(90 days)
For Sysmex® CS-2100i:
The Sysmex CS-2100i is a fully automated blood coagulation analyzer intended for in vitro diagnostic use using plasma collected from venous blood samples in 3.2% sodium citrate tubes to analyze clotting, chromogenic and immunoassay methods in the clinical laboratory.
For determination of:
- Prothrombin Time (PT) seconds and PT INR with Dade® Innovin® .
- . Activated Partial Thromboplastin Time (APTT) with Dade® Actin® FSL
- . Fibrinogen (Fbg) with Dade® Thrombin Reagent
- . Coagulation Factor V with Dade® Innovin®
- . Coagulation Factor VII with Dade® Innovin®
- . Protein C with Protein C Reagent
- . Antithrombin (AT) with INNOVANCE® Antithrombin
- Protein C with Berichrom® Protein C
- D-dimer with INNOVANCE® D-Dimer
The performance of this device has not been established in neonate and pediatric patient populations.
For Coagulation Factor V Deficient Plasma:
In vitro diagnostic reagent for the determination of the activity of coagulation factor V in human plasma.
For Coagulation Factor VII Deficient Plasma:
In vitro diagnostic reagents for the determination of the activity of coagulation factor II (prothrombin), coagulation factor VII and coagulation factor X in human plasma by coagulometric methods.
For Protein C Reagent:
Protein C Reagent is a coagulation test for the quantitative determination of protein C activity in human plasma.
For Berichrom® Protein C:
For the quantitative determination of functionally active protein C using a chromogenic substrate as an aid in the diagnosis of inherited and acquired deficiencies.
The Sysmex® CS-2100i is an automated blood coagulation instrument which can analyze samples using clotting, chromogenic and immunoassay methods. Analysis results are displayed on the Information Processing Unit (IPU) screen. They can be printed on external printers or transmitted to a host computer. Sold separately from the instrument are the associated Reagents, Controls, Calibrators, and Consumable materials. The subject of this 510(k) notification are reagent applications which perform the coagulation tests Coagulation Factor V with Dade® Innovin®, Coagulation Factor VII with Dade® Innovin®, Protein C with Protein C Reagent and Protein C with Berichrom® Protein C.
The document describes the performance data for the Sysmex® CS-2100i Automated Blood Coagulation Analyzer and its associated reagents for several coagulation factors and proteins. The study aims to demonstrate substantial equivalence to a predicate device, the Sysmex® CA-1500.
Here's the breakdown of the acceptance criteria and study information:
1. A table of acceptance criteria and the reported device performance
The document does not explicitly state numerical acceptance criteria for all performance metrics (e.g., a specific threshold for %CV for reproducibility). However, it repeatedly states that "Results from each application met the predetermined acceptance criteria" and "Data for all tested reagents met the predetermined acceptance criteria."
Based on the provided tables and text, the implicit acceptance criteria relate to:
- Method Comparison: Strong correlation (high 'r' value) and a slope and intercept close to 1 and 0, respectively, indicating comparable results to the predicate device.
- Reproducibility: Within-run, between-run, between-day, and total %CVs within acceptable ranges for clinical laboratory assays, demonstrating precision.
- Detection Capability (Limit of Quantitation): Measured Limit of Quantitation being at or below the claimed Lower Limit of Clinically Reportable Range, with acceptable maximum total error.
- Linearity/Measuring Range: Measured linear range encompassing or exceeding the claimed clinically reportable range.
- Reference Interval: Establishment of reference intervals from a healthy population.
Below is a table summarizing the reported device performance for several key metrics:
| Application | Performance Metric | Predetermined Acceptance Criteria (Implicit) | Reported Device Performance |
|---|---|---|---|
| Method Comparison (vs. Sysmex® CA-1500) | |||
| Factor V with Dade® Innovin® | r (correlation coefficient) | High (e.g., >0.95 or similar to predicate) | 0.983 |
| Slope (95% CI) | Close to 1 (e.g., 0.9-1.1 range) | 0.990 (0.977, 1.003) | |
| Intercept (95% CI) | Close to 0 (e.g., -5 to 5 range) | 1.861 (1.025, 2.784) | |
| Factor VII with Dade® Innovin® | r (correlation coefficient) | High | 0.991 |
| Slope (95% CI) | Close to 1 | 1.039 (1.028, 1.051) | |
| Intercept (95% CI) | Close to 0 | 0.636 (-0.135, 1.104) | |
| Protein C with Protein C Reagent | r (correlation coefficient) | High | 0.977 |
| Slope (95% CI) | Close to 1 | 0.966 (0.952, 0.981) | |
| Intercept (95% CI) | Close to 0 | -0.372 (-1.207, 0.470) | |
| Protein C with Berichrom® Protein C | r (correlation coefficient) | High | 0.994 |
| Slope (95% CI) | Close to 1 | 0.942 (0.934, 0.951) | |
| Intercept (95% CI) | Close to 0 | -0.292 (-1.037, 0.399) | |
| Reproducibility (20-day precision study) | Ranges of %CV reported across sites and combined | ||
| Factor V with Dade® Innovin® | Within Run (%CV) | Demonstrated clinical acceptability | 3.16 - 5.01 |
| Between Run (%CV) | Demonstrated clinical acceptability | 1.76 - 2.55 | |
| Between Day (%CV) | Demonstrated clinical acceptability | 0.00 - 1.64 | |
| Total CV Sites Combined (%CV) | Demonstrated clinical acceptability | 4.78 - 10.43 | |
| Factor VII with Dade® Innovin® | Total CV Sites Combined (%CV) | Demonstrated clinical acceptability | 2.57 - 3.59 |
| Protein C with Protein C Reagent | Total CV Sites Combined (%CV) | Demonstrated clinical acceptability | 3.47 - 5.85 |
