(259 days)
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 Thromboplast Time (APTT) with Dade® Actin® FSL
- Fibrinogen (Fbg) with Dade® Thrombin Reagent
- Antithrombin (AT) with INNOVANCE® Antithrombin
- D-dimer with INNOVANCE® D-Dimer.
The performance of this device has not been established in neonate and pediatric patient populations.
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 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; Antithrombin (AT) with INNOVANCE® Antithrombin; and D-dimer with INNOVANCE® D-Dimer. 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.
Device Acceptance Criteria and Study Analysis for Sysmex CS-2100i
This document summarizes the acceptance criteria applied to the Sysmex CS-2100i automated coagulation analyzer and the studies conducted to demonstrate its performance, as described in the provided FDA 510(k) summary.
Device Name: Sysmex CS-2100i
Intended Use: Fully automated blood coagulation analyzer for in vitro diagnostic use, analyzing clotting, chromogenic, and immunoassay methods in clinical laboratories, for determination of PT, APTT, Fibrinogen, Antithrombin, and D-dimer.
1. Table of Acceptance Criteria and Reported Device Performance
The provided document does not explicitly state pre-defined acceptance criteria values for certain performance metrics (e.g., specific thresholds for correlation coefficients or CVs). However, it consistently states that "All reagents met the pre-determined acceptance criteria" and "Results from each application met the pre-established acceptance criteria." The table below presents the reported performance data from the studies, which implicitly represent the device meeting the acceptance criteria set by the manufacturer.
| Performance Metric Category | Specific Test/Application | Acceptance Criteria (Implicit from meeting) | Reported Device Performance (Combined Sites) |
|---|---|---|---|
| Method Comparison | |||
| (Passing-Bablok Rgression) | PT with Dade® Innovin® (seconds) | Regression line close to y=x, high 'r' | y = 1.000x + 0.000, r = 0.999 |
| PT (INR) with Dade® Innovin® | Regression line close to y=x, high 'r' | y = 1.047x - 0.052, r = 0.999 | |
| APTT with Dade® Actin® FSL | Regression line close to y=x, high 'r' | y = 1.077x - 2.305, r = 0.996 | |
| Fibrinogen with Dade® Thrombin Reagent | Regression line close to y=x, high 'r' | y = 1.048x - 4.417, r = 0.994 | |
| Antithrombin with INNOVANCE® Antithrombin | Regression line close to y=x, high 'r' | y = 0.970x + 1.321, r = 0.994 | |
| D-dimer with INNOVANCE® D-Dimer | Regression line close to y=x, high 'r' | y = 0.982x + 0.015, r = 0.997 | |
| Reproducibility | Max CV % within acceptable range for IVD devices | ||
| (Within Run CV) | PT with Dade® Innovin® (seconds) | (Implicitly met based on report) | 0.62 – 1.87 |
| PT (INR) with Dade® Innovin® | (Implicitly met based on report) | 0.49 – 2.02 | |
| APTT with Dade® Actin® FSL | (Implicitly met based on report) | 0.87 – 3.99 | |
| Fibrinogen with Dade® Thrombin Reagent | (Implicitly met based on report) | 1.44 – 4.60 | |
| Antithrombin with INNOVANCE® Antithrombin | (Implicitly met based on report) | 1.51 – 4.53 | |
| D-dimer with INNOVANCE® D-Dimer | (Implicitly met based on report) | 2.15 – 4.06 | |
| (Between Run CV) | PT with Dade® Innovin® (seconds) | (Implicitly met based on report) | 0.00 – 2.00 |
| PT (INR) with Dade® Innovin® | (Implicitly met based on report) | 0.46 – 1.84 | |
| APTT with Dade® Actin® FSL | (Implicitly met based on report) | 0.00 – 3.18 | |
| Fibrinogen with Dade® Thrombin Reagent | (Implicitly met based on report) | 0.00 – 0.95 | |
| Antithrombin with INNOVANCE® Antithrombin | (Implicitly met based on report) | 0.27 – 3.51 | |
| D-dimer with INNOVANCE® D-Dimer | (Implicitly met based on report) | 0.00 – 2.36 | |
| (Between Day CV) | PT with Dade® Innovin® (seconds) | (Implicitly met based on report) | 0.32 – 1.87 |
| PT (INR) with Dade® Innovin® | (Implicitly met based on report) | 0.17 – 1.77 | |
| APTT with Dade® Actin® FSL | (Implicitly met based on report) | 0.32 – 1.54 | |
| Fibrinogen with Dade® Thrombin Reagent | (Implicitly met based on report) | 0.00 – 1.44 | |
| Antithrombin with INNOVANCE® Antithrombin | (Implicitly met based on report) | 0.00 – 1.06 | |
| D-dimer with INNOVANCE® D-Dimer | (Implicitly met based on report) | 0.62 – 3.22 | |
| (Total CV (Within Site)) | PT with Dade® Innovin® (seconds) | (Implicitly met based on report) | 1.01 – 2.95 |
| PT (INR) with Dade® Innovin® | (Implicitly met based on report) | 0.76 – 2.98 | |
| APTT with Dade® Actin® FSL | (Implicitly met based on report) | 0.96 – 6.58 | |
| Fibrinogen with Dade® Thrombin Reagent | (Implicitly met based on report) | 1.98 – 4.62 | |
| Antithrombin with INNOVANCE® Antithrombin | (Implicitly met based on report) | 2.79 – 7.24 | |
| D-dimer with INNOVANCE® D-Dimer | (Implicitly met based on report) | 2.90 – 6.55 | |
| (Site-to-Site CV) | PT with Dade® Innovin® (seconds) | (Implicitly met based on report) | 0.00 - 0.70 |
| PT (INR) with Dade® Innovin® | (Implicitly met based on report) | 0.00 - 0.88 | |
| APTT with Dade® Actin® FSL | (Implicitly met based on report) | 0.11 - 3.86 | |
| Fibrinogen with Dade® Thrombin Reagent | (Implicitly met based on report) | 0.00 - 2.05 | |
| Antithrombin with INNOVANCE® Antithrombin | (Implicitly met based on report) | 2.00 - 4.43 | |
| D-dimer with INNOVANCE® D-Dimer | (Implicitly met based on report) | 0.00 - 3.99 | |
| Detection Capability | Measured Limit of Quantitation ≤ Lower Limit of Clinical Reportable Range; Max Total Error % acceptable | ||
| Fibrinogen with Dade® Thrombin Reagent | 46.1 mg/dL ≤ 50.0 mg/dL, 14.83% TE | 46.1 mg/dL, 14.83% | |
| Antithrombin with INNOVANCE® Antithrombin | 8.78% of norm ≤ 9.0% of norm, 26.17% TE | 8.78% of norm, 26.17% | |
