Predicate Devices

Reference Devices

No reference devices were used in this submission.

AI/ML (Artificial Intelligence / Machine Learning)

No
The document describes a standard automated blood coagulation analyzer and its associated reagents, focusing on analytical performance studies. There is no mention of AI, ML, or related concepts like image processing or training/test sets for algorithmic development.

Therapeutic

No.
The device is an in vitro diagnostic (IVD) blood coagulation analyzer, meaning it analyzes blood samples to provide diagnostic information, rather than directly treating a disease or condition in a patient.

Diagnostic

Yes

The "Intended Use / Indications for Use" section explicitly states that the device is "intended for in vitro diagnostic use."

SaMD (Software as a Medical Device)

No

The device description explicitly states it is an "automated blood coagulation instrument" and mentions hardware components like the "Information Processing Unit (IPU) screen" and the ability to print on "external printers". While software is involved in processing results, the core device is a physical instrument.

IVD (In Vitro Diagnostic)

Yes, this device is an IVD (In Vitro Diagnostic).

Here's why:

Explicit Statement: The "Intended Use / Indications for Use" section explicitly states: "The Sysmex® CS-5100 is a fully automated blood coagulation analyzer intended for in vitro diagnostic use..."
Purpose: The device is designed to analyze plasma collected from venous blood samples to determine various coagulation parameters (PT, APTT, Fibrinogen, Antithrombin, D-dimer). This analysis is performed in vitro (outside the body) on biological specimens to provide information for diagnostic purposes.
Clinical Laboratory Setting: The intended user/care setting is a "clinical central/hospital laboratory," which is where IVD devices are typically used.
Associated Materials: The description mentions the use of associated Reagents, Controls, and Calibrators, which are common components of IVD systems.

All these points align with the definition and characteristics of an In Vitro Diagnostic device.

PCCP (Predetermined Change Control Plan) Authorized

N/A

Overview

Intended Use / Indications for Use

The Sysmex CS-5100 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.

Product codes (comma separated list FDA assigned to the subject device)

JPA

Device Description

The Sysmex CS-5100 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 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:

Clotting (extrinsic pathway) for PT, Prothrombin Time (seconds) with Dade® Innovin®
Clotting, calculated for PT, Prothrombin Time (INR) with Dade® Innovin®
Clotting (intrinsic pathway) for APTT, Activated Partial Thromboplastin Time with Dade® Actin® FSL
Clotting (common pathway) for Fibrinogen quantitation with Dade® Thrombin Reagent
Chromogenic for Antithrombin quantitation with INNOVANCE® Antithrombin
Immunochemical for D-dimer quantitation with INNOVANCE® D-Dimer

The instrument features a light shield lid, power switch, left door holding the Pneumatic Unit, alarm indicator LED, mechanical stop switch, start button, sampler, and right door. The Informational Processing Unit (IPU) consists of a touch panel display, IPU Main Unit, keyboard, and mouse. Options and accessories include a waste tank, wand barcode reader, 2D barcode reader, IPU cart, external indicator light, and IPU holder. The instrument is capable of measuring in Normal mode (capped sample tube analysis, automatic re-analysis) and Micro-sample mode (uncapped sample tubes, less sample volume, no automatic re-analysis).

Mentions image processing

Not Found

Mentions AI, DNN, or ML

Not Found

Input Imaging Modality

Not Found

Anatomical Site

Not Found

Indicated Patient Age Range

The performance of this device has not been established in neonate and pediatric patient populations.

Intended User / Care Setting

clinical central/hospital laboratory.

Description of the training set, sample size, data source, and annotation protocol

Not Found

Description of the test set, sample size, data source, and annotation protocol

Not Found

Summary of Performance Studies (study type, sample size, AUC, MRMC, standalone performance, key results)

Method comparison:

Study Type: Method comparison studies designed according to EP09-A3 CLSI Guideline "Measurement Procedure Comparison and Bias Estimation Using Patient Samples".
Sample Size: Varies by application. For Prothrombin Time (seconds) using Dade® Innovin®, n=469. For Prothrombin Time (INR) using Dade® Innovin®, n=465. For Activated Partial Thromboplastin Time using Dade® Actin® FSL, n=466. For Fibrinogen quantitation using Dade® Thrombin Reagent, n=368. For Antithrombin quantitation using INNOVANCE® Antithrombin, n=381. For D-dimer quantitation using INNOVANCE® D-Dimer, n=361.
Data Source: Three external sites in the United States.
Key Results: Results were compared by Passing-Bablok regression analysis as well as Bland-Altman plots. Results from each application met the pre-established acceptance criteria, showing that the proposed and predicate devices provide equivalent results.