| Protein C with Berichrom® Protein C | Total CV Sites Combined (%CV) | Demonstrated clinical acceptability | 2.19 - 5.69 |
| Detection Capability (Limit of Quantitation) | |||
| Factor V with Dade® Innovin® | Measured LoQ (% of norm) | ≤ Lower Clinically Reportable Range | 4.80 (Lower RR: 6.0) |
| Maximum Total Error (% of norm) | Clinically acceptable | 2.04 | |
| Factor VII with Dade® Innovin® | Measured LoQ (% of norm) | ≤ Lower Clinically Reportable Range | 3.39 (Lower RR: 6.0) |
| Maximum Total Error (% of norm) | Clinically acceptable | 0.21 | |
| Protein C with Protein C Reagent | Measured LoQ (% of norm) | ≤ Lower Clinically Reportable Range | 9.35 (Lower RR: 10.1) |
| Maximum Total Error (% of norm) | Clinically acceptable | 3.62 | |
| Protein C with Berichrom® Protein C | Measured LoQ (% of norm) | ≤ Lower Clinically Reportable Range | 8.32 (Lower RR: 10.0) |
| Maximum Total Error (% of norm) | Clinically acceptable | 2.07 | |
| Linearity & Measuring Range | Measured Linear Range | Must cover or exceed Clinically Reportable Range | Factor V: 3.4 – 180.7% (Clinical: 6.0 – 149.0%); Factor VII: 4.3 – 179.5% (Clinical: 6.0 – 149.0%); Protein C (Reagent): 7.0 – 187.7% (Clinical: 10.1 – 131.0%); Protein C (Berichrom): 7.1 – 181.3% (Clinical: 10.0 – 138.0%) |
| Reference Interval | Established Reference Interval | Determined from a healthy population in line with CLSI guidelines | Factor V: 79.8%; Factor VII: 65.6%; Protein C (Reagent): 75.6%; Protein C (Berichrom): 84.9% (all 5th Percentile) |
2. Sample sizes used for the test set and the data provenance (e.g. country of origin of the data, retrospective or prospective)
- Method Comparison:
- Sample Sizes: N = 589 for Factor V, N = 492 for Factor VII, N = 584 for Protein C Reagent, N = 507 for Berichrom® Protein C. These are patient samples.
- Data Provenance: Conducted at four external sites in the United States. This suggests prospective collection for the study, as samples were "measured on both the predicate device... as well as the new device... in random order."
- Reproducibility Studies:
- Sample Sizes: Not explicitly stated as a count of unique patient samples, but the study involved "two runs per day, with two replicates per run" over "Twenty-day precision studies." These likely used control materials and potentially some patient-derived pools to cover the measuring interval.
- Data Provenance: Conducted at two external sites in Germany and one external site in the United States. Prospective.
- Detection Capability (Limit of Quantitation) & Linearity:
- Sample Sizes: Not explicitly detailed, but these studies typically involve dilutional series of control or spiked samples.
- Data Provenance: Not specified, but likely conducted by the manufacturer or at external sites involved in the broader study.
- Reference Interval:
- Sample Sizes: N = 193 for Factor V, Factor VII, and Protein C Reagent; N = 191 for Berichrom® Protein C. These are samples from "healthy subjects" to establish reference intervals.
- Data Provenance: Conducted at three clinical study sites in the United States. The study population "did not include neonate and pediatric sample populations." This is prospective.
3. Number of experts used to establish the ground truth for the test set and the qualifications of those experts (e.g. radiologist with 10 years of experience)
This device is an in vitro diagnostic (IVD) instrument for blood coagulation studies. The "ground truth" in this context refers to the accuracy and precision of the measurements relative to established analytical methods or reference values, rather than consensus interpretation by human experts.
- The study used a predicate device (Sysmex® CA-1500) as the comparator for method comparison, which is considered a legally marketed and presumably accurate device for the same intended use.
- Ground truth for things like reference intervals would be established by measuring samples from a statistically relevant population of healthy individuals and determining the distribution of results, following CLSI guidelines (EP28-A3c).
- Ground truth for linearity and detection capability would be established using validated methods, often involving known dilutions or spiked samples.
Therefore, the concept of "number of experts" and "qualifications of experts" for establishing ground truth is not directly applicable in the same way as for medical image analysis where human interpretation is the ground truth standard. The accuracy of the device is assessed by its analytical performance against recognized standards and methods, not subjective expert consensus.
4. Adjudication method (e.g. 2+1, 3+1, none) for the test set
Not applicable for an in vitro diagnostic device study assessing analytical performance. Adjudication methods are typically used in studies where human interpretation or classification is involved, such as in clinical trials or image analysis, to resolve discrepancies between readers. Here, the comparison is quantitative instrument-to-instrument.
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 IVD device, not an AI-assisted diagnostic tool that involves human readers. The study focuses on comparing the analytical performance of the new instrument against a predicate instrument.
6. If a standalone (i.e. algorithm only without human-in-the-loop performance) was done
This study is inherently a standalone performance evaluation of the Sysmex® CS-2100i instrument when used with its associated reagents. The instrument is an automated analyzer producing quantitative results. The comparison is against another automated instrument (the predicate), not against unassisted human performance or an "AI assistance" scenario.
