(486 days)
For in vitro diagnostic use only. Rx Only.
VITROS Chemistry Products hsCRP Reagent is used on the VITROS 5,1 FS Chemistry System, the VITROS 4600 Chemistry System and the VITROS 5600 Integrated System to quantitatively measure C-reactive protein (CRP) in human serum and plasma. CRP is used to evaluate conditions thought to be associated with inflammation in otherwise healthy individuals.
The quantitative measurement of C-reactive protein (CRP) is performed using the VITROS Chemistry Products hsCRP Reagent in conjunction with the VITROS Chemistry Products Calibrator Kit 17 and VITROS Chemistry Products FS Calibrator 1 on the VITROS 5,1 FS/4600 Chemistry System and the VITROS 5600 Integrated System. The VITROS Chemistry Products hsCRP Reagent is a dual chambered package containing ready-to-use liquid reagents. Samples, calibrators and controls are mixed with Reagent 1 containing a buffer. Addition of anti-CRP antibodies coupled to latex microparticles (Reagent 2) produces an immunochemical reaction yielding CRP antigen/antibody complexes. The turbidity is measured spectrophotometrically at 660 nm. Once a calibration has been performed for each reagent lot, the CRP concentration in each unknown sample can be determined using the stored calibration curve and the measured absorbance obtained in the assay of the sample.
The provided document describes the K160712 510(k) submission for the VITROS Chemistry Products hsCRP Reagent. This is an in vitro diagnostic (IVD) device, not an AI/ML medical device. Therefore, the information regarding acceptance criteria and study design (especially related to human readers, ground truth establishment, and test set/training set specifics) is described through the lens of an IVD device, focusing on analytical performance rather than diagnostic accuracy based on images or clinical data interpreted by AI.
Here's a breakdown of the information provided, tailored to the context of an IVD device:
1. Table of Acceptance Criteria and Reported Device Performance
| Performance Characteristic | Acceptance Criteria (Implied/Standard for IVDs) | Reported Device Performance |
|---|---|---|
| Method Comparison | Acceptable correlation with predicate method. | VITROS 5600 vs. Diazyme hsCRP Method: VITROS 5600 = 1.02 x Diazyme hsCRP Method + 0.26VITROS 4600 vs. VITROS 5600: VITROS 4600 = 1.02 x VITROS 5600 System + 0.01VITROS 5.1 FS vs. VITROS 5600: VITROS 5,1 FS System = 1.07 x VITROS 5600 System + 0.11Demonstrates acceptable correlation. |
| Precision | Acceptable %CV and SD at various concentrations. | See "Table 1: Precision study" on page 6.Total %CV ranges from 1.23% to 6.96% across different analyzers, reagent lots, and concentrations. SD is also provided for within-run, between-run, and total precision. |
| Assay Range | Clearly defined and clinically relevant range. | 0.34 to 15.00 mg/L |
| Linearity | Linear response across the measuring range. | Linearity found to extend across the measuring range of 0.34 to 15 mg/L. |
| Limits of Blank (LoB) | Specified limit for blank samples. | 0.21 mg/L |
| Limits of Detection (LoD) | Specified limit for detecting analyte. | 0.26 mg/L |
| Limits of Quantitation (LoQ) | Specified limit for reliable quantitation. | 0.34 mg/L |
| Reference Interval | Verified range for healthy individuals. | < 5.0 mg/L (verified with 50% male and 50% female population). |
2. Sample Size Used for the Test Set and Data Provenance
- Method Comparison Test Set Sample Size: 119 human serum samples were tested. Of these, 113 were within the measuring range of both the VITROS hsCRP assay and the predicate Diazyme hsCRP assay.
- Data Provenance: The document does not explicitly state the country of origin. It refers to "human serum samples" and "human serum sample pools." Given the FDA submission, it is likely the data was generated in the US or at sites compliant with US regulatory standards. The study was retrospective in nature as it involved testing collected samples.
- Precision Study Sample Size: Three human serum sample pools were used, tested in five replicates, once per day for five days.
3. Number of Experts Used to Establish the Ground Truth for the Test Set and Qualifications of Those Experts
For this IVD device, the "ground truth" for the test set is established by the results from the predicate device (Diazyme hsCRP assay on Hitachi 917 Systems) for method comparison, and by traceability to internationally recognized reference materials (ERM®-DA474/IFCC, ERM®-DA472/IFCC) for analytical performance characteristics.
There are no "experts" in the traditional sense (e.g., radiologists interpreting images) involved in establishing ground truth for analytical performance of an IVD reagent in this context. The truth is defined by the established analytical methods and reference standards.
4. Adjudication Method for the Test Set
Not applicable in the context of an IVD analytical performance study. Adjudication methods like "2+1" or "3+1" are typically used for establishing ground truth in image-based diagnostic studies where human interpretation is the primary source of truth or where disagreement among experts needs resolution.