| D-dimer with INNOVANCE® D-Dimer | 0.15 mg/L FEU ≤ 0.19 mg/L FEU, 40.40% TE | 0.15 mg/L FEU, 40.40% | |
| Linearity | Measured Linear Range includes Clinical Reportable Range | ||
| Fibrinogen with Dade® Thrombin Reagent | 40.3-1124.0 mg/dL includes 50-860 mg/dL | 40.3 to 1124.0 mg/dL | |
| Antithrombin with INNOVANCE® Antithrombin | 6.28-152.30% of norm includes 9.0-128.0% of norm | 6.28 to 152.30% of norm | |
| D-dimer with INNOVANCE® D-Dimer | 0.15-50.86 mg/L FEU includes 0.19-35.20 mg/L FEU | 0.15 to 50.86 mg/L FEU | |
| D-Dimer PE Exclusion | High Sensitivity and NPV | ||
| (Combined US & OUS) | Sensitivity | (Implicitly met >90%) | 97.0% (95% LCL=91.6%) |
| Specificity | (Implicitly met) | 54.5% (95% LCL=51.9%) | |
| NPV | (Implicitly met >98%) | 99.6% (95% LCL=98.8%) | |
| NPV* (15% prevalence) | (Implicitly met >97%) | 99.0% (95% LCL=97.2%) | |
| PPV | (Implicitly met) | 13.6% (95% LCL=11.3%) | |
| PPV* (15% prevalence) | (Implicitly met) | 27.4% (95% LCL=23.3%) |
2. Sample Sizes Used for the Test Set and Data Provenance
- Method Comparison Studies: Samples were collected at three external sites in the United States. The studies were retrospective, comparing the new device (Sysmex CS-2100i) against the predicate device (Sysmex CA-1500) using the same samples.
- Sample Sizes (n) per application (across all 3 sites combined):
- PT (seconds): 460
- PT (INR): 454
- APTT: 432
- Fibrinogen: 356
- Antithrombin: 372
- D-dimer: 349
- Sample Sizes (n) per application (across all 3 sites combined):
- Reproducibility Studies: Samples were collected at two external sites in Germany and one external site in the United States. The studies involved conducting multiple runs over 20 days.
- Sample Sizes: The exact number of individual patient samples used is not specified, but the study design involves multiple replicates of various samples (likely control materials and patient samples spanning the reportable range) over 20 days.
- Detection Capability Studies: Not specified, but involved calibrated assays measured on the Sysmex CS-2100i.
- Linearity & Measuring Range Studies: Not specified, but involved calibrated assays measured on the Sysmex CS-2100i.
- Reference Interval Studies: Conducted at three clinical study sites in the United States. The number of samples for each application is not explicitly stated.
- D-Dimer PE Exclusion Validation Study: This was a multi-center study using frozen specimens collected prospectively from outpatients presenting with suspected PE.
- Initial Enrollment: 1930 consecutive outpatients.
- Patients after exclusions: 1834 patients.
- Patients for final analysis: n=1467.
- Data Provenance: Combined US and OUS (Outside US, likely European, given the mention of European population prevalence).
3. Number of Experts Used to Establish the Ground Truth for the Test Set and Qualifications of Those Experts
The document does not provide information on the number or qualifications of experts used to establish ground truth for any of the studies (method comparison, reproducibility, detection capability, linearity, reference interval).
For the D-Dimer PE Exclusion Validation Study:
- The "ground truth" for PE diagnosis was established by imaging methods (e.g., spiral CT and/or VQ scan) for patients with positive D-dimer results or at physician's discretion, and clinical follow-up after three months to evaluate potential development of PE for patients with negative D-dimer results. This indicates clinical diagnostic standards were used, but not necessarily an "expert panel" establishing ground truth for the test set itself in terms of interpretation of the device results.
4. Adjudication Method for the Test Set
The document does not specify any adjudication method (e.g., 2+1, 3+1, none) for any of the test sets. For the D-Dimer PE exclusion study, the reference standard involved objective imaging and clinical follow-up rather than expert consensus on test results.
5. If a Multi Reader Multi Case (MRMC) Comparative Effectiveness Study Was Done
No, an MRMC comparative effectiveness study was not done. The studies focused on comparing the performance of the new instrument (Sysmex CS-2100i) to a predicate instrument (Sysmex CA-1500) and establishing its analytical and clinical performance characteristics (e.g., reproducibility, linearity, detection capability, PE exclusion). There is no mention of human readers or evaluating their improvement with or without AI assistance.
6. If a Standalone (i.e., Algorithm Only Without Human-in-the-Loop Performance) Was Done
Yes, the studies presented are standalone performance evaluations of the Sysmex CS-2100i instrument. The device is an automated coagulation analyzer that provides quantitative results for various assays. The studies assess the accuracy, precision, and clinical utility of these quantitative measurements as performed by the instrument itself, without direct human-in-the-loop interpretation that would alter the algorithm's output. The D-Dimer PE exclusion study evaluated the D-dimer assay's performance on the Sysmex CS-2100i against a clinical cut-off, which is a standalone assessment of the device's diagnostic performance for that specific indication.
7. The Type of Ground Truth Used
- Method Comparison: The predicate device (Sysmex CA-1500) served as the reference or "ground truth" for comparison, as the study aimed to demonstrate substantial equivalence between the new and predicate devices.
- Reproducibility, Detection Capability, Linearity, Reference Interval: These studies establish the inherent analytical performance characteristics of the device. The ground truth here is derived from controlled measurements against expected values (e.g., known concentrations for linearity, statistical analysis of repeated measurements for reproducibility).