Reproducibility Studies:

Study Type: Twenty-day precision studies theo CLSI EP05-A2 "Evaluation of Precision Performance of Quantitative Measurement Methods".
Data Source: Two external sites in Germany and one external site in the United States.
Key Results: Within Run, Between Run, Between Day, and Total With-in Site precision were calculated. The data is summarized in tables with %CV values for each application and site.

Detection Capability Results:

Study Type: Detection capability studies theo CLSI document EP17-A2 'Evaluation of Detection Capability for Clinical Laboratory Measurement Procedures'.
Key Results: Data for Fibrinogen, Antithrombin, and D-dimer met pre-determined acceptance criteria and support the lower limit of the clinical reportable range claim.

Linearity & Measuring Range:

Study Type: Linearity studies theo CLSI EP6-A "Evaluation of the Linearity of Quantitative Measurement Procedures: A Statistical Approach".
Key Results: For calibrated assays (Fibrinogen, Antithrombin, D-dimer), all reagents met pre-determined acceptance criteria and support the clinical reportable range claim. Linearity testing is not applicable to non-calibrated assays (PT seconds, PT INR, APTT).

Reference Interval:

Study Type: Reference interval studies.
Data Source: Three clinical study sites in the United States.
Key Results: Reference intervals (2.5th – 97.5th percentile) were established for all five assays. The study population did not include neonate and pediatric sample populations.

D-Dimer PE Exclusion Validation Study:

Study Type: Multi-center study to validate the exclusion of Pulmonary Embolism (PE) using frozen specimens.
Sample Size: 1930 consecutive outpatients, reduced to 1467 for final analysis.
Data Source: Outpatients presenting to emergency or ambulatory department with suspected PE.
Key Results: The INNOVANCE® D-Dimer assay on the Sysmex CS-5100 had high sensitivity and NPV for PE exclusion, with results detailed for US, OUS, and combined populations.

Key Metrics (Sensitivity, Specificity, PPV, NPV, etc.)

D-dimer PE Exclusion Validation Study (US population):

Sensitivity % = 97.6 (95% LCL = 91.8)
Specificity % = 54.0 (95% LCL = 51.3)
NPV % = 99.7 (95% LCL = 99.0)
NPV* % = 99.2 (95% LCL = 97.3) (standardized to a prevalence of 15%)
PPV % = 11.9 (95% LCL = 9.7)
PPV* % = 27.2 (95% LCL = 23.0) (standardized to a prevalence of 15%)

D-dimer PE Exclusion Validation Study (OUS population):

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) (standardized to a prevalence of 15%)
PPV % = 76.2 (95% LCL = 54.9)
PPV* % = 48.8 (95% LCL = 26.6) (standardized to a prevalence of 15%)

D-dimer PE Exclusion Validation Study (US and OUS combined population):

Sensitivity % = 98.0 (95% LCL = 93.0)
Specificity % = 54.5 (95% LCL = 51.9)
NPV % = 99.7 (95% LCL = 99.0)
NPV* % = 99.4 (95% LCL = 97.7) (standardized to a prevalence of 15%)
PPV % = 13.8 (95% LCL = 11.4)
PPV* % = 27.6 (95% LCL = 23.5) (standardized to a prevalence of 15%)

Predicate Device(s): If the device was cleared using the 510(k) pathway, identify the Predicate Device(s) K/DEN number used to claim substantial equivalence and list them here in a comma separated list exactly as they appear in the text. List the primary predicate first in the list.

Sysmex CA-1500 (K011235)

Reference Device(s): Identify the Reference Device(s) K/DEN number and list them here in a comma separated list exactly as they appear in the text.

No reference devices were used in this submission.