7. The type of ground truth used (expert consensus, pathology, outcomes data, etc)
The ground truth for this device's performance evaluation is based on:
- Established analytical methods and predicate device measurements: For method comparison, the results from the predicate device (Sysmex® CA-1500), which is a legally marketed device for the same purpose, serve as the comparative standard.
- CLSI (Clinical and Laboratory Standards Institute) guidelines: These provide the statistical and methodological framework for evaluating analytical performance parameters like precision, linearity, and detection capability.
- Measurements from healthy donor populations: For establishing reference intervals.
8. The sample size for the training set
The document does not explicitly describe a "training set" in the context of machine learning or AI. This is an IVD device, and its development would involve internal validation and optimization by the manufacturer, but the submitted performance data represents the final validated product. The studies described are for performance validation and comparison, not for training a model.
9. How the ground truth for the training set was established
As there is no "training set" discussed in the context of an AI/ML model for this IVD device, this question is not applicable. The device's operational parameters and algorithms for measurement are established through engineering design, chemical/biological principles, and internal development/validation processes, adhering to industry standards and regulatory requirements.
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Image /page/0/Picture/1 description: The image shows the seal of the Department of Health & Human Services - USA. The seal is circular, with the text "DEPARTMENT OF HEALTH & HUMAN SERVICES - USA" arranged around the perimeter. In the center of the seal is a stylized image of a caduceus, a symbol often associated with healthcare. The caduceus is composed of three intertwined snakes and a staff.
Food and Drug Administration 10903 New Hampshire Avenue Document Control Center - WO66-G609 Silver Spring, MD 20993-0002
December 26, 2016
Siemens Healthcare Diagnostics Products GmbH Ms. Donna Noeh Regulatory Affairs Manager Emil-von-Behring Strasse 76 35041 Marburg, Germany
Re: K162688 Trade/Device Name: Sysmex® CS-2100i Coagulation Factor V Deficient Plasma Coagulation Factor II. VII and X Deficient Plasmas Protein C Reagent Berichrom® Protein C Regulation Number: 21 CFR 864.5425 Regulation Name: Multipurpose system for in vitro coagulation studies Regulatory Class: Class II Product Code: JPA, GGP, GJT Dated: September 26, 2016 Received: September 27, 2016
Dear Ms. Noeh:
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. Isting 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.
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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.
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,
Leonthena R. Carrington -S
Leonthena R. Carrington, MS, MBA, MT(ASCP) Director Division of Immunology and Hematology 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) K162688
Device Name
Sysmex® CS-2100i, Coagulation Factor V Deficient Plasma, Coagulation Factor II, VII, and X Deficient Plasmas, Protein C Reagent, Berichrom® Protein C
Indications for Use (Describe)
For Sysmex® CS-2100i:
The Sysmex CS-2100i is a fully automated blood coagulation analyzer intended for in vitro diagnostic use using plasma collected from venous blood samples in 3.2% sodium citrate tubes to analyze clotting, chromogenic and immunoassay methods in the clinical laboratory.
For determination of:
- Prothrombin Time (PT) seconds and PT INR with Dade® Innovin® .
- . Activated Partial Thromboplastin Time (APTT) with Dade® Actin® FSL
- . Fibrinogen (Fbg) with Dade® Thrombin Reagent
- . Coagulation Factor V with Dade® Innovin®
- . Coagulation Factor VII with Dade® Innovin®
- . Protein C with Protein C Reagent
- . Antithrombin (AT) with INNOVANCE® Antithrombin
- Protein C with Berichrom® Protein C
- D-dimer with INNOVANCE® D-Dimer
The performance of this device has not been established in neonate and pediatric patient populations.
For Coagulation Factor V Deficient Plasma:
Intended Use
In vitro diagnostic reagent for the determination of the activity of coagulation factor V in human plasma.
For Coagulation Factor VII Deficient Plasma:
Intended Use
In vitro diagnostic reagents for the determination of the activity of coagulation factor II (prothrombin), coagulation factor VII and coagulation factor X in human plasma by coagulometric methods.
For Protein C Reagent: Intended Use Protein C Reagent is a coagulation test for the quantitative determination of protein C activity in human plasma.
For Berichrom® Protein C:
Intended Use
For the quantitative determination of functionally active protein C using a chromogenic substrate as an aid in the diagnosis of inherited and acquired deficiencies.
Type of Use (Select one or both, as applicable)
X Prescription Use (Part 21 CFR 801 Subpart D)
Over-The-Counter Use (21 CFR 801 Subpart C)
CONTINUE ON A SEPARATE PAGE IF NEEDED.
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510(k) Summary
This summary of 510(k) safety and effectiveness information is submitted in accordance with the requirements of 21 CFR §807.92 and follows the FDA guidance 'The 510(k) Program: Evaluating Substantial Equivalence in Premarket Notifications [510(k)]', issued July 28, 2014.