- D-Dimer PE Exclusion Validation Study: The ground truth for the presence or absence of Pulmonary Embolism was established by a combination of:
- Imaging methods: (e.g., spiral CT and/or VQ scan).
- Clinical follow-up: After three months to assess for the development of PE.
8. The Sample Size for the Training Set
The document does not specify a separate "training set" as this is an in vitro diagnostic device for quantitative measurements, not a machine learning or AI algorithm in the context typically requiring explicit training and testing sets from labeled data for learning. The instrument's algorithms are pre-defined based on physicochemical principles.
If "training set" is implicitly referring to data used to initially develop or calibrate the methods on the instrument prior to the validation studies, that information is not provided in this 510(k) summary. The presented studies are validation studies performed on the final device design.
9. How the Ground Truth for the Training Set Was Established
As noted above, no explicit "training set" is mentioned in the context of machine learning. The device utilizes established methodologies (clotting, chromogenic, immunochemical) for which the "ground truth" for method development would be based on well-characterized calibrators and reference materials, following standard laboratory practices for IVD development. However, details of such development-phase activities are not part of this 510(k) submission.
{0}------------------------------------------------
Food and Drug Administration 10903 New Hampshire Avenue Document Control Center - WO66-G609 Silver Spring, MD 20993-0002
January 26, 2016
Siemens Healthcare Diagnostics Products GmbH Mr. Nils Neumann Regulatory Manager, US Affairs Emil-von-Behring-Str. 76 35041 Marburg, Germany
Re: K151259
Trade/Device Name: Sysmex CS-2100i Regulation Number: 21 CFR 864.5425 Regulation Name: Multipurpose system for in vitro coagulation studies Regulatory Class: Class II Product Code: JPA Dated: December 24, 2015 Received: December 28, 2015
Dear Mr. Neumann:
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
{1}------------------------------------------------
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 vours.
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
{2}------------------------------------------------
DEPARTMENT OF HEALTH AND HUMAN SERVICES Food and Drug Administration
Indications for Use
510(k) Number (if known) K151259
Device Name Sysmex CS-2100i
Indications for Use (Describe)
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
- Antithrombin (AT) with INNOVANCE® Antithrombin
- · D-dimer with INNOVANCE® D-Dimer.
The performance of this device has not been established in neonate and pediatric patient populations.
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)
PLEASE DO NOT WRITE BELOW THIS LINE - CONTINUE ON A SEPARATE PAGE IF NEEDED.
FOR FDA USE ONLY
Concurrence of Center for Devices and Radiological Health (CDRH) (Signature)
{3}------------------------------------------------
This section applies only to requirements of the Paperwork Reduction Act of 1995.
DO NOT SEND YOUR COMPLETED FORM TO THE PRA STAFF EMAIL ADDRESS BELOW.
The burden time for this collection of information is estimated to average 79 hours per response, including the time to review instructions, search existing data sources, gather and maintain the data needed and complete and review the collection of information. Send comments regarding this burden estimate or any other aspect of this information collection, including suggestions for reducing this burden, to:
Department of Health and Human Services Food and Drug Administration Office of Chief Information Officer Paperwork Reduction Act (PRA) Staff PRAStaff(@fda.hhs.gov
"An agency may not conduct or sponsor, and a person is not required to respond to, a collection of information unless it displays a currently valid OMB number."
{4}------------------------------------------------
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.
1. Submitter
Siemens Healthcare Diagnostics Products GmbH Emil-von-Behring-Str. 76 35041 Marburg, Germany Contact Person: Nils Neumann Email: neumann.nils@siemens.com Phone: + 49 6421 39 7133 Facsimile: + 49 6421 39 4977 Date Prepared: January 14, 2016 2. Device
| Name of Device: | Sysmex CS-2100i |
|---|---|
| Common or Usual Name: | Automated Coagulation Instrument |
| Classification Name: | Multipurpose system for in vitro coagulation studies (21 CFR864.5425) |
| Regulatory Class: | 2 |
| Product Code: | JPA |
| 510(k) Review Panel: | Hematology |
3. Predicate Device
| Name of Device: | Sysmex CA-1500 (K011235) |
|---|---|
| Common or Usual Name: | Automated Coagulation Instrument |
| Classification Name: | Multipurpose system for in vitro coagulation studies (21 CFR864.5425) |
| Regulatory Class: | 2 |
| 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.
4. Device Description / Test Principle
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:
510(k) Summary K151259 Sysmex CS-2100i
{5}------------------------------------------------
- Reagents I
- Controls
- 트 Calibrators
- 트 Consumable materials
The subject of this 510(k) notification are reagent applications which perform the coagulation tests 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; Antithrombin (AT) with INNOVANCE® Antithrombin; and D-dimer with INNOVANCE® D-Dimer. 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® | PT, Prothrombin Time (seconds) | Clotting (extrinsic pathway) |
| Dade® Innovin® | PT, Prothrombin Time (INR) | Clotting, calculated |
| Dade® Actin® FSL | APTT, Activated Partial Thromboplastin Time | Clotting (intrinsic pathway) |
| Dade® Thrombin Reagent | Fibrinogen quantitation | Clotting (common pathway) |
| INNOVANCE® Antithrombin | Antithrombin quantitation | Chromogenic |
| INNOVANCE® D-Dimer | D-dimer quantitation | Immunochemical |
The intended Environment of Use is a clinical central/hospital laboratory.
{6}------------------------------------------------
Instrument (main unit)
Image /page/6/Figure/2 description: This image is a line drawing of a piece of equipment with multiple labeled parts. The labels are numbers 1 through 9 and point to different parts of the machine. The machine 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.
{7}------------------------------------------------
Informational Processing Unit (IPU)
Image /page/7/Figure/2 description: The image shows a desktop computer setup with four labeled components. Label (1) points to the computer monitor, which is rectangular and sits atop a stand. Label (2) points to the computer case, which is a rectangular box that sits below the monitor. Label (3) points to the keyboard, which is a standard QWERTY keyboard. Label (4) points to the computer mouse, which is a standard two-button mouse.
(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.
Options and Accessories
Options and accessories that can be used for this instrument are as follows:
(1) Waste tank (with float switch for waste tank): Waste fluids discharged from the Main Unit enter this tank.