Predetermined Change Control Plan (PCCP) - All Relevant Information for the subject device only (e.g. presence / absence, what scope was granted / cleared under the PCCP, any restrictions, etc).

Not Found

Regulation Number and Section

§ 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.

Summary

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Image /page/0/Picture/1 description: The image shows the logo for the U.S. Department of Health & Human Services. The logo consists of a circular seal with the text "DEPARTMENT OF HEALTH & HUMAN SERVICES - USA" around the perimeter. Inside the circle is an abstract symbol that resembles a stylized human figure or a series of overlapping profiles. The symbol is composed of three curved lines that create the impression of faces or heads in profile.

Food and Drug Administration 10903 New Hampshire Avenue Document Control Center - WO66-G609 Silver Spring, MD 20993-0002

January 11, 2016

Siemens Healthcare Diagnostics Products GmbH Ms. Donna Noeh Regulatory Manager, US Affairs Emil-von-Behring-Str. 76 35041 Marburg, Germany

Re: K150678

Trade/Device Name: Sysmex CS-5100 Regulation Number: 21 CFR 864.5425 Regulation Name: Multipurpose system for in vitro coagulation studies Regulatory Class: Class II Product Code: JPA Dated: December 10, 2015 Received: December 11, 2015

Dear Ms. Noah:

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

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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 yours.

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) K150678

Device Name Sysmex CS-5100

Indications for Use (Describe)

The Sysmex® CS-5100 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)

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Image /page/4/Picture/0 description: The image shows the word "SIEMENS" in a bold, sans-serif font. The color of the text is a teal or turquoise shade. The letters are evenly spaced and appear to be a logo or brand name.

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: Donna Noeh Email: donna.noeh@siemens.com Phone: + 49 6421 39 5107 Facsimile: + 49 6421 39 4977 Date Prepared: January 7, 2016 2. Device Sysmex CS-5100 Name of Device: Common or Usual Name: Automated Coagulation Instrument Multipurpose system for in vitro coagulation studies (21 CFR Classification Name: 864.5425) 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 CFR 864.5425) Regulatory Class: 2 Product Code: JPA Hematology 510(k) Review Panel

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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4. Device Description / Test Principle

The Sysmex CS-5100 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.

Table of Sysmex CS-5100 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.

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Front View of the Instrument

Image /page/6/Figure/2 description: This image shows a diagram of a machine with several parts labeled with numbers. The top part of the machine is labeled (1), and there are buttons labeled (4), (5), and (6). The middle section has a part labeled (7), and the bottom section has parts labeled (3) and (8), with a button labeled (2) on the side.

(1) Light shield lid: Open this cover to set reagents, perform maintenance, etc.
(2) Power switch: Turns the power ON/OFF.
(3) Left door: Holds the Pneumatic Unit inside. Open this door to adjust the positive pressure (0.22 MPa).
(4) Alarm indicator LED: Indicates the instrument status.
(5) Mechanical stop switch: Press this switch to immediately stop the instrument's mechanical movement.
(6) Start button: Press this button to immediately start an analysis. This button is the same as the [Start] button on the IPU toolbar.
(7) Sampler: Automatically transports samples that are set in the sample rack to the aspiration position.
(8) Right door: Open the door for maintenance or to discard cuvettes.

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Informational Processing Unit

Image /page/7/Figure/2 description: The image shows a desktop computer with a monitor, CPU, keyboard, and mouse. The monitor is labeled as (1), the CPU is labeled as (2), the keyboard is labeled as (3), and the mouse is labeled as (4). The computer is a desktop model, with the CPU placed under the monitor and the keyboard and mouse connected to the CPU.

(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.
(4) IPU cart: The IPU (which includes the keyboard, PC and touch panel display), and the tanks for waste, rinse and CA Clean II can be placed on this cart.
(5) External indicator light: The status of the instrument is indicated with a red, yellow or green light that can be seen when the operator is not directly in front of the instrument.
(6) IPU holder: This is an optional holder for the IPU which includes the keyboard, PC and touch panel display which can be installed on the right side of the instrument to minimize the instrument footprint.

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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: Samples set in the sampler or STAT holder are taken into the instrument for each analysis through a secondary dispensing sample probe. When measurements are to be 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-5100 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.