Submitter 1
Siemens Healthcare Diagnostics Products GmbH
Emil-von-Behring-Str. 76
35041 Marburg, Germany
| Contact Person: | Donna Noeh |
|---|---|
| Email: | donna.noeh@siemens.com |
| Phone: | + (49) 6421 39 5107 |
| Facsimile: | + (49) 6421 39 4977 |
| Date Prepared: | November 18, 2016 |
2 Device
3
| Name of Device: | Sysmex® Automated Blood Coagulation Analyzer CS-2100 |
|---|---|
| Common or Usual Name: | Sysmex® CS-2100i; CS-2100i |
| Classification Name: | Multipurpose system for in vitro coagulation studies(21 CFR 864.5425) |
| Regulatory Class: | II |
| Product Code: | JPA |
| 510(k) Review Panel | Hematology |
| Predicate Device | |
| Name of Device: | Sysmex® Automated Blood Coagulation Analyzer CA-1500(K011235) |
| Common or Usual Name: | Sysmex® CA-1500 |
| Classification Name: | Multipurpose system for in vitro coagulation studies(21 CFR 864.5425) |
| Regulatory Class: | II |
| Product Code: | JPA |
| 510(k) Review Panel | Hematology |
The predicate has not been subject to a design-related recall for any of the applications associated with this premarket notification. No reference devices were used in this submission.
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| Reagent Name | K number | RegulationNumber | RegulatoryClass | Product Code | Panel |
|---|---|---|---|---|---|
| Factor V withDade®Innovin® | K993299 | 864.7290 | 2 | GJT | Hematology |
| Factor VII withDade®Innovin® | K993299 | 864.7290 | 2 | GJT | Hematology |
| Protein C withProtein CReagent | K000649 | 864.7290 | 2 | GGP | Hematology |
| Protein C withBerichrom®Protein C | K001645 | 864.7290 | 2 | GGP | Hematology |
Reagent Applications that are the subject of this 510(k) notification:
Device Description / Test Principle 4
The Sysmex® CS-2100i is an automated blood coagulation instrument which can analyze samples using clotting, chromogenic and immunoassay methods. Analysis results are displayed on the Information Processing Unit (IPU) screen. They can be printed on external printers or transmitted to a host computer. Sold separately from the instrument are the associated
- Reagents
- Controls
- Calibrators ●
- Consumable materials ●
The subject of this 510(k) notification are reagent applications which perform the coagulation tests Coagulation Factor V with Dade® Innovin®, Coagulation Factor VII with Dade® Innovin®, Protein C with Protein C Reagent and Protein C with Berichrom® Protein C.
The analysis principles used on the instrument are reflected by the reagent application testing provided in this 510(k) notification and is described in the below table.
| Table of Sysmex® CS-2100i Analysis Principles | ||
|---|---|---|
| Reagent | Application | Methodology |
| Dade® Innovin® withCoagulation Factor VDeficient Plasma | Coagulation Factor V withDade® Innovin® | Clotting(extrinsic pathway) |
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| Dade® Innovin® withCoagulation Factor VIIDeficient Plasma | Coagulation Factor VII withDade® Innovin® | Clotting(extrinsic pathway) |
|---|---|---|
| Protein C Reagent | Protein C withProtein C Reagent | Clotting |
| Berichrom® Protein C | Protein C withBerichrom® Protein C | Chromogenic |
The intended Environment of Use is a clinical central/hospital laboratory.
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Instrument (main unit)
Front View of the Sysmex CS-2100i (main unit) Figure 1:
Image /page/7/Figure/3 description: This image is a line drawing of a piece of equipment with multiple labeled parts. The parts are labeled with the numbers 1 through 9. The equipment has a boxy shape with multiple compartments and openings.
(1) Power connector: Connected to the power cable.
- (2) Power Switch: Turns the power ON and OFF.
- (3) Light shield lid: Open this cover to set reagents and perform maintenance.
- (4) Alarm indicator LED: This displays alarms affecting the instrument.
- (5) Cuvette hopper: Holds cuvettes and automatically supplies them to the instrument.
- (6) Start button: This is the same as the Start button on the IPU screen.
(7) Mechanical stop switch: Press this switch to immediately stop the instrument's mechanical movement.
(8) Cuvette trash tray: Used cuvettes are discarded here.
(9) Sampler: The sampler automatically transports samples that are set in the sample rack to the aspiration position.
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Figure 2: Informational Processing Unit (IPU) Sysmex CS-2100i
Image /page/8/Figure/2 description: The image shows a computer setup with four labeled parts. The labels point to the monitor (1), the computer tower (2), the keyboard (3), and the mouse (4). The monitor is placed on top of the computer tower, and the keyboard is in front of the tower. The mouse is located to the right of the keyboard.
- (1) Touch panel display: Displays the IPU screen. It can also be used as a touch panel.
- (2) IPU Main Unit: This is the Main Unit of IPU.
- (3) Keyboard: Used to operate the IPU together with the touch panel.
- (4) Mouse: Used to operate the IPU together with the touch panel.
The instrument is capable of measuring in the following analysis modes:
(1) Normal mode: Samples for all the analyses including re-analyses are taken into the instrument at the same time and analyzed. Automatic re-analysis can also be performed.
(2) Micro-sample mode: The sample volume from samples set in the sampler or STAT holder is taken into the instrument for each analysis through dispensing sample probe and analyzed. This analysis mode can also be performed with less sample volume than normal mode; however, automatic re-analysis cannot be performed.
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5 Intended Use / Indications for Use
The Sysmex® CS-2100i is a fully automated blood coagulation analyzer intended for in vitro diagnostic use using plasma collected from venous blood samples in 3.2% sodium citrate tubes to analyze clotting, chromogenic and immunoassay methods in the clinical laboratory.
For determination of:
- Prothrombin Time (PT) seconds and PT INR with Dade® Innovin®
- Activated Partial Thromboplastin Time (APTT) with Dade® Actin® FSL
- Fibrinogen (Fbg) with Dade® Thrombin Reagent
- Coagulation Factor V with Dade® Innovin® ●
- Coagulation Factor VII with Dade® Innovin®
- Protein C with Protein C Reagent ●
- Antithrombin (AT) with INNOVANCE® Antithrombin ●
- Protein C with Berichrom® Protein C
- D-dimer with INNOVANCE® D-Dimer .