5. If a Multi-Reader Multi-Case (MRMC) Comparative Effectiveness Study was done, and its effect size
Not applicable. This is an analytical performance study for an in vitro diagnostic reagent, not a cognitive AI/ML device assisting human readers with clinical decision-making. No human readers are involved in the "interpretation" of the analytical results in a comparative effectiveness study design typically seen for AI devices.
6. If a Standalone (i.e. algorithm only without human-in-the loop performance) was done
The entire performance study for this IVD device is "standalone" in the sense that it evaluates the performance of the reagent and instrument system itself, independent of human interpretive bias. The measurements are quantitative chemical analyses performed by automated systems.
7. The Type of Ground Truth Used
- Method Comparison: Ground truth for comparison was the measurement result from the legally marketed predicate device (Diazyme hsCRP assay).
- Precision, Linearity, Detection Limits: Ground truth is linked to international reference materials (ERM®-DA474/IFCC, ERM®-DA472/IFCC) and established analytical chemistry principles and CLSI guidelines which dictate how these performance characteristics are defined and measured. The concept here is analytical accuracy and precision against known values or standards, rather than a diagnostic 'truth' about a patient's condition.
- Reference Range: Established against a healthy population, consistent with CLSI EP28-A3 guidelines.
8. The Sample Size for the Training Set
Not applicable. This document describes the validation of an IVD reagent, not an AI/ML algorithm that requires a "training set." The reagent and instrument system are developed and optimized through standard chemical and engineering processes, not through machine learning on a data set.
9. How the Ground Truth for the Training Set was Established
Not applicable, as there is no "training set" in the context of this IVD reagent's development as described in the document.
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Food and Drug Administration 10903 New Hampshire Avenue Document Control Center - WO66-G609 Silver Spring, MD 20993-0002 July 14, 2017
ORTHO-CLINICAL DIAGNOSTICS, INC. MARLENE HANNA, SENIOR MANAGER, REGULATORY AFFAIRS 100 INDIGO CREEK DRIVE ROCHESTER, NY 14626
Re: K160712
Trade/Device Name: VITROS Chemistry Products hsCRP Reagent Regulation Number: 21 CFR 866.5270 Regulation Name: C-reactive protein immunological test system Regulatory Class: II Product Code: DCK Dated: June 9, 2017 Received: June 12, 2017
Dear Marlene Hanna:
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 regulation (21 CFR Part 801), 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" (21CFR 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,
Kellie B. Kelm -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)
K160712
Device Name VITROS Chemistry Products hsCRP Reagent
Indications for Use (Describe)
VITROS Chemistry Products hsCRP Reagent:
For in vitro diagnostic use only. Rx Only.
VITROS Chemistry Products hsCRP Reagent is used on the VITROS 5,1 FS Chemistry System, the VITROS 4600 Chemistry System and the VITROS 5600 Integrated System to quantitatively measure C-reactive protein (CRP) in human serum and plasma. CRP is used to evaluate conditions thought to be associated with inflammation in otherwise healthy individuals.
X Prescription Use (Part 21 CFR 801 Subpart D)
| Over-The-Counter Use (21 CFR 801 Subpart C)
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510(k) Summary: K160712
| VITROS Chemistry Products hsCRP Reagent: A summary of 510(k) safety and effectiveness |
|---|
| information in accordance with the requirements of 21 CFR 807.92. |
| Submitter Information | |
|---|---|
| Name | Ortho-Clinical Diagnostics, Inc. |
| Address | 100 Indigo Creek DriveRochester, New York 14626 |
| Phone number | 585-453-4041 |
| Fax number | 585-453-3368 |
| EstablishmentRegistration | 1319681 |
| Name of contact person | Marlene Hanna |
| Date prepared | July 13, 2017 |
| Trade or proprietaryname | VITROS Chemistry Products hsCRP Reagent |
| Common or usual name | C-reactive protein immunological test system |
| Classification name | Cardiac c-reactive protein, antigen, antiserum |
| Classification panel | Immunology |
| Regulation | 21 CFR 866.5270: C-Reactive Protein immunological test systemClassification: Class II |
| Product Code(s) | DCK |
| Legally marketeddevice(s) to whichequivalence is claimed | The Diazyme high sensitivity C-reactive protein (hsCRP) assay(K103557) |