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 the CS-5100 and CA-1500

Similarities between Sysmex CS-5100 and Sysmex CA-1500
Analyzer Component	Proposed Device
Sysmex CS-5100	Predicate Device
Sysmex CA-1500
Regulatory Classification	JPA, Class 2
System, Multipurpose for in
vitro coagulation studies	Same
Sample Type	Human plasma
3.2% sodium citrate	Same
Similarities between Sysmex CS-5100 and Sysmex CA-1500
Analyzer Component	Proposed Device	Predicate Device
	Sysmex CS-5100	Sysmex CA-1500
Application type	Clotting Applications:
Prothrombin Time (PT) with
Dade® Innovin®;
Activated Partial Thromboplastin
Time (APTT) with Dade® Actin®
FSL;
Fibrinogen (Clauss) with Dade®
Thrombin Reagent

Chromogenic Application:
Antithrombin with
INNOVANCE® Antithrombin

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There are no technological differences between the subject and predicate devices. However the following minor changes exist between the subject and predicate devices:

Differences between Sysmex CS-5100 and Sysmex CA-1500
Analyzer Component	Proposed Device	Predicate Device
	Sysmex CS-5100	Sysmex CA-1500
Intended Use Statement	The Sysmex CS-5100 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.	The intended use of the Sysmex CA-
1500 is as a fully automated,
computerized blood plasma
coagulation analyzer for in vitro
diagnostic use in clinical
laboratories.
The instrument uses citrated
human plasma to perform the
following parameters and
calculated parameters:
Clotting Analysis Prameters:
Prothrombin Time (PT); Activated
Partial Thromboplastin Time
(APTT); Fibrinogen (Clauss);
Batroxobin Time; Extrinsic Factors
(II, V, VII, X); Intrinsic Factors
(VIII, IX, XI, XII); Protein C.
Chromogenic Analysis
Parameters: Antithrombin III;
Factor VIII; Plasminogen;
Heparin; Protein C; α2-
Antiplasmin.
Immunologic Analysis Parameters:
D-dimer.
Calculated Parameters: PT Ratio;
PT INR; PT %; Derived Fibrinogen;
Factor Assays % Activity
Differences between Sysmex CS-5100 and Sysmex CA-1500
	Proposed Device	Predicate Device
Analyzer Component	Sysmex CS-5100	Sysmex CA-1500
Operating Principle
Clotting	Transmitted Light Detection
(Absorbance) at 340, 405, 575, 660 or
800 nm. Wavelengths 340 and 575 are
technically available but not validated in
combination with the intended
applications.	Scattered Light Detection at 660 nm
Chromogenic	Transmitted Light Detection
(Absorbance) at 340, 405, 575, 660,
800 nm. Wavelengths 340, 575, 660,
and 800 are technically available but not
validated in combination with the
intended applications.	Transmitted Light Detection
(Absorbance) 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 technically available but not
validated in combination with the
intended applications.	Transmitted Light Detection
(Absorbance) at 405, 575, or 800 nm
Wavelengths* used in Analysis
*The default wavelength is normally
used to generate the reported value of
the measurement. The sub-wavelength	Clotting Applications:
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® FSL
Activated PTT Reagent (Default =
660 nm; Sub-Wavelength= 800 nm) | Clotting Applications:
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® FSL
Activated PTT Reagent (Default
= 660 nm; Sub-Wavelength=
none) |
| is run in parallel. If a light intensity
error occurs by using the default
wavelength the value from the sub-
wavelength is used automatically. | Fibrinogen with Dade® Thrombin
Reagent (Default = 405 nm; Sub-
Wavelength= none)

Immuno-chemical Application:
D-dimer with INNOVANCE®
D-Dimer (Default = 660 nm; Sub-
Wavelength= none) | Fibrinogen with Dade® Thrombin
(Default = 660 nm;
Sub-Wavelength= none)