The performance of this device has not been established in neonate and pediatric patient populations.
Coagulation Factor V with Dade® Innovin®
In vitro diagnostic reagent for the determination of the activity of factor V in human plasma.
Coagulation Factor VII with Dade® Innovin® Plasma
In vitro diagnostic reagent for the determination of the activity of coagulation factor VII (prothrombin), coagulation factor VII and coagulation factor X in human plasma by coagulometric methods.
Protein C with Protein C Reagent
Protein C Reagent is a coagulation test for the quantitative determination of protein C activity in human plasma.
Protein C with Berichrom® Protein C
For the quantitative determination of functionally active protein C using a chromogenic substrate as an aid in the diagnosis of inherited and acquired deficiencies.
Comparison of Technological Characteristics with the Predicate Device 6
Both the subject and predicate instruments employ the same technological characteristics in that they automatically analyze various clotting tests using reagents, calibrators and controls previously cleared for automated coagulation analyzers. The reagents perform at least equally well on both the subject and predicate instruments. At a high level, the devices have the following same technological elements:
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| Similarities between CS-2100i and CA-1500 | ||
|---|---|---|
| Analyzer Component | Proposed DeviceSysmex® CS-2100i | Predicate DeviceSysmex® CA-1500 |
| Regulatory Classification | JPA, Class IISystem, Multipurpose for invitro coagulation studies | Same |
| Intended Use Statement | The Sysmex® CS-2100i is a fullyautomated blood coagulationanalyzer intended for in vitrodiagnostic use using plasma collectedfrom venous blood samples in 3.2%sodium citrate tubes to analyzeclotting, chromogenic andimmunoassay methods in the clinicallaboratory.For determination of:• Prothrombin Time (PT) secondsand PT INR with Dade®Innovin®• Activated Partial ThromboplastinTime (APTT) with Dade®Actin® FSL• Fibrinogen (Fbg) with Dade®Thrombin Reagent• Coagulation Factor V withDade® Innovin®• Coagulation Factor VII withDade® Innovin®• Protein C with Protein C Reagent• Antithrombin (AT) withINNOVANCE® Antithrombin• Protein C with Berichrom®Protein C• D-dimer with INNOVANCE® D-DimerThe performance of this device hasnot been established in neonate andpediatric patient populations. | The intended use of the Sysmex®CA-1500 is as a fully automated,computerized blood plasmacoagulation analyzer for in vitrodiagnostic use in clinicallaboratories.The instrument uses citratedhuman plasma to perform thefollowing parameters andcalculated parameters:Clotting Analysis Parameters:Prothrombin Time (PT); ActivatedPartial Thromboplastin Time(APTT); Fibrinogen (Clauss);Batroxobin Time; Extrinsic Factors(II, V, VII, X); Intrinsic Factors(VIII, IX, XI, XII); Protein C.Chromogenic AnalysisParameters: Antithrombin III;Factor VIII; Plasminogen;Heparin; Protein C; α2-Antiplasmin.Immunologic Analysis Parameters:D-dimer.Calculated Parameters: PT Ratio;PT INR; PT %; DerivedFibrinogen; Factor Assays %Activity. |
| Sample Type | Human plasma3.2% sodium citrate | Same |
| Similarities between CS-2100i and CA-1500 | ||
| Analyzer Component | Proposed DeviceSysmex® CS-2100i | Predicate DeviceSysmex® CA-1500 |
| Application type | Clotting Applications: | Same |
| Prothrombin Time (PT) withDade® Innovin®; | ||
| Activated Partial ThromboplastinTime (APTT) withDade® Actin® FSL; | ||
| Fibrinogen (Clauss) withDade® Thrombin Reagent; | ||
| Coagulation Factor V withDade® Innovin® | ||
| Coagulation Factor VII withDade® Innovin® | ||
| Protein C with Protein C Reagent | ||
| Chromogenic Application: | ||
| Antithrombin withINNOVANCE® Antithrombin;Protein C withBerichrom® Protein C | Same | |
| Immuno-Chemical Application: | ||
| D-dimer withINNOVANCE® D-Dimer | Same | |
| Calculated Application: | ||
| PT INR with Dade® Innovin® | Same | |
| Clinical Reportable Range | Fibrinogen with Dade® ThrombinReagent 50 to 860 mg/dL; | Same |
| Antithrombin with INNOVANCE®Antithrombin 9.0 to 128% of norm; | ||
| D-dimer with INNOVANCE® D-dimer 0.19 to 35.2 mg/L FEU; | ||
| Coagulation Factor V with Dade®Innovin® 6.0 to 149.0% of norm; | ||
| Coagulation Factor VII with Dade®Innovin® 6.0 to 149.0% of norm; | ||
| Protein C with Protein C Reagent10.1 to 131.0% of norm | ||
| Specimen Processing | Automatic Pipetting and Dilution | Same |
| Similarities between CS-2100i and CA-1500 | ||
| Analyzer Component | Proposed DeviceSysmex® CS-2100i | Predicate DeviceSysmex® CA-1500 |
| Random Access | Yes | Same |
| Liquid Level Sensing | Yes - reagent and sample | Same |
| Bar Code Reader | Sample and reagent | Same |
| STAT Testing | Yes | Same |