| Device description | The quantitative measurement of C-reactive protein (CRP) isperformed using the VITROS Chemistry Products hsCRP Reagent inconjunction with the VITROS Chemistry Products Calibrator Kit 17and VITROS Chemistry Products FS Calibrator 1 on the VITROS 5,1FS/4600 Chemistry System and the VITROS 5600 IntegratedSystem. The VITROS Chemistry Products hsCRP Reagent is a dualchambered package containing ready-to-use liquid reagents. Samples,calibrators and controls are mixed with Reagent 1 containing abuffer. Addition of anti-CRP antibodies coupled to latexmicroparticles (Reagent 2) produces an immunochemical reactionyielding CRP antigen/antibody complexes. The turbidity is measuredspectrophotometrically at 660 nm. Once a calibration has beenperformed for each reagent lot, the CRP concentration in eachunknown sample can be determined using the stored calibration curveand the measured absorbance obtained in the assay of the sample. |
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| Intended Use | VITROS hsCRP Reagent: |
|---|---|
| For in vitro diagnostic use only. Rx ONLY. | |
| VITROS Chemistry Products hsCRP Reagent is used on theVITROS 5,1 FS Chemistry System, the VITROS 4600Chemistry System and the VITROS 5600 Integrated System toquantitatively measure C-reactive protein (CRP) in human serum andplasma. CRP is used to evaluate conditions thought to be associatedwith inflammation in otherwise healthy individuals. |
Comparison with Predicate Devices:
Table 1: VITROS Chemistry Products hsCRP Reagent
| Characteristic | Predicate (Diazyme high sensitivityC-Reactive Protein: K103557) | New Device (VITROS hsCRPReagent (Modified)) |
|---|---|---|
| Intended Use | For in vitro diagnostic use only. RxONLY.The Diazyme high sensitivity C-reactive protein (hsCRP) assay is forthe in vitro quantitative determinationof C-reactive protein (CRP) in humanserum and plasma on automatedclinical chemistry analyzers.Measurement of CRP is of use for thedetection and evaluation ofinflammatory disorders andassociated diseases, infection andtissue injury. | For in vitro diagnostic use only. RxONLY.VITROS Chemistry Products hsCRPReagent is usedto quantitatively measure C-reactiveprotein (CRP) in human serum andplasma. CRP is used to evaluateconditions thought to be associated withinflammation in otherwise healthyindividuals. |
| Basic Principle | Latex enhanced immunoturbidimetricassay | Two-point rate, 2mmune-turbidimetricassay |
| Sample type | Serum, plasma | Serum, plasma |
| Assay Range Serum,Plasma | 0.20 to 20.0 mg/L | 0.34 to 15.00 mg/L |
Performance Summary:
Substantial Equivalence was demonstrated by testing several performance characteristics including method comparison, precision, reference interval, linearity and detection limit.
Method Comparison:
Method Comparison testing followed CLSI Protocol EP09-A3, Measurement Procedure Comparison and Bias Estimation Using Patient Samples. Approved Guideline - Third Edition. A total of 119 human serum samples were tested. The 119 samples were measured with VITROS hsCRP assay on the VITROS 5600, 4600, and 5,1 Systems and a predicate method, Diazyme
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hsCRP assay on the Hitachi 917 Systems. Of the 119 samples tested 113 were within the measuring range of both the VITROS hsCRP assay (0.34-15.0 mg/L) and the Diazyme hsCRP assay (0.20 - 20.0 mg/L).
The relationship between the VITROS hsCRP method and the Predicate method (Diazyme hsCRP) based on data from 113 samples on the VITROS 5600 Chemistry System is as follows:
VITROS 5600 Integrated System = 1.02 x Diazyme hsCRP Method + 0.26
The relationship between the VITROS hsCRP method on the VITROS 4600 System and the VITROS 5600 System based on data from 110 samples is as follows;
VITROS 4600 Integrated System = 1.02 x VITROS 5600 System + 0.01
The relationship between the VITROS hsCRP method on the VITROS 5.1 FS System and the VITROS 5600 System based on data from 109 samples is as follows;
VITROS 5,1 FS System = 1.07 x VITROS 5600 System + 0.11
The data demonstrates acceptable correlation was obtained between the VITROS hsCRP assay (traceable to European Reference Material ERM®-DA474/IFCC) versus the predicate method (traceable to European Reference Material ERM®-DA472/IFCC) and between VITROS Systems.
Precision:
The method was based upon the Clinical and Laboratory Standards Institute (CLSI) Protocol EP05-A3, Evaluation of Precision of Ouantitative Measurement Procedures; Approved Guideline-Third Edition, October 2014. Five replicates of three human serum sample pools were run once per day for five days using two hsCRP Reagent lots and two Calibrator Kit 17 lots across three VITROS Chemistry Systems.
Testing was conducted using VITROS Chemistry Products hsCRP Reagent calibrated with VITROS Chemistry Products Calibrator Kit 17 and VITROS Chemistry Products FS Calibrator 1 traceable to ERM-DA474. Precision study results for the VITROS hsCRP assay are listed in table 1.