Reagent probe: 37°C ± 1.0°C |
| Reagent Cooling | 10°C ± 2°C, when ambient temperature is 20°C - 28°C.
During operation 4°C -15°C, when ambient temperature is 15°C – 30°C | 15°C ± 2°C, when ambient temperature is 15°C - 30°C |
| Pipetting Capabilities | Reagent probe:
20 – 200 μL
Sample probe:
4 – 270 μL | Reagent probe:
3 – 200 μL
Sample probe:
5 – 450 μL |
| Sample Volumes in Micro
Mode (Plasma) | Antithrombin with INNOVANCE® Antithrombin 14 μL
D-dimer with INNOVANCE® D-Dimer 15 µL | Antithrombin with INNOVANCE® Antithrombin 10 μL
D-dimer with INNOVANCE® D-Dimer 13 µL |
| Bidirectional Interface
communication protocols | CA-, ASTM-, CS- Protocol | CA-, ASTM-Protocol |

Differences between CS-5100 and CA-1500

12

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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 protocol.

14

Samples were measured on both the predicate device (Sysmex CA-1500) as well as the new device (Sysmex CS-5100), 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 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.

Sysmex CS-5100: Method Comparison Summary Table, Passing-Bablok regression
Application
(measuring interval)	Site 01	Site 02	Site 03	Sites Combined
Prothrombin
Time using
Dade® Innovin®
(8.7 - 90.0
seconds)	n=125
$y = 1.000x + 0.400$
r = 0.997	n=209
$y = 1.000x + 0.000$
r = 0.999	n=135
$y = 0.987x +0.374$
r = 0.999	n=469
$y = 1.000x + 0.100$
r = 0.998
Prothrombin
Time (INR) using
Dade® Innovin®
(0.93 - 8.00 INR)	n=122
$y = 1.044x - 0.037$
r = 0.997	n=208
$y = 1.030x-0.038$
r = 0.999	n=135
$y = 1.039x - 0.019$
r = 0.999	n=465
$y = 1.047x-0.047$
r = 0.999
Activated Partial
Thromboplastin
Time using
Dade® Actin®
FSL
(20.0 - 139.0
seconds)	n=126
$y = 1.029x - 1.112$
r = 0.994	n=210
$y = 1.017x-1.203$
r = 0.998	n=130
$y = 1.027x - 1.225$
r = 0.994	n=466
$y = 1.026x - 1.315$
r = 0.996
Fibrinogen
quantitation
using Dade®
Thrombin Reagent
(50 - 860 mg/dL)	n=145
$y = 1.052x -4.466$
r = 0.994	n=91
$y = 1.028x + 5.491$
r = 0.996	n=132
$y = 0.982x + 9.889$
r = 0.998	n=368
$y = 1.018x + 4.633$
r = 0.995
Antithrombin
quantitation
using
INNOVANCE®
Antithrombin
(9.0 - 128.0% of
norm)	n=135
$y = 0.990x-0.413$
r = 0.996	n=120
$y = 0.957x + 1.825$
r = 0.994	n=126
$y = 0.985x - 0.359$
r = 0.997	n=381
$y = 0.980x + 0.222$
r = 0.996

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Sysmex CS-5100: Method Comparison Summary Table, Passing-Bablok regression
D-dimer
quantitation
using
INNOVANCE®
D-Dimer (0.19 –
35.20 mg/L FEU¹)	n=137	n= 108	n=116	n=361
	$y = 1.058x-0.013$
r = 0.997	$y = 1.000x - 0.035$
r = 0.997	$y = 1.000x + 0.000$
r = 0.998	$y = 1.021x - 0.007$
r = 0.996

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 With-in Site was calculated. The data is summarized in the following tables.

Sysmex CS-5100: Reproducibility Summary Table, Within Run
Application
(CRR/
Clotting time range)	Sample
Range (mean
of all sites)	Site 01
Within Run
(%CV)	Site 02
Within Run
(%CV)	Site 03
Within Run
(%CV)	Sites
Combined
(%CV)
Prothrombin Time
using Dade® Innovin®
(8.7 - 90.0 seconds)	9.27 - 79.67
seconds	0.64 – 1.85	0.47 – 0.98	0.51 - 3.61	0.59 — 2.35
Prothrombin Time
(INR) using Dade®
Innovin® (0.93 - 8.00
INR)	1.02 - 7.76
INR	0.62 - 2.21	0.45 - 0.92	0.44 - 1.31	0.51 - 1.50
Activated Partial
Thromboplastin Time
using Dade® Actin®
FSL
(20.0 - 139.0 seconds)	22.02 -
123.25
seconds	0.71 - 5.51	0.51 - 3.05	0.56 - 2.67	0.76 - 3.93
Fibrinogen
quantitation using
Dade® Thrombin
Reagent
(50 - 860 mg/dL)	56.2 - 752.6
mg/dL	1.14 - 6.18	0.99 - 3.27	1.41 - 2.72	1.20 - 4.20