(2) Wand barcode reader: Reads barcodes to input sample numbers, rack numbers and reagent IDs.
(3) 2D barcode reader: Reads barcodes to input calibrator's or reagent's assay sheet values, normal values and ISI values, and control's targets/limits.
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. In a normal mode, a capped sample tube analysis can be performed. Automatic re-analysis can also be performed.
(2) Micro-sample mode: Sampler or STAT holder are taken into the instrument for each analysis through a secondary dispensing sample probe. When measurements are to be
{8}------------------------------------------------
performed in Micro mode, sample tubes must be uncapped. The instrument detects capped tubes automatically and displays an error message. This analysis mode can be performed with less sample volume than normal mode (consult instruction manual for further information). However, automatic re-analysis cannot be performed.
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:
- I Prothrombin Time (PT) seconds and PT INR with Dade® Innovin®
- 트 Activated Partial Thromboplastin Time (APTT) with Dade® Actin® FSL
- Fibrinogen (Fbq) with Dade® Thrombin Reagent l
- Antithrombin (AT) with INNOVANCE® Antithrombin
- D-dimer with INNOVANCE® D-Dimer.
The performance of this device has not been established in neonate and pediatric patient populations.
6. Comparison of Technological Characteristics with the Predicate Device
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:
| Similarities between Sysmex CS-2100i and Sysmex CA-1500 | ||
|---|---|---|
| Analyzer Component | Proposed DeviceSysmex CS-2100i | Predicate DeviceSysmex CA-1500 |
| RegulatoryClassification | JPA Class 2System, Multipurpose for in vitrocoagulation studies | Same |
| Sample Type | Human plasma,3.2% sodium citrate | Same |
| Applications | Clotting Applications:Prothrombin Time (PT) with Dade®Innovin®;Activated Partial ThromboplastinTime (APTT) with Dade® Actin®FSL | Same |
| Similarities between Sysmex CS-2100i and Sysmex CA-1500 | ||
| Analyzer Component | Proposed DeviceSysmex CS-2100i | Predicate DeviceSysmex CA-1500 |
| Fibrinogen (Clauss) with Dade®Thrombin Reagent | ||
| Chromogenic Application:Antithrombin with INNOVANCE®Antithrombin | Same | |
| Immuno-chemical Application:D-dimerwith INNOVANCE® D-Dimer | Same | |
| Calculated Application:PT INR with Dade® Innovin® | Same | |
| Clinical ReportableRange | Fibrinogen with Dade®Thrombin Reagent50 to 860 mg/dL | Same |
| Antithrombin withINNOVANCE®Antithrombin9.0 to 128 % of norm | Same | |
| D-dimer withINNOVANCE® D-Dimer0.19 to 35.2 mg/L FEU | Same | |
| Specimen Processing | Automatic Pipetting and Dilution | Same |
| Random Access | Yes | Same |
| Liquid Level Sensing | Yes - reagent and sample | Same |
| Bar code Reader | Sample + reagent | Same |
| STAT Testing | Yes | Same |
| Sampling Capabilities | Normal and Micro Mode | Same |
| Sample Volumes inNormal Mode | PT with Dade® Innovin® 50 μLAPTT with Dade® Actin® FSL 50 μLFibrinogen with Dade® Thrombin | Same |
| Similarities between Sysmex CS-2100i and Sysmex CA-1500 | ||
| Analyzer Component | Proposed DeviceSysmex CS-2100i | Predicate DeviceSysmex CA-1500 |
| Reagent 10 μL | ||
| Antithrombin with INNOVANCE®Antithrombin 10 µL | ||
| D-dimer with INNOVANCE® D-Dimer 13 µL | ||
| PT with Dade® Innovin® 50 μL | ||
| Sample Volumes inMicro Mode (Plasma) | APTT with Dade® Actin® FSL 50 μL | Same |
| Fibrinogen with Dade® ThrombinReagent 10 μL | ||
| Rinse & BufferSolutions | ||
| • On-board | • CA-CLEAN I• CA-CLEAN II• Dade Owren's Buffer | • Same• Same• Same |
| • External | • Water | • Same |
| Light SourceChromogenic | Halogen Lamp | Same |
| Immuno-chemical | Halogen Lamp | Same |
| Probes | 1 Sample probe;1 Reagent probe | 1 Sample probe;1 Reagent probe |
| Wavelengths used inAnalysis | Antithrombin with INNOVANCE®Antithrombin (405 nm) | Same |
| Temperature Control | Sample incubation well: 37°C ±1.0°C | Same |
| Analyzer Component | Proposed DeviceSysmex CS-2100i | Predicate DeviceSysmex CA-1500 |
| Intended UseStatement | The Sysmex CS-2100i is a fullyautomated blood coagulationanalyzer intended for in vitrodiagnostic use using plasmacollected from venous bloodsamples in 3.2% sodium citratetubes to analyze clotting,chromogenic and immunoassaymethods in the clinical laboratory.For determination of:Prothrombin Time (PT)seconds and PT INR with Dade®Innovin® Activated PartialThromboplastin Time (APTT) withDade® Actin® FSL Fibrinogen (Fbg) with Dade®Thrombin Reagent Antithrombin (AT) withINNOVANCE® Antithrombin D-dimer with INNOVANCE® D-Dimer The performance of this devicehas not been established inneonate and pediatric patientpopulations. | The intended use of the SysmexCA-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 Prameters:Prothrombin Time (PT);Activated Partial ThromboplastinTime (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 AnalysisParameters: D-dimer.Calculated Parameters: PTRatio; PT INR; PT %; DerivedFibrinogen; Factor Assays %Activity |
| Differences between Sysmex CS-2100i and Sysmex CA-1500 | ||
| Analyzer Component | Proposed DeviceSysmex CS-2100i | Predicate DeviceSysmex CA-1500 |
| Clinical ReportableRange | ||
| PT with Dade® Innovin® | 8.7 – 90.0 seconds0.93 – 8.00 INR | 8.7 to 148.7 seconds0.80 to13.90 INR |
| APTT withDade® Actin® FSL | 20.0 - 139.0 seconds | 17.2 to 153.4 seconds |
| Operating Principle | ||
| Clotting | Transmitted Light Detection(Absorbance) at 340, 405, 575,660 or 800 nm. Wavelengths 340and 575 are technically availablebut not validated in combinationwith the intended 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 technicallyavailable but not validated incombination with the intendedapplications. | Rate of change of opticaldensity at 405, 575, 800 nm |
