calcium ions react with a calcium specific polyamino carboxylic acid under alkaline conditions to form a complex. This complex reacts in the second step with EDTA. The calcium concentration is directly proportional to the change in absorbance which is measured photometrically. |
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510(k) Summary - Calcium Generation 2 Assay, continued
| Intended use | The Calcium Gen.2 assay is an in vitro diagnostics reagent systemintended for quantitative determination of calcium in human serum,plasma and urine on Roche/Hitachi cobas c systems. |
|---|---|
| Predicatedevice | Roche claims substantial equivalence to the currently marketedCalcium test system cleared in K921661. |
The following table compares the features of the draft device with the Substantial equivalence predicate device.
| Feature | Predicate Device:Calcium (K921661) | Draft Device:Calcium Gen. 2 |
|---|---|---|
| Intended Use | In vitro test for the quantitativedetermination of calcium inhuman serum, plasma and urineon Roche automated clinicalchemistry analyzers. | same |
| Sample Types | Serum, Heparin Plasma, and Urine | Serum, Li-Heparin Plasma andUrine |
| InstrumentPlatform | Roche Hitachi analyzers | cobas c 501 analyzer |
| Calibrator | Calibrator f.a.s. | same |
| CalibrationFrequency | Every 3 days if the reagent bottlesare onboard the analyzer for morethan 3 days; after reagent bottlechange if the previous bottles wereonboard the analyzer for more than3 days; after reagent lot change;and as required following qualitycontrol procedures | After reagent lot change and asrequired following quality controlprocedures. |
| CalibrationMode | Two point linear | same |
| Feature | Predicate Device:Calcium (K921661) | Draft Device:Calcium Gen. 2 |
| Controls | • Preinorm U Plus• Precipath U Plus• Preinorm U• Precipath U | • Preinorm U Plus• Precipath U Plus• Preinorm U• Precipath U• PreciControl ClinChemMulti1• PreciControl ClinChemMulti2 |
| Reagent ActiveIngredients | o-Cresolphthalein complexone, 8-hydroxyquinoline, HCl acid | 5-nitro-5'-methyl-BAPTA |
| ReagentStability | Unopened15-25°C until expiration dateOn-board in useR1: 42 daysR2: 90 days | Unopened2-8°C until expiration dateOn-board in use42 days |
| MeasuringRange | Serum/Plasma:0.2 – 20 mg/dLUrine:0.48 – 48 mg/dL | Serum/Plasma:0.8 – 20.1 mg/dLUrine:0.8 – 30.1 mg/dL |
| Lower Limitsof Measure | Not Established | Serum/PlasmaLoB: 0.4 mg/dLLoD: 0.8 mg/dLLoQ: 0.8 mg/dLUrineLoB: 0.4 mg/dLLoD: 0.8 mg/dLLoQ: 0.8 mg/dL |
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510(k) Summary - Calcium Generation 2 Assay, continued
Substantial equivalence (continued)
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510(k) Summary - Calcium Generation 2 Assay, conlinued
| Feature | Predicate Device:Calcium (K921661) | Draft Device:Calcium Gen. 2 | |||||
|---|---|---|---|---|---|---|---|
| Serum/plasma | Serum/plasma | ||||||
| Mean | CVRepeatability | Mean | CVRepeatability | CVIntermediate precision | |||
| Humanserum | $8.49$ mg/dL | 0.9% | Humanserum 1 | $2.4$ mg/dL | 2.0% | 2.5% | |
| PrecitrolN | $9.18$ mg/dL | 0.7% | Humanserum 2 | $10.2$ mg/dL | 0.8% | 0.9% | |
| PrecitrolA | $13.3$ mg/dL | 0.4% | Humanserum 3 | $17.9$ mg/dL | 0.8% | 0.9% | |
| Mean | CVIntermediateprecision | PrecinormU | $9.0$ mg/dL | 0.8% | 0.8% | ||
| Humanserum | $8.41$ mg/dL | 1.6% | PrecipathU | $14.1$ mg/dL | 0.8% | 0.9% | |
| PrecitrolN | $9.12$ mg/dL | 1.7% | |||||
| Precision | PrecitrolA | $13.1$ mg/dL | 1.1% | ||||
| Urine | Urine | ||||||
| Mean | CVRepeatability | Mean | CVRepeatability | CVIntermediate precision | |||
| Humanurine | $14.3$ mg/dL | 0.8% | Humanurine 1 | $2.3$ mg/dL | 3.0% | 3.1% | |
| ControlUrine 1 | $6.12$ mg/dL | 1.2% | Humanurine 2 | $15.7$ mg/dL | 1.1% | 1.2% | |
| ControlUrine 2 | $10.8$ mg/dL | 0.9% | Humanurine 3 | $20.8$ mg/dL | 0.9% | 1.1% | |