1 D-dimer results are reported in fibrinogen equivalent units (FEU).

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Sysmex CS-5100: Reproducibility Summary Table, Within Run
Antithrombin
quantitation using
INNOVANCE®
Antithrombin
(9.0 - 128.0% of norm)	10.17 -
119.41% of
norm	0.71 - 2.66	0.81 - 3.45	0.97 - 3.13	0.92 - 3.11
D-dimer quantitation
using INNOVANCE®
D-Dimer (0.19 - 35.20
mg/L FEU)	0.25 - 33.81
mg/L FEU	0.91 - 2.15	0.80 - 1.56	1.27 – 2.51	1.08 – 2.07

Sysmex CS-5100: Reproducibility Summary Table, Between Run
Application
(CRR/
Clotting time range)	Sample Range
(mean of all
sites)	Site 01
Between Run
(%CV)	Site 02
Between Run
(%CV)	Site 03
Between Run
(%CV)	Sites
Combined
(%CV)
Prothrombin Time
using Dade®
Innovin®
(8.7 - 90.0 sec)	9.27 - 79.67
seconds	0.12 - 1.73	0.00 - 1.15	0.00 - 1.45	0.35 - 1.42
Prothrombin Time
(INR) using Dade®
Innovin® (0.93 –
8.00 INR)	1.02 – 7.76
INR	0.00 - 2.05	0.00 - 1.12	0.53 - 1.30	0.25 - 1.37
Activated Partial
Thromboplastin
Time using Dade®
Actin® FSL
(20.0 - 139.0 sec)	22.02 - 123.25
seconds	0.00 - 0.97	0.00 - 2.50	0.29 - 2.66	0.34 - 2.40
Fibrinogen
quantitation using
Dade® Thrombin
Reagent
(50 - 860 mg/dL)	56.2 - 752.6
mg/dL	0.00 - 1.25	0.00 - 1.07	0.00 - 1.26	0.00 - 0.88
Antithrombin
quantitation using
INNOVANCE®
Antithrombin
(9.0 - 128.0% of
norm)	10.17 -
119.41% of
norm	0.42 - 1.40	0.00 - 4.33	0.94 - 4.45	0.78 - 3.73

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Sysmex CS-5100: Reproducibility Summary Table, Between Run
D-dimer
quantitation using
INNOVANCE® D-
Dimer (0.19 – 35.20
mg/L FEU)	0.25 - 33.81
mg/L FEU	0.33 - 1.18	0.00 - 1.50	0.00 - 2.12	0.30 - 1.61

Sysmex CS-5100: Reproducibility Summary Table, Between Day
Application
(CRR/
Clotting time
range)	Sample Range
(mean of all
sites)	Site 01
Between Day
(%CV)	Site 02
Between Day
(%CV)	Site 03
Between Day
(%CV)	Sites
Combined
(%CV)
Prothrombin Time
using Dade®
Innovin®
(8.7 - 90.0 sec)	9.27 - 79.67
seconds	0.00 - 0.97	0.00 - 0.57	0.00 - 2.45	0.17 - 1.45
Prothrombin Time
(INR) using Dade®
Innovin® (0.93 –
8.00 INR)	1.02 - 7.76
INR	0.00 - 2.81	0.00 - 0.60	0.44 - 2.38	0.26 - 1.78
Activated Partial
Thromboplastin
Time using Dade®
Actin® FSL
(20.0 - 139.0 sec)	22.02 - 123.25
seconds	0.00 - 3.84	0.00 - 1.94	0.00 - 3.82	0.11 - 2.77
Fibrinogen
quantitation using
Dade® Thrombin
Reagent
(50 - 860 mg/dL)	56.2 - 752.6
mg/dL	0.00 - 1.11	0.00 - 1.02	0.00 - 1.11	0.00 - 0.74
Antithrombin
quantitation using
INNOVANCE®
Antithrombin
(9.0 - 128.0% of
norm)	10.17 -
119.41% of
norm	0.00 - 1.84	0.00 - 1.62	0.00 - 1.18	0.00 - 1.22
D-dimer
quantitation using
INNOVANCE® D-
Dimer (0.19 - 35.20
mg/L FEU)	0.25 - 33.81
mg/L FEU	1.49 - 5.95	0.00 - 1.56	0.85 - 3.19	1.14 - 3.86