| Immuno-chemical | Transmitted Light Detection(Absorbance) at 340, 405, 575,660 or 800 nm. Wavelengths 340,405, 575, and 800 are technicallyavailable but not validated incombination with the intendedapplications. | Optical Density at 405, 575, or800 nm |
| Differences between Sysmex CS-2100i and Sysmex CA-1500 | ||
| Analyzer Component | Proposed DeviceSysmex CS-2100i | Predicate DeviceSysmex CA-1500 |
| Wavelengths* used inAnalysis*The default wavelengthis normally used togenerate the reportedvalue of themeasurement. The sub-wavelength is run inparallel. If a lightintensity error occurs byusing the defaultwavelength the valuefrom the sub-wavelengthis used automatically. | PT (seconds) Dade® Innovin®(Default = 660 nm; Sub-Wavelength= 800 nm)PT (INR) with Dade® Innovin®(Default = 660 nm; Sub-Wavelength= 800 nm)APTT with Dade® Actin® FSLActivated PTT Reagent (Default =660 nm; Sub-Wavelength= 800nm)Fibrinogen with Dade® ThrombinReagent (Default = 405 nm; Sub-Wavelength= none)D-dimer with INNOVANCE® D-Dimer (Default = 660 nm; Sub-Wavelength= none) | PT (seconds) with Dade®Innovin® Default = 660 nm;Sub-Wavelength= none)PT (INR) with Dade® Innovin®(Default = 660 nm; Sub-Wavelength= none)APTT with Dade® Actin® FSLActivated PTT Reagent (Default= 660 nm; Sub-Wavelength=none)Fibrinogen with Dade®Thrombin (Default = 660 nm;Sub-Wavelength= none)D-dimer with INNOVANCE® D-Dimer (Default = 800 nm; Sub-Wavelength= none) |
| Light SourceClotting | Halogen Lamp | Light Emitting DiodeBoth options available:Cap Piercer and Non-CapPiercer |
| Cap Piercing | Cap Piercer only | |
| Temperature Control | -Detector : 37 °C ± 0.5 °C-Reagent probe :37.5 °C ± 0.5 °C | -Detector: 37°C ± 1.0°C-Reagent incubation probe:37°C ± 1.0°C |
| Reagent Cooling | 10°C ± 2°C, when ambienttemperature is 20°C - 28°C.During operation 4°C -15°C,when ambient temperature is15°C – 30°C | 15°C ± 2°C, when ambienttemperature is 15°C – 30°C |
| Pipetting Capabilities | Reagent probe:20 – 200 μLSample probe:4 – 270 μL | Reagent probe:3 – 200 μLSample probe:5 - 450 μL |
{9}------------------------------------------------
{10}------------------------------------------------
{11}------------------------------------------------
There are no technological differences between the subject and predicate devices. However the following minor changes exist between the subject and predicate devices:
{12}------------------------------------------------
{13}------------------------------------------------
{14}------------------------------------------------
| Differences between Sysmex CS-2100i and Sysmex CA-1500 | ||
|---|---|---|
| Analyzer Component | Proposed DeviceSysmex CS-2100i | Predicate DeviceSysmex CA-1500 |
| Sample Volumes inMicro Mode | Antithrombin with INNOVANCE®Antithrombin 14 µLD-dimer with INNOVANCE® D-Dimer 15 µL | Antithrombin withINNOVANCE® Antithrombin 10 µLD-dimer with INNOVANCE® D-Dimer 13 µL |
| Bidirectional Interfacecommunicationprotocols | CA-, ASTM-, CS- Protocol | CA-, ASTM-Protocol |
The above described differences do not raise new questions as to safety and effectiveness of the new device.
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 three external sites in the United States, all sites using the same protocols.
Samples were measured on both the predicate device (Sysmex CA-1500) as well as the new device (Sysmex CS-2100i), in random order as 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 pre-established acceptance criteria. The following summary of Passing-Bablok regression shows that the proposed and predicate devices provide equivalent results when used in a clinical setting.
{15}------------------------------------------------
| Sysmex CS-2100i: Method Comparison Summary Table, Passing-Bablok regression | ||||
|---|---|---|---|---|
| Application(Clinical ReportableRange) | Site 01 | Site 02 | Site 03 | Sites Combined |
| Prothrombin Timewith Dade®Innovin®(8.7 -90.0seconds) | n=120y = 1.000x +0.200r = 0.997 | n=215y = 1.000x +0.000r = 0.999 | n=125y = 0.985x +0.299r = 1.000 | n=460y = 1.000x +0.000r = 0.999 |
| Prothrombin Time(INR) with Dade®Innovin® (0.93 –8.00 INR) | n=117y = 1.045x -0.037r = 0.996 | n=213y = 1.026 x -0.037r = 0.999 | n=124y = 1.040x -0.030r = 1.000 | n=454y = 1.047x -0.052r = 0.999 |
| Activated PartialThromboplastinTime with Dade®Actin® FSL(20.0 - 139.0seconds) | n=119y = 1.083x -2.242r = 0.994 | n=211y = 1.055x -1.829r = 0.996 | n=102y = 1.079x -2.147r = 0.998 | n=432y = 1.077x -2.305r = 0.996 |
| Fibrinogenquantitation withDade® ThrombinReagent(50 – 860 mg/dL) | n=146y = 1.053x +0.112r = 0.996 | n=95y = 1.064x -3.587r = 0.997 | n=115y = 0.984x -0.520r = 0.995 | n=356y=1.048x -4.417r = 0.994 |
| Antithrombinquantitation withINNOVANCE®Antithrombin(9.0 - 128.0% ofnorm) | n=135y = 0.978x -0.196r = 0.993 | n=120y = 0.972x +2.517r = 0.994 | n=117y = 0.975x +0.843r = 0.995 | n=372y = 0.970x +1.321r = 0.994 |
| D-dimerquantitation withINNOVANCE® D-Dimer (0.19 - 35.20mg/L FEU¹) | n=129y = 1.031x +0.005r = 0.999 | n=112y = 0.967x -0.021r = 0.998 | n=108y = 0.982x +0.017r = 0.998 | n=349y = 0.982x +0.015r = 0.997 |
1 D-dimer results are reported in fibrinogen equivalent units (FEU).
{16}------------------------------------------------
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 was varied so as not to add 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) variability were calculated. The data for normal mode are summarized in the following tables.