| Sampling Capabilities | Normal and Micro Mode | Same |
| Sample Volumes (Plasma) | PT with Dade® Innovin® (50 µL)APTT with Dade® Actin® FSL(50 µL)Fibrinogen with Dade® ThrombinReagent (10 µL)Coagulation Factor V with Dade®Innovin® (5 µL)Coagulation Factor VII with Dade®Innovin® (5 µL)Protein C with Protein C Reagent(5 µL)Protein C with Berichrom®Protein C (5 µL) | Same |
| Similarities between CS-2100i and CA-1500 | ||
| Analyzer Component | Proposed DeviceSysmex® CS-2100i | Predicate DeviceSysmex® CA-1500 |
| Sample Volumes in Micro Mode(Plasma) | PT with Dade® Innovin® (50 µL)APTT with Dade® Actin® FSL(50 µL)Fibrinogen with Dade® ThrombinReagent (10 µL)Coagulation Factor V with Dade®Innovin® (5 µL)Coagulation Factor VII with Dade®Innovin® (5 µL)Protein C with Protein C Reagent(5 µL)Protein C with Berichrom®Protein C (15 µL) | Same |
| Rinse & Buffer Solutions | ||
| On-boardExternal | CA-CLEAN ICA-CLEAN IIDade® Owren's BufferWater | Same |
| Light Source | ||
| ChromogenicImmuno-chemical | Halogen LampHalogen Lamp | SameSame |
| Probes | 1 Sample probe;1 Reagent probe | Same |
| Wavelengths used in Analysis | Antithrombin withINNOVANCE® Antithrombin(405 nm)Coagulation Factor V withDade® Innovin®(Default = 660 nm;sub-wavelength = none)Coagulation Factor VII with Dade®Innovin®(Default = 660 nm; Sub-wavelength=none)Protein C with Protein C Reagent(Default = 660 nm; Sub-wavelength= | Same |
| Similarities between CS-2100i and CA-1500 | ||
| Analyzer Component | Proposed DeviceSysmex® CS-2100i | Predicate DeviceSysmex® CA-1500 |
| none)Protein C withBerichrom® Protein C(Default = 405 nm; Sub-wavelength=none) | ||
| Temperature Control | Sample incubation well:37 °C ± 1.0 °C | Same |
| Differences between CS-2100i and CA-1500 | ||
| Analyzer Component | Proposed DeviceSysmex® CS-2100i | Predicate DeviceSysmex® CA-1500 |
| Clinical Reportable Range | Protein C with Berichrom® Protein C10.0 to 138% of norm | 5.0 to 138% of norm |
| Operating Principle | Clotting:Transmitted Light Detection(Absorbance) at 340, 405, 575, 660 or800 nm. Wavelengths 340, 405 and575 are technically available but notvalidated in combination with theintended applications. | Scattered Light Detection at 660nm |
| Chromogenic:Transmitted Light Detection(Absorbance) at 340, 405, 575, 660,800 nm. Wavelengths 340, 575, 660,and 800 are technically available but notvalidated in combination with theintended applications. | Transmitted Light Detection(Absorbance) at 405, 575, 800 nm | |
| Immunochemical:Transmitted Light Detection(Absorbance) at 340, 405, 575, 660 or800 nm. Wavelengths 340, 405, 575,and 800 are technically available but notvalidated in combination with theintended applications. | Transmitted Light Detection(Absorbance) at 405, 575, or 800nm | |
| Wavelengths* used in Analysis | ||
| *The default wavelength isnormally used to generate thereported value of the measurement.The sub-wavelength is run in | PT (seconds) Dade® Innovin®(Default = 660 nm; Sub- Wavelength=800 nm) | PT (seconds) with Dade®Innovin® Default = 660 nm; Sub-Wavelength= none) |
| parallel. If a light intensity erroroccurs by using the defaultwavelength the value from the sub-wavelength is used automatically. | PT (INR) with Dade® Innovin®(Default = 660 nm; Sub-Wavelength=800 nm) | PT (INR) with Dade® Innovin®(Default = 660 nm; Sub-Wavelength= none) |
| APTT with Dade® Actin® FSLActivated PTT Reagent (Default = 660nm; Sub-Wavelength= 800 nm) | APTT with Dade® Actin® FSLActivated PTT Reagent (Default =660 nm; Sub-Wavelength= none) | |
| Differences between CS-2100i and CA-1500 | ||
| Analyzer Component | Proposed DeviceSysmex® CS-2100i | Predicate DeviceSysmex® CA-1500 |
| Light SourceClotting | Halogen Lamp | Light Emitting Diode |
| Cap Piercing | Cap Piercer only | Both Cap Piercer model and Non-Cap Piercer models are available |
| Temperature Control | Detector: 37 ± 0.5 °CReagent probe: 37.5 ± 0.5 °C | Detector: 37 ± 1.0 °CReagent probe: 37 ± 1.0 °C |
| Reagent Cooling | 10 ± 2 °C, when ambienttemperature is 20 – 28 °C.During operation 4 – 15 °C, whenambient temperature is 15 – 30 °C | 15 ± 2 °C, when ambienttemperature is 15 - 30 °C |
| Pipetting Capabilities | Reagent probe:20 – 200 μLSample probe:4 – 270 μL | Reagent probe:3 – 200 μLSample probe:5 – 450 μL |
| Sample Volumes (Plasma) | Antithrombin withINNOVANCE® Antithrombin(14 μL)D-dimer with INNOVANCE®D-Dimer (15 μL) | Antithrombin withINNOVANCE® Antithrombin(10 μL)D-dimer with INNOVANCE®D-Dimer (13 μL) |
Similarities between CS-2100i and CA-1500
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Differences between Sysmex® CS-2100i and Sysmex® CA-1500
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The above described differences do not raise new questions as to safety and effectiveness of the new device.