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Sysmex CS-5100: Reproducibility Summary Table, Site-to-Site
Application
(CRR/
Clotting time range)	Sample Range (mean of all
sites)	Sites
Combined
(%CV)
Prothrombin Time using Dade®
Innovin®
(8.7 - 90.0 sec)	9.27 - 79.67 seconds	0.00 – 0.95
Prothrombin Time (INR) using Dade®
Innovin® (0.93 - 8.00 INR)	1.02 - 7.76
INR	0.09 - 1.21
Activated Partial Thromboplastin
Time using Dade® Actin® FSL
(20.0 - 139.0 sec)	22.02 - 123.25 seconds	0.04 - 5.16
Fibrinogen quantitation using Dade®
Thrombin Reagent
(50 – 860 mg/dL)	56.2 - 752.6 mg/dL	0.97 - 3.96
Antithrombin quantitation using
INNOVANCE® Antithrombin
(9.0 – 128.0% of norm)	10.17 - 119.41% of norm	0.85 — 2.88
D-dimer quantitation using
INNOVANCE® D-Dimer (0.19 - 35.20
mg/L FEU)	0.25 - 33.81 mg/L FEU	0.61 - 2.93

CS-5100: Reproducibility Summary Table, Total CV (Within Site)
Application
(CRR/
Clotting time
range)	Sample
Range (mean
of all sites)	Site 01
Total Within
Site (%CV)	Site 02
Total Within
Site (%CV)	Site 03
Total Within
Site (%CV)	Sites
Combined
(%CV)
Prothrombin Time
using Dade®
Innovin®
(8.7 - 90.0 sec)	9.27 - 79.67
seconds	0.82 - 2.42	0.52 - 1.39	1.00 - 4.17	0.86 - 2.95
Prothrombin Time
(INR) using Dade®
Innovin® (0.93 –
8.00 INR)	1.02 - 7.76
INR	0.73 - 4.12	0.49 - 1.36	0.86 - 3.00	0.72 - 2.96
Activated Partial
Thromboplastin
Time using Dade®
Actin® FSL
(20.0 - 139.0 sec)	22.02 –
123.25
seconds	0.85 - 6.78	0.58 – 3.95	0.72 - 5.37	1.00 - 7.45

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CS-5100: Reproducibility Summary Table, Total CV (Within Site)
Fibrinogen
quantitation using
Dade® Thrombin
Reagent
(50 - 860 mg/dL)	56.2 - 752.6
mg/dL	1.31 - 6.18	1.29 – 3.52	1.60 - 2.94	2.08 - 4.33
Antithrombin
quantitation using
INNOVANCE®
Antithrombin
(9.0 - 128.0% of
norm)	10.17 -
119.41% of
norm	1.07 - 3.53	1.17 - 5.53	1.55 - 5.44	1.81 - 5.64
D-dimer
quantitation using
INNOVANCE® D-
Dimer (0.19 - 35.20
mg/L FEU)	0.25 - 33.81
mg/L FEU	2.0 - 6.40	1.31 - 2.21	2.16 - 4.58	2.05 - 5.51

7.3 Detection Capability Results

Detection capability studies were measured for the calibrated assays on the Sysmex CS-5100: Fibrinogen with Dade® Thrombin Reagent, Antithrombin with INNOVANCE® Antithrombin, and D-dimer with INNOVANCE® D-Dimer. 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 pre-determined acceptance criteria and support the lower limit of the clinical reportable range claim.