| Sysmex CS-2100i: Reproducibility Summary Table, Within Run | |||||
|---|---|---|---|---|---|
| Application(CRR/ Clotting timerange) | Sample Range(mean of allsites) | Site 01WithinRun (%CV) | Site 02WithinRun (%CV) | Site 03WithinRun (%CV) | SitesCombined(% CV) |
| Prothrombin Timeusing Dade® Innovin®(8.7 - 90.0 seconds) | 9.23 - 78.94seconds | 0.55 – 2.21 | 0.63 – 1.94 | 0.66 - 1.79 | 0.62 – 1.87 |
| Prothrombin Time(INR) using Dade®Innovin® (0.93 – 8.00INR) | 1.016 - 7.658INR | 0.45 – 2.83 | 0.40 - 1.53 | 0.60 - 1.57 | 0.49 – 2.02 |
| Activated PartialThromboplastin Timeusing Dade® Actin®FSL(20.0 - 139.0 seconds) | 22.10 - 127.52seconds | 0.81 – 4.51 | 0.73 - 3.98 | 0.85 - 2.88 | 0.87 – 3.99 |
| Fibrinogenquantitation usingDade® ThrombinReagent(50 – 860 mg/dL) | 55.9 - 738.5mg/dL | 1.19 – 3.99 | 1.41 - 5.14 | 1.44 – 4.60 | 1.44 – 4.60 |
| Antithrombinquantitation usingINNOVANCE®Antithrombin(9.0 – 128.0% of norm) | 11.39 - 121.05%of norm | 1.18 – 4.36 | 1.31 - 4.55 | 1.44 – 4.63 | 1.51 – 4.53 |
| D-dimer quantitationusing INNOVANCE®D-Dimer (0.19 - 35.20mg/L FEU) | 0.258 - 31.767mg/L FEU | 2.00 – 3.51 | 2.25 – 4.62 | 2.00 – 5.11 | 2.15 – 4.06 |
{17}------------------------------------------------
| Sysmex CS-2100i: Reproducibility Summary Table, Between Run | |||||
|---|---|---|---|---|---|
| Application(CRR / Clottingtime range) | Sample Range(mean of allsites) | Site 01BetweenRun (% CV) | Site 02BetweenRun (% CV) | Site 03BetweenRun (% CV) | SitesCombined(% CV) |
| ProthrombinTime using Dade®Innovin®(8.7 – 90.0 sec) | 9.23–78.94seconds | 0.24 - 2.37 | 0.00 - 2.09 | 0.00 - 2.46 | 0.00 - 2.00 |
| ProthrombinTime (INR) usingDade® Innovin®(0.93 – 8.00 INR) | 1.016 – 7.658INR | 0.00 - 2.19 | 0.00 - 1.35 | 0.54 - 1.75 | 0.46 - 1.84 |
| Activated PartialThromboplastinTime using Dade®Actin® FSL(20.0 – 139.0 sec) | 22.10 - 127.52seconds | 0.00 - 3.23 | 0.00 - 1.47 | 0.33 - 3.47 | 0.00 - 3.18 |
| Fibrinogenquantitation usingDade® ThrombinReagent(50 – 860 mg/dL) | 55.9 - 738.5mg/dL | 0.00 - 0.87 | 0.00 - 1.60 | 0.00 - 1.56 | 0.00 - 0.95 |
| Antithrombinquantitation usingINNOVANCE®Antithrombin(9.0 – 128.0% ofnorm) | 11.39 - 121.05% of norm | 0.00 - 4.59 | 0.00 - 3.49 | 0.00 - 2.80 | 0.27 - 3.51 |
| D-dimerquantitation usingINNOVANCE® D-Dimer (0.19 –35.20 mg/L FEU) | 0.258 – 31.767mg/L FEU | 0.00 - 2.92 | 0.00 - 1.57 | 0.00 - 2.81 | 0.00 - 2.36 |
{18}------------------------------------------------
| Sysmex CS-2100i: Reproducibility Summary Table, Between Day | |||||
|---|---|---|---|---|---|
| Application(CRR / Clottingtime range) | Sample Range(mean of allsites) | Site 01BetweenDay (% CV) | Site 02BetweenDay (% CV) | Site 03BetweenDay (% CV) | SitesCombined(% CV) |
| ProthrombinTime using Dade®Innovin®(8.7 – 90.0 sec) | 9.23– 78.94seconds | 0.00 – 1.59 | 0.00 – 1.91 | 0.00 – 2.93 | 0.32 – 1.87 |
| ProthrombinTime (INR) usingDade® Innovin®(0.93 – 8.00 INR) | 1.016 – 7.658INR | 0.00 – 2.41 | 0.00 – 2.24 | 0.30 – 2.85 | 0.17 – 1.77 |
| Activated PartialThromboplastinTime using Dade®Actin® FSL(20.0 – 139.0 sec) | 22.10 – 127.52seconds | 0.15 – 3.53 | 0.03 – 2.25 | 0.00 – 2.05 | 0.32 – 1.54 |
| Fibrinogenquantitation usingDade® ThrombinReagent(50 – 860 mg/dL) | 55.9 – 738.5mg/dL | 1.10 – 2.39 | 0.00 – 0.71 | 0.00 – 0.99 | 0.00 – 1.44 |
| Antithrombinquantitation usingINNOVANCE®Antithrombin(9.0 – 128.0% ofnorm) | 11.39 –121.05% ofnorm | 0.00 – 1.58 | 0.00 – 0.77 | 0.00 – 1.54 | 0.00 – 1.06 |
| D-dimerquantitation usingINNOVANCE® D-Dimer (0.19 –35.20 mg/L FEU) | 0.258 – 31.767mg/L FEU | 0.00 – 4.63 | 0.00 – 2.16 | 0.00 – 4.39 | 0.62 – 3.22 |
{19}------------------------------------------------
| Sysmex CS-2100i: Reproducibility Summary Table, Total CV (Within Site) | |||||
|---|---|---|---|---|---|
| Application(CRR / Clottingtime range) | Sample Range(mean of allsites) | Site 01(% CV) | Site 02(% CV) | Site 03(% CV) | SitesCombined(% CV) |