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Table 1: Precision study
| ReagentMean | Within-run | Between-run | Total | |||||
|---|---|---|---|---|---|---|---|---|
| Analyzer | Lot | Conc. | SD | %CV | SD | %CV | SD | %CV |
| 5,1 FSPM675 | 35-5544 | 0.96 | 0.067 | 6.96 | 0.000 | 0.00 | 0.067 | 6.96 |
| 9.65 | 0.104 | 1.08 | 0.080 | 0.83 | 0.132 | 1.37 | ||
| 13.41 | 0.156 | 1.16 | 0.081 | 0.60 | 0.176 | 1.31 | ||
| 36-5726 | 1.02 | 0.060 | 5.90 | 0.024 | 2.36 | 0.065 | 6.39 | |
| 9.89 | 0.151 | 1.53 | 0.124 | 1.25 | 0.196 | 1.98 | ||
| 13.86 | 0.266 | 1.92 | 0.134 | 0.97 | 0.298 | 2.15 | ||
| 4600PM102 | 35-5544 | 0.97 | 0.063 | 6.53 | 0.000 | 0.00 | 0.063 | 6.53 |
| 9.52 | 0.188 | 1.97 | 0.000 | 0.00 | 0.188 | 1.97 | ||
| 13.12 | 0.269 | 2.05 | 0.067 | 0.51 | 0.277 | 2.11 | ||
| 36-5726 | 1.01 | 0.047 | 4.66 | 0.021 | 2.08 | 0.052 | 5.16 | |
| 9.79 | 0.253 | 2.58 | 0.144 | 1.47 | 0.291 | 2.97 | ||
| 13.64 | 0.400 | 2.93 | 0.078 | 0.57 | 0.408 | 2.99 | ||
| 5600PM109 | 35-5544 | 0.92 | 0.053 | 5.77 | 0.000 | 0.00 | 0.053 | 5.77 |
| 9.34 | 0.081 | 0.87 | 0.081 | 0.87 | 0.115 | 1.23 | ||
| 12.78 | 0.126 | 0.99 | 0.110 | 0.86 | 0.167 | 1.31 | ||
| 36-5726 | 1.00 | 0.054 | 5.40 | 0.000 | 0.00 | 0.054 | 5.40 | |
| 9.54 | 0.113 | 1.18 | 0.121 | 1.27 | 0.165 | 1.73 | ||
| 13.26 | 0.278 | 2.10 | 0.148 | 1.12 | 0.315 | 2.38 |
Expected values/Reference range:
The reference interval was verified according to CLSI EP28-A3 Defining, Establishing, and Verifying Reference Intervals in the Clinical Laboratory; Approved Guideline – Third Edition; a 50% male and 50% female population was utilized. Reference intervals may differ for each population studied and therefore each laboratory should confirm the validity of these intervals for the population it serves. Increases in CRP values are non-specific and should be interpreted together with a complete clinical history. Follow-up testing of patients with elevated CRP values should be performed.
| Conventional and SI Units (mg/L) |
|---|
| $<5.0$ |
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Linearity:
Linearity was determined following CLSI EP6-A: Evaluation of the Linearity of Quantitative Measurement Procedures: a Statistical Approved Guideline. A high CRP serum pool was intermixed with a low serum pool to generate 13 concentration levels each tested in three replicate determinations. Linear results were compared to 2m and 3w order polynomial fits against a pre-specified allowable error. The linearity range was found to extend across the measuring range of 0.34 to 15 mg/L.
Limits of blank, detection, and quantitation:
The Limit of Blank (LoB) for VITROS Chemistry Products hsCRP Reagent is 0.21 mg/L. The Limit of Detection (LOD) is 0.26 mg/L. The Limit of Quantitation (LOQ) is 0.34 mg/L. All results were determined according to the guidelines listed in CLSI EP17-A2 and the guidance for Industry and FDA Staff Review Criteria for Assessment of High Sensitivity C-Reactive Protein (hsCRP) issued September 22, 2005.
| LoB* | LoD** | LoQ*** |
|---|---|---|
| 0.21 mg/L | 0.26 mg/L | 0.34 mg/L |
- Limit of Blank: The highest result to be reported for a blank sample with a 95% level of confidence (o. = 0.05).
** Limit of Detection: The amount of analyte where 95% of measurement results (ß = 0.05) exceed the Limit of Blank.
*** Limit of Quantitation: The minimum amount of analyte that can be quantitatively determined based on acceptable precision.
Conclusion:
The conclusions drawn from the nonclinical tests (discussed above) demonstrate the modified VITROS Chemistry Products hsCRP Reagent is as safe, effective, and perform as well as the predicate device. The information submitted in the premarket notification is complete and supports a substantial equivalence decision.
§ 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).