| Mean | CVIntermediateprecision | Humanurine 4 | $24.4$ mg/dL | 1.3% | 1.3% | ||
| Humanurine | $14.0$ mg/dL | 1.4% | ControlLevel 1 | $7.4$ mg/dL | 1.3% | 1.5% | |
| ControlUrine 1 | $6.04$ mg/dL | 1.6% | ControlLevel 2 | $10.9$ mg/dL | 1.1% | 1.3% | |
| ControlUrine 2 | $10.7$ mg/dL | 1.4% | |||||
| Serum/plasma:8.6-10.2 mg/dL | Reference range acc. To TietzSerum/plasma: | ||||||
| 24 Hour Urine:100-321 mg/24 h, corresponding to6.8-21.3 mg/dL | Children (0-10 days): 7.6-10.4 mg/dL | ||||||
| Reference range acc. To TietzSerum/plasma: | Children (10 days -2 years): 9.0-11.0 mg/dL | ||||||
| ExpectedValues | Children (0-10 days): 7.6-10.4 mg/dL | Children (2 years-12 years): 8.8-10.8 mg/dL | |||||
| Children (10 days -2 years): 9.0-11.0 mg/dL | Children (12-18 years): 8.4-10.2 mg/dL | ||||||
| Children (2 years-12 years): 8.8-10.8 mg/dL | Adults (18-60 years): 8.6-10.0 mg/dL | ||||||
| Children (12-18 years): 8.4-10.2 mg/dLAdults (18-60 years): 8.6-10.0 mg/dL | Adults (60-90 years): 8.8-10.2 mg/dLAdults (>90 years): 8.2-9.6 mg/dL | ||||||
| Adults (60-90 years): 8.8-10.2 mg/dLAdults (>90 years): 8.2-9.6 mg/dL | Urine100-300 mg/24 h with normalfood intake | ||||||
| Urine100-300 mg/24 h with normal foodintake |
Substantial equivalence (continued)
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510(k) Summary - Calcium Generation 2 Assay, continued
Substantial equivalence (continued)
| Feature | Predicate Device:Calcium (K921661) | Draft Device:Calcium Gen. 2 |
|---|---|---|
| Interferences | Serum/PlasmaIcterus:no significant interference up to an Iindex of 60Hemolysis:no significant interference up to andH index of 1000Lipemia:no significant interference up to an Lindex of 1000Drugs:Drugs containing strontium saltsmay lead to significantly increasedcalcium results.Other:-Intravenously administered contrastmedia for MRI contain chelatingcomplexes which may interfere withthe determination of calcium.-A sharp decrease in calcium valueswas observed when gadodiamidewas administered. Follow theinstructions of the manufacturer withregard to the retention time of thecontrast medium.-In very rare cases gammopathy, inparticular type IgM (Waldenstrom'smacroglulinemia), may causeunreliable results.Urine:Drugs: Drugs containing strontiumsalts may lead to significantlyincreased calcium results. | Serum/PlasmaSame Endogenous InterferentClaimsAnd in Addition:-The interference of intravenouslyadministered gadolinium containingMRI (magnetic resonance imaging)contrast media was tested (Omniscan®,Optimark®) but no interference wasfound at the therapeutic concentration.Interference at higher concentrations wasobserved.-In very rare cases gammopathy, inparticular type IgM (Waldenstrom'smacroglulinemia), may cause unreliableresults.Urine:Icterus:no significant interference up to aconjugated bilirubin concentration of60 mg/dLHemolysis:no significant interference up to ahemoglobin concentration of 1000mg/dLMagnesium:no significant interference up to aconcentration of 60 mmol/LDrugs:No interference was found attherapeutic concentrations usingcommon drug panels.Other:-The interference of intravenouslyadministered gadolinium containingMRI (magnetic resonance imaging)contrast media was tested (Omniscan®,Optimark®). For Omniscan® nointerference was observed at thetherapeutic concentration, but there wasinterference at higher concentrations.For Optimark® interference wasobserved at therapeutic and higherconcentrations. |
End of Summary
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DEPARTMENT OF HEALTH & HUMAN SERVICES
Image /page/5/Picture/1 description: The image shows the logo for the U.S. Department of Health & Human Services. The logo consists of a circular seal with the text "DEPARTMENT OF HEALTH & HUMAN SERVICES - USA" arranged around the perimeter. Inside the circle is a stylized image of an eagle or bird-like figure, with flowing lines representing its wings or feathers.