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7 Performance Data
The following performance data were provided in support of the substantial equivalence determination.
7.1 Method comparison
Method comparison studies designed according to EP09-A3 CLSI Guideline 'Measurement Procedure Comparison and Bias Estimation Using Patient Samples' were conducted at four external sites in the United States, all sites using the same protocol.
Samples were measured on both the predicate device (Sysmex® CA-1500) as well as the new device (Sysmex® CS-2100i), in random order to eliminate any inherent bias. Results were compared by Passing-Bablok regression analysis as well as Bland-Altman plots. Results from each application met the predetermined acceptance criteria. The following summary of Passing-Bablok regression from the multi-center study shows that the proposed and predicate devices provide equivalent results when used in a clinical setting.
| Application | N | Sample range(% of norm) | r | Slope(95% CI) | Intercept(95% CI) |
|---|---|---|---|---|---|
| Factor V with Dade® Innovin® | 589 | 7.2 - 145.1 | 0.983 | 0.990(0.977, 1.003) | 1.861(1.025, 2.784) |
| Factor VII with Dade® Innovin® | 492 | 6.2 - 148.8 | 0.991 | 1.039(1.028, 1.051) | 0.636(-0.135, 1.104) |
| Protein C with Protein C Reagent | 584 | 10.3 - 129.3 | 0.977 | 0.966(0.952, 0.981) | -0.372(-1.207, 0.470) |
| Protein C with Berichrom® Protein C | 507 | 11.3 - 134.7 | 0.994 | 0.942(0.934, 0.951) | -0.292(-1.037, 0.399) |
7.2 Reproducibility Studies
Twenty-day precision studies were performed at two external sites in Germany and one external site in the United States. Testing followed the scheme of two runs per day, with two replicates per run, at each of the three sites according to CLSI EP05-A2 'Evaluation of Precision Performance of Quantitative Measurement Methods'. The order of the analysis of parameter, samples and quality control samples for each run and day varied to avoid an inherent bias to the study. One calibration curve of each calibrated application was used in the study. Within Run, Between Run, Between Day, and Total (within site) were calculated. The data is summarized in the following tables.
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| Sysmex® CS-2100i: Reproducibility Summary Table, Within Run | ||||
|---|---|---|---|---|
| Application(measuring interval) | 1st SiteWithin Run(%CV) | 2nd SiteWithin Run(%CV) | 3rd SiteWithin Run(%CV) | Sites Combined(%CV) |
| Coagulation Factor V withDade® Innovin®(6.0 - 149.0% of norm) | 4.07 – 7.40 | 2.07 - 3.34 | 2.70 - 6.09 | 3.16 - 5.01 |
| Coagulation Factor VII withDade® Innovin®(6.0 - 149.0% of norm) | 1.74 - 2.38 | 1.71 – 2.87 | 1.99 - 2.59 | 1.85 - 2.63 |
| Protein C withProtein C Reagent(10.1 - 131.0% of norm) | 2.26 - 3.75 | 2.08 - 2.68 | 2.43 - 7.02 | 2.46 - 4.78 |
| Protein C withBerichrom® Protein C(10.0 - 138.0% of norm) | 1.02 - 5.34 | 1.00 - 4.56 | 1.20 - 5.26 | 1.15 - 4.63 |
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| Sysmex® CS-2100i: Reproducibility Summary Table, Between Run | ||||
|---|---|---|---|---|
| Application(measuring interval) | 1st SiteBetweenRun(%CV) | 2nd SiteBetweenRun(%CV) | 3rd SiteBetweenRun(%CV) | Sites Combined(%CV) |
| Coagulation Factor V withDade® Innovin®(6.0 - 149.0% of norm) | 0.00 - 2.80 | 0.00 - 3.87 | 0.00 - 3.36 | 1.76 - 2.55 |
| Coagulation Factor VII withDade® Innovin®(6.0 - 149.0% of norm) | 0.65 - 1.41 | 0.00 - 1.35 | 0.00 - 2.32 | 0.00 - 1.72 |
| Protein C withProtein C Reagent(10.1 - 131.0% of norm) | 0.00 - 1.65 | 0.85 - 2.70 | 0.00 - 2.50 | 0.56 - 1.95 |
| Protein C withBerichrom® Protein C(10.0 - 138.0% of norm) | 0.54 - 2.51 | 0.32 - 2.23 | 0.00 - 1.20 | 0.84 - 1.66 |
| Sysmex® CS-2100i: Reproducibility Summary Table, Between Day | ||||
|---|---|---|---|---|
| Application(measuring interval) | 1st SiteBetweenDay(%CV) | 2nd SiteBetweenDay(%CV) | 3rd SiteBetweenDay(%CV) | Sites Combined(%CV) |
| Coagulation Factor V withDade® Innovin®(6.0 - 149.0% of norm) | 0.00 - 1.55 | 0.00 - 2.56 | 0.00 - 2.81 | 0.00 - 1.64 |
| Coagulation Factor VII withDade® Innovin®(6.0 - 149.0% of norm) | 0.00 - 1.02 | 1.48 – 2.68 | 0.00 - 1.92 | 0.89 - 1.67 |
| Protein C withProtein C Reagent(10.1 - 131.0% of norm) | 0.00 - 2.41 | 0.00 - 1.20 | 0.00 - 2.60 | 0.00 - 2.17 |
| Protein C withBerichrom® Protein C(10.0 - 138.0% of norm) | 0.00 - 0.57 | 0.00 - 1.02 | 0.00 - 2.36 | 0.00 - 1.40 |
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| CS-2100i: Reproducibility Summary Table, Total CV (Within Site and Sites Combined) | ||||
|---|---|---|---|---|
| Application(measuring interval) | 1st SiteTotal CVWithin Site(%CV) | 2nd SiteTotal CVWithin Site(%CV) | 3rd SiteTotal CVWithin Site(%CV) | Total CVSites Combined(%CV) |