Sysmex CS-5100: Summary of Limit of Quantitation Studies
Reagent	Lower Limit of
Clinical Reportable
Range	Measured Limit of
Quantitation	Maximum Total
Error (%) Result
Fibrinogen quantitation using
Dade® Thrombin Reagent	50 mg/dL	46.1 mg/dL	16.66%
Antithrombin quantitation using
INNOVANCE® Antithrombin	9.0% of norm	8.783% of norm	27.34%
D-dimer quantitation using
INNOVANCE® D-Dimer	0.19 mg/L FEU	0.146 mg/L FEU	31.76%

The Sysmex CS-5100 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.

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Linearity & Measuring Range 7.4

Linearity studies were performed for the following calibrated assays on the Sysmex CS-5100: 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-5100 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 noncalibrated assays. Studies were conducted as described in CLSI EP6-A "Evaluation of the Linearity of Quantitative Measurement Procedures: A Statistical Approach".

Sysmex CS-5100: Linearity and Measuring Range Summary
Reagent	Measured Linear Range	Clinical Reportable
Range
Prothrombin Time (seconds)
using Dade® Innovin®	Not applicable	8.7 - 90.0 seconds
Prothrombin Time (INR)
using Dade® Innovin®	Not applicable	0.93 - 8.00 INR
Activated Partial
Thromboplastin Time
(seconds) using Dade®
Actin® FSL	Not applicable	20.0 - 139.0 seconds
Fibrinogen quantitation
(mg/dL) using Dade®
Thrombin Reagent	40.300 to 1124.000 mg/dL	50 to 860 mg/dL
Antithrombin quantitation
(% of norm) using
INNOVANCE® Antithrombin	6.280 to 152.300% of norm	9.0 to 128.0% of norm
D-dimer quantitation (mg/L
FEU) using INNOVANCE®
D-Dimer	0.149 to 50.862 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. The study population did not include neonate and pediatric sample populations.

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Application	Sysmex CS-5100 Reference Interval
Prothrombin Time (seconds) using
Dade® Innovin®	2.5th – 97.5th perc.
9.6 – 12.3
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 – 29.9
Fibrinogen quantitation using
Dade® Thrombin Reagent (mg/dL)	2.5th – 97.5th perc.
194 – 448
Antithrombin quantitation using
INNOVANCE® Antithrombin
(% of norm)	2.5th – 97.5th perc.
80.7 – 121.9
D-dimer quantitation using
INNOVANCE® D-Dimer
(mg/L FEU)	2.5th – 97.5th perc.
0.50 mg/L FEU was considered positive. The instrument-specific sensitivity, specificity, negative predictive value (NPV) and positive predictive value (PPV) with lower bound (LCL) of two-sided 95%

22

confidence interval 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.

US	Reference (Imaging and 3-month follow-up)
		Positive	Negative	Total
INNOVANCE
® D-Dimer on
Sysmex CS-5100	Positive	83	616	699
	Negative	2	723	725
	Total	85	1339	1424
Sensitivity %=	97.6	95% LCL=	91.8
Specificity %=	54.0	95% LCL=	51.3
NPV %=	99.7	95% LCL=	99.0
NPV* %=	99.2	95% LCL=	97.3
PPV %=	11.9	95% LCL=	9.7
PPV* %=	27.2	95% LC=	23.0

OUS	Reference (Imaging and 3-month follow-up)
		Positive	Negative	Total
INNOVANCE
® D-Dimer on
Sysmex CS-5100	Positive	16	5	21
	Negative	0	22	22
	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

23

US and OUS		Reference (Imaging and 3-month follow-up)
		Positive	Negative	Total
INNOVANCE
® D-Dimer on
Sysmex CS-
5100	Positive	99	621	720
	Negative	2	745	747
	Total	101	1366	1467
Sensitivity %=	98.0	95% LCL=	93.0
Specificity %=	54.5	95% LCL=	51.9
NPV %=	99.7	95% LCL=	99.0
NPV* %=	99.4	95% LCL=	97.7
PPV %=	13.8	95% LCL=	11.4
PPV* %=	27.6	95% LCL=	23.5

*standardized to a prevalence of 15%

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 hardware and software verification and validation demonstrate that the Sysmex CS-5100 performs as intended in the specified use conditions.

The clinical data demonstrate that the Sysmex CS-5100 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.