| Prothrombin Timeusing Dade®Innovin®(8.7 – 90.0 sec) | 9.23 – 78.94seconds | 0.92 – 3.30 | 0.71 – 2.74 | 0.96 – 3.33 | 1.01 – 2.95 |
| Prothrombin Time(INR) using Dade®Innovin® (0.93 –8.00 INR) | 1.016 – 7.658INR | 0.78 – 4.05 | 0.42 – 2.71 | 0.87 – 3.24 | 0.76 – 2.98 |
| Activated PartialThromboplastinTime using Dade®Actin® FSL(20.0 – 139.0 sec) | 22.10 – 127.52seconds | 1.01 – 6.57 | 0.78 – 4.80 | 0.98 – 4.51 | 0.96 – 6.58 |
| Fibrinogenquantitation usingDade® ThrombinReagent(50 – 860 mg/dL) | 55.9 – 738.5mg/dL | 2.05 – 4.14 | 1.55 – 5.23 | 1.47 – 4.86 | 1.98 – 4.62 |
| Antithrombinquantitation usingINNOVANCE®Antithrombin(9.0 – 128.0% ofnorm) | 11.39 – 121.05 %of norm | 1.34 – 6.33 | 1.54 – 5.74 | 1.95 – 5.38 | 2.79 – 7.24 |
| D-dimerquantitation usingINNOVANCE® D-Dimer (0.19 – 35.20mg/L FEU) | 0.258 – 31.767mg/L FEU | 2.78 – 6.50 | 2.66 – 5.10 | 3.02 – 5.95 | 2.90 – 6.55 |
{20}------------------------------------------------
| Sysmex CS-2100i: Reproducibility Summary Table, Site-to-Site | ||
|---|---|---|
| Application(CRR / Clotting time range) | Sample Range(mean of all sites) | BetweenSites (%CV) |
| Prothrombin Time usingDade® Innovin®(8.7 – 90.0 sec) | 9.23–78.94seconds | 0.00 - 0.70 |
| Prothrombin Time (INR) usingDade® Innovin® (0.93 – 8.00INR) | 1.02 – 7.66INR | 0.00 - 0.88 |
| Activated PartialThromboplastin Time usingDade® Actin® FSL(20.0 - 139.0 sec) | 22.10 - 127.52seconds | 0.11 - 3.86 |
| Fibrinogen quantitation usingDade® Thrombin Reagent(50 - 860 mg/dL) | 55.9 - 738.5 mg/dL | 0.00 - 2.05 |
| Antithrombin quantitationusing INNOVANCE®Antithrombin(9.0- 128.0% of norm) | 11.39 - 121.05%of norm | 2.00 - 4.43 |
| D-dimer quantitation usingINNOVANCE® D-Dimer (0.19 –35.20 mg/L FEU) | 0.26 – 31.77 mg/LFEU | 0.00 - 3.99 |
7.3 Detection Capability Results
Detection capability studies were measured for the calibrated assays on the Sysmex CS-2100i: Fibrinogen with Dade® Thrombin Reagent, Antithrombin with INNOVANCE® Antithrombin, and Ddimer with INNOVANCE® D-Dimer. Studies were conducted following the description in CLSI document EP17-A2 'Evaluation of Detection Capability for Clinical Laboratory Measurement Procedures'. All reagents met the pre-determined acceptance criteria and support the lower limit of the clinical reportable range claim.
{21}------------------------------------------------
| Sysmex CS-2100i: Summary of Limit of Quantitation | ||||
|---|---|---|---|---|
| Reagent | Lower Limit ofClinical ReportableRange | Measured Limitof Quantitation | Maximum TotalError (%)Result | |
| Fibrinogen quantitationwith Dade® ThrombinReagent | 50.0 mg/dL | 46.1 mg/dL | 14.83% | |
| Antithrombin quantitationwith INNOVANCE®Antithrombin | 9.0% of norm | 8.78% of norm | 26.17% | |
| D-dimer quantitation withINNOVANCE® D-Dimer | 0.19 mg/L FEU | 0.15 mg/L FEU | 40.40% |
The Sysmex CS-2100i performs tests with three non-calibrated test applications: PT seconds with Dade® Innovin®, PT INR with Dade® Innovin®, and APTT with Dade® Actin® FSL Activated PTT Reagent. There is no detection limit for these reagents and the measuring interval is set at the lower end of the measurement interval by a software setting.
7.4 Linearity & Measuring Range
Linearity studies were performed for the following calibrated assays on the Sysmex CS-2100i: Fibrinogen with Dade® Thrombin Reagent, Antithrombin with INNOVANCE® Antithrombin, and D-dimer with INNOVANCE® D-Dimer. All reagents met the pre-determined acceptance criteria and support the clinical reportable range claim. The Sysmex CS-2100i performs tests with three non-calibrated test applications: PT seconds with Dade® Innovin®, PT INR with Dade® Innovin®, and APTT with Dade® Actin® FSL. Linearity testing is not applicable to non-calibrated assays. Studies were conducted as described in CLSI EP6-A "Evaluation of the Linearity of Quantitative Measurement Procedures: A Statistical Approach".