Food and Drug Administration
10903 New Hampshire Avenue Silver Spring, MD 20993
Roche Diagnostics Operations, Inc. c/o Lisa Klinedinst 9115 Hague Road · P. O. Box 50416 Indianapolis, IN 46250
MAY - 8 2002
Re: K113521 Trade Name: Calcium Gen.2 Regulation Number: 21 CFR §862.1145 Regulation Name: Calcium Test System Regulatory Class: Class II Product Codes: CHW Dated: March 30, 2012 Received: April 2, 2012
Dear Ms. Klinedinst:
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 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); and good manufacturing practice requirements as set forth in the quality systems (QS) regulation (21 CFR Part 820).
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If you desire specific advice for your device on our labeling regulation (21 CFR Part 801), please contact the Office of In Vitro Diagnostic Device Evaluation and Safety at (301) 796-5450. Also, please note the regulation entitled, "Misbranding by reference to premarket notification" (21 CFR Part 807.97). For questions regarding postmarket surveillance, please contact CDRH's Office of Surveillance and Biometric's (OSB's) Division of Postmarket Surveillance at (301) 796-5760. For questions regarding the reporting of adverse events under the MDR regulation (21 CFR Part 803), please go to http://www.fda.gov/Medical
Devices/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 Small Manufacturers, International and Consumer Assistance at its toll-free number (800) 638-2041 or (301) 796-5680 or at its Internet address http://www.fda.gov/MedicalDevices/ResourcesforYou/Industry/default.htm
Sincerely yours,
signature
Counney H. Lias, Ph.D. Director Division of Chemistry and Toxicology Devices Office of In Vitro Diagnostic Device Evaluation and Safety Center for Devices and Radiological Health
Enclosure
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k 11352 510(k) Number (if known):
Device Name: Roche/Hitachi cobas c Calcium Gen.2
Indications For Use:
The Calcium Gen.2 assay is an in vitro diagnostics reagent system intended for the quantitative determination of calcium in human serum, plasma, and urine on Roche/Hitachi cobas c systems. Calcium measurements are used in the diagnosis and treatment of parathyroid disease, a variety of bone diseases, chronic renal disease, and tetany.
Prescription Use (Part 21 CFR 801 Subpart D) AND/OR
Over-The-Counter Use (21 CFR 801 Subpart C)
(PLEASE DO NOT WRITE BELOW THIS LINE-CONTINUE ON ANOTHER PAGE IF NEEDED)
Concurrence of CDRH, Office of In Vitro Diagnostic Devices (OIVD)
Ruta Clim
Division Sign-Off Office of In Vitro Diagnostic Device Evaluation and Safety
510(k) K113521
Page 1 of
§ 862.1145 Calcium test system.
(a)
Identification. A calcium test system is a device intended to measure the total calcium level in serum. Calcium measurements are used in the diagnosis and treatment of parathyroid disease, a variety of bone diseases, chronic renal disease and tetany (intermittent muscular contractions or spasms).(b)
Classification. Class II.