| Coagulation Factor V withDade® Innovin®(6.0 - 149.0% of norm) | 4.64 - 7.40 | 3.37 - 5.12 | 3.85 - 6.95 | 4.78 - 10.43 |
| Coagulation Factor VII withDade® Innovin®(6.0 - 149.0% of norm) | 2.01 - 2.81 | 2.58 – 3.56 | 2.23 - 3.31 | 2.57 - 3.59 |
| Protein C withProtein C Reagent(10.1 - 131.0% of norm) | 2.78 - 4.55 | 2.36 - 3.83 | 3.47 - 7.49 | 3.47 - 5.85 |
| Protein C withBerichrom® Protein C(10.0 - 138.0% of norm) | 1.40 - 5.91 | 1.40 - 5.18 | 1.70 - 5.26 | 2.19 - 5.69 |
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Detection Capability Results 7.3
Detection capability studies were measured for the calibrated assays on the Sysmex® CS-2100i: Coagulation Factor V with Dade® Innovin®, Coagulation Factor VII with Dade® Innovin®, Protein C with Protein C Reagent, and Protein C with Berichrom® Protein C. Studies were conducted following the CLSI document EP17-A2 'Evaluation of Detection Capability for Clinical Laboratory Measurement Procedures'. Data for all tested reagents met the predetermined acceptance criteria and support the lower limit of the clinically reportable range claim.
| Sysmex® CS-2100i: Summary of Limit of Quantitation Studies | |||||
|---|---|---|---|---|---|
| Application | Lower Limit ofClinicallyReportableRange(% of norm) | Measured Limitof Quantitationbased onpredicate(% of norm) | MaximumTotal Error(% of norm) | ||
| Coagulation Factor V with Dade®Innovin® | 6.0 | 4.80 | 2.04 | ||
| Coagulation Factor VII withDade® Innovin® | 6.0 | 3.39 | 0.21 | ||
| Protein C withProtein C Reagent | 10.1 | 9.35 | 3.62 | ||
| Protein C withBerichrom® Protein C | 10.0 | 8.32 | 2.07 |
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Linearity & Measuring Range 7.4
Linearity studies were performed for the calibrated assays on the Sysmex® CS-2100i: Coagulation Factor V with Dade® Innovin®, Coagulation Factor VII with Dade® Innovin®, Protein C with Protein C Reagent, and Protein C with Berichrom® Protein C. All reagents met the predetermined acceptance criteria and support the clinically reportable range claim. Studies were conducted as described in CLSI EP6-A 'Evaluation of the Linearity of Quantitative Measurement Procedures: A Statistical Approach'.
| Application | Measured Linear Range | Clinically Reportable Range |
|---|---|---|
| Coagulation Factor V withDade® Innovin® | 3.4 – 180.7% of norm | 6.0 – 149.0% of norm |
| Coagulation Factor VII withDade® Innovin® | 4.3 – 179.5% of norm | 6.0 – 149.0% of norm |
| Protein C withProtein C Reagent | 7.0 – 187.7% of norm | 10.1 – 131.0% of norm |
| Protein C withBerichrom® Protein C | 7.1 – 181.3% of norm | 10.0 – 138.0% of norm |
7.5 Reference Interval
Reference interval studies were conducted at three clinical study sites in the United States following the guidance of CLSI document EP28-A3c 'Defining, Establishing, and Verifying Reference Intervals in the Clinical Laboratory'. The summary is provided below. The study population did not include neonate and pediatric sample populations.
| Sysmex® CS-2100i: Reference Interval Summary Table | ||
|---|---|---|
| Application | N | Sysmex® CS-2100i Reference Interval(5th Percentile of norm) |
| Coagulation Factor V withDade® Innovin® | 193 | 79.8% |
| Coagulation Factor VII withDade® Innovin® | 193 | 65.6% |
| Protein C withProtein C Reagent | 193 | 75.6% |
| Protein C withBerichrom® Protein C | 191 | 84.9% |
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8 Conclusions
Because the predicate device was cleared based in part on the results of clinical studies, and because clinical settings are required for a well-validated device, clinical testing was required to support substantial equivalence.
The non-clinical data support the safety of the device.
The clinical data demonstrate that the Sysmex® CS-2100i performs comparably to the predicate device that is currently marketed for the same intended use.
The data submitted for this premarket notification demonstrates that the device raises no new concerns as to safety and effectiveness when compared to the predicate device, and is substantially equivalent to the predicate device.
§ 864.5425 Multipurpose system for in vitro coagulation studies.
(a)
Identification. A multipurpose system for in vitro coagulation studies is a device consisting of one automated or semiautomated instrument and its associated reagents and controls. The system is used to perform a series of coagulation studies and coagulation factor assays.(b)
Classification. Class II (special controls). A control intended for use with a multipurpose system for in vitro coagulation studies is exempt from the premarket notification procedures in subpart E of part 807 of this chapter subject to the limitations in § 864.9.