{22}------------------------------------------------
| Sysmex CS-2100i: Summary of Linearity and Measuring Range | ||
|---|---|---|
| Reagent | Measured Linear Range | Clinical Reportable Range |
| Prothrombin Time(seconds) with Dade®Innovin® | Not applicable | 8.7 to 90.0 seconds |
| Prothrombin Time (INR)with Dade® Innovin® | Not applicable | 0.93 to 8.00 INR |
| Activated PartialThromboplastin Time(seconds) with Dade®Actin® FSL | Not applicable | 20.0 to 139.0 seconds |
| Fibrinogen quantitation(mg/dL) with Dade®Thrombin Reagent | 40.3 to 1124.0 mg/dL | 50 to 860 mg/dL |
| Antithrombin quantitation(% of norm) withINNOVANCE® Antithrombin | 6.28 to 152.30% of norm | 9.0 to 128.0% of norm |
| D-dimer quantitation (mg/LFEU) with INNOVANCE® D-Dimer | 0.15 to 50.86 mg/L FEU | 0.19 to 35.20 mg/L FEU |
7.5 Reference Interval
Reference interval studies were conducted at three clinical study sites in the United States. The summary is provided below.
| Application | Sysmex CS-2100i ReferenceInterval |
|---|---|
| Prothrombin Time (seconds) using Dade®Innovin® | 2.5th – 97.5th perc.9.5 – 12.1 |
| Prothrombin Time (INR) using Dade®Innovin® | 2.5th – 97.5th perc.0.93 – 1.15 |
| Activated Partial Thromboplastin Time(seconds) using Dade® Actin® FSL | 2.5th – 97.5th perc.23.9 – 30.7 |
{23}------------------------------------------------
| Application | Sysmex CS-2100i ReferenceInterval |
|---|---|
| Fibrinogen quantitation using Dade®Thrombin Reagent (mg/dL) | 2.5th – 97.5th perc.187 – 446 |
| Antithrombin quantitation usingINNOVANCE® Antithrombin (% of norm) | 2.5th – 97.5th perc.79.2 – 125.3 |
| D-dimer quantitation using INNOVANCE®D-Dimer (mg/L FEU) | 2.5th – 97.5th perc.<0.19 – 1.12 |
7.6 D-Dimer PE Exclusion Validation Study Study
The INNOVANCE® D-Dimer assay was evaluated on the Sysmex CS-2100i in a multi-center study to validate the exclusion of Pulmonary Embolism (PE) using frozen specimens collected prospectively from 1930 consecutive outpatients presenting to the emergency or ambulatory department with suspected PE. Of these 1930 patients, 96 were excluded for a total of 1834 patients.
All potentially eligible patients were evaluated using the Wells' rules to estimate their pre-test probability (PTP) with regard to PE, and then categorized into high, intermediate or low PTP. Patients with a high PTP score were excluded from enrollment. Patients with no or a positive Ddimer result with the D-dimer assay used at the respective study center were evaluated by imaging methods, e.q. spiral CT and/or VQ scan. Patients with a negative D-dimer result with the D-dimer assay used at the respective study center underwent imaging at the physician's discretion. All patients with a negative diagnosis of PE at presentation were followed up after three months to evaluate potential development of PE. Patients with unobtainable follow-up data were excluded from analysis resulting in n=1467 patients available for final analysis.
The overall prevalence of PE in the 1467 patients was 6.9 % (101 of 1467) with 6.0 % in the US population and 37.2 % in the European population. The specimens were tested with the INNOVANCE® D-Dimer assay and results were compared to a cut-off value of 0.50 mg/L FEU. A D-dimer result <0.50 mg/L FEU was considered negative and a D-dimer result ≥0.50 mg/L FEU was considered positive. The instrument-specific sensitivity, negative predictive value (NPV) and positive predictive value (PPV) with lower bound of a two-sided 95 % confidence limits (LCL) were obtained with the INNOVANCE® D-Dimer clinical cut-off of 0.50 mg/L FEU. Results obtained for each study population are detailed below.
{24}------------------------------------------------
| US | Reference (Imaging and 3-month follow-up) | |||
|---|---|---|---|---|
| Positive | Negative | Total | ||
| INNOVANCE® D-Dimer on SysmexCS-2100i | Positive | 82 | 616 | 698 |
| Negative | 3 | 723 | 726 | |
| Total | 85 | 1339 | 1424 | |
| Sensitivity %= | 96.5 | 95% LCL= | 90.0 | |
| Specificity %= | 54.0 | 95% LCL= | 51.3 | |
| NPV %= | 99.6 | 95% LCL= | 98.8 | |
| NPV* %= | 98.9 | 95% LCL= | 96.7 | |
| PPV %= | 11.7 | 95% LCL= | 9.6 | |
| PPV* %= | 27.0 | 95% LCL= | 22.7 |
| OUS | Reference (Imaging and 3-month follow-up) | |||
|---|---|---|---|---|
| Positive | Negative | Total | ||
| INNOVANCE® D-Dimer on SysmexCS-2100i | Positive | 16 | 5 | 21 |
| INNOVANCE® D-Dimer on SysmexCS-2100i | Negative | 0 | 22 | 22 |
| INNOVANCE® D-Dimer on SysmexCS-2100i | Total | 16 | 27 | 43 |
| Sensitivity %= | 100.0 | 95% LCL= | 79.4 | |
| Specificity %= | 81.5 | 95% LCL= | 61.9 | |
| NPV %= | 100.0 | 95% LCL= | 85.1 | |
| NPV* %= | 100.0 | 95% LCL= | 95.1 | |
| PPV % | 76.2 | 95% LCL= | 54.9 | |
| PPV* %= | 48.8 | 95% LCL= | 26.6 |
| US and OUS | Reference (Imaging and 3-month follow-up) | |||
|---|---|---|---|---|
| Positive | Negative | Total | ||
| INNOVANCE® D-Dimer on SysmexCS-2100i | Positive | 98 | 621 | 719 |
| Negative | 3 | 745 | 748 | |
| Total | 101 | 1366 | 1467 | |
| Sensitivity %= | 97.0 | 95% LCL= | 91.6 | |
| Specificity %= | 54.5 | 95% LCL= | 51.9 | |
| NPV %= | 99.6 | 95% LCL= | 98.8 | |
| NPV* %= | 99.0 | 95% LCL= | 97.2 | |
| PPV %= | 13.6 | 95% LCL= | 11.3 | |
| PPV* %= | 27.4 | 95% LCL= | 23.3 |
*standardized to a prevalence of 15%
{25}------------------------------------------------
8. Conclusion
Since the predicate device was cleared based in part on the results of clinical studies, and since 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 hardware and software verification and validation demonstrate that the Sysmex CS-2100i performs as intended in the specified use conditions. The clinical data demonstrates 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 demonstrate 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.