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.

Device Description

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 is to expand the use of the INNOVANCE® D-Dimer for the exclusion of Deep Vein Thrombosis on Sysmex CS-2100i. All other established indications, performance and technology characteristics as cleared under K151259 remain unchanged.

AI/ML Overview

Here's an analysis of the acceptance criteria and study detailed in the provided document:

The document describes the Sysmex CS-2100i, a fully automated blood coagulation analyzer, and focuses on the expansion of its use for the INNOVANCE® D-Dimer assay for the exclusion of Deep Vein Thrombosis (DVT).

1. Table of Acceptance Criteria and Reported Device Performance

The document does not explicitly state pre-defined acceptance criteria for the DVT exclusion performance. Instead, it reports the diagnostic performance metrics obtained from the study. The implication is that these reported metrics were deemed acceptable for market clearance.

Performance Metric	Acceptance Criteria (Implicit from context or general clinical requirements)	Reported Device Performance (US and OUS sites combined)
Sensitivity	High (crucial for DVT exclusion – to minimize false negatives)	97.5% (95% LCL = 91.3%)
Specificity		46.1% (95% LCL = 43.3%)
Negative Predictive Value (NPV)	Very High (crucial for DVT exclusion – to minimize false negatives and rule out DVT)	99.7% (95% LCL = 98.7%)
NPV (standardized to 15% prevalence)		99.1% (95% LCL = 96.6%)
Positive Predictive Value (PPV)		10.5% (95% LCL = 8.5%)
PPV (standardized to 15% prevalence)		24.2% (95% LCL = 20.2%)

Note: The FDA's clearance implies that the reported NPV of 99.7% (and 99.1% standardized) met the necessary threshold for indicating substantial equivalence for DVT exclusion, as a high NPV is critical for "ruling out" the disease.

2. Sample Size Used for the Test Set and Data Provenance

Total Initial Patient Sample Size: 1907 consecutive outpatients.
Excluded from Analysis: 368 patients (including 213 with previously documented or chronic DVT).
Patients for Final Analysis: 1317 patients.
- US Sites: 803 patients
- OUS (Outside US) Sites: 514 patients
Data Provenance: Multicenter study. Data was collected prospectively from patients in the US and Europe (OUS sites are likely European, given the company's origin in Germany). The study included consecutive outpatients presenting to emergency or ambulatory departments.

3. Number of Experts Used to Establish the Ground Truth for the Test Set and Qualifications

The document specifies that the reference standard for DVT diagnosis involved imaging methods, e.g., ultrasound, and a 3-month follow-up to evaluate potential DVT development. It does not explicitly state the number or specific qualifications of experts (e.g., radiologists, vascular specialists) involved in interpreting these imaging studies or clinical follow-ups. However, "Reference (Imaging and 3-month follow-up)" implies that the ground truth was established by standard clinical diagnostic procedures, which inherently involve qualified medical professionals.

4. Adjudication Method for the Test Set

The document does not explicitly describe an adjudication method for conflicting interpretations of imaging results or clinical diagnoses. It states that patients with "no or a positive D-dimer result with the D-dimer assay used at the respective study center were evaluated by imaging methods, e.g. ultrasound," and "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 clinical diagnosis were followed up. This suggests that the final clinical diagnosis, incorporating imaging and follow-up, served as the ground truth. There is no mention of multiple expert readers or a consensus process for the ground truth determination itself, beyond the standard practices for diagnostic imaging interpretation and clinical follow-up.

5. Multi-Reader Multi-Case (MRMC) Comparative Effectiveness Study

No. The study described is a diagnostic accuracy study for the device (Sysmex CS-2100i with INNOVANCE® D-Dimer) in a standalone manner compared to clinical ground truth. It is not an MRMC comparative effectiveness study involving human readers with and without AI assistance. Therefore, there is no effect size reported for human readers improving with AI.

6. Standalone Performance Study

Yes. The study evaluates the standalone performance of the INNOVANCE® D-Dimer assay on the Sysmex CS-2100i system. The performance metrics (Sensitivity, Specificity, NPV, PPV) are calculated for the device's output (D-dimer result <0.50 mg/L FEU vs. ≥0.50 mg/L FEU) against the established ground truth. This is a direct measurement of the algorithm/device's performance without human intervention in result interpretation for the primary DVT exclusion claim.

7. Type of Ground Truth Used

The ground truth used was a composite clinical diagnosis based on:

Imaging methods (e.g., ultrasound).
3-month clinical follow-up to confirm the absence or presence of DVT.

8. Sample Size for the Training Set

The document is for a 510(k) submission, which typically focuses on demonstrating substantial equivalence rather than detailing the development (training) of the assay itself. The information provided relates to the validation study for the expanded indication.

Therefore, the sample size for the training set is not provided in this document. The INNOVANCE® D-Dimer assay is a reagent manufactured by Siemens, and the Sysmex CS-2100i is the analyzer. The assay itself would have undergone its own development and validation by the manufacturer, which is not covered in this 510(k) extension for the analyzer's use with that assay for this specific indication.

9. How the Ground Truth for the Training Set Was Established

As the training set information is not provided, the method for establishing its ground truth is also not available in this document.

Summary

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

September 01, 2016

Siemens Healthcare Diagnostics Products GmbH Mr. Nils Neumann Regulatory Manager, US Affairs Emil-von-Behring-Str. 76 35041 Marburg, Germany

Re: K161312

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: July 28, 2016 Received: August 1, 2016

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

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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 vours.

Kelly Oliner S

For.

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) K161312

Device Name Sysmex CS-2100i

Indications for Use (Describe)

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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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:	August 26, 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

The predicate has not been subject to a design-related recall for any of the applications associated with this Premarket Notification.

Hematology

No reference devices were used in this submission.

510(k) Review Panel:

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4. Device Description / Test Principle

Reagents ■
. Controls
트 Calibrators
I Consumable materials

5. Intended Use / Indications for Use

For determination of:

. Prothrombin Time (PT) seconds and PT INR with Dade® Innovin®
. Activated Partial Thromboplastin Time (APTT) with Dade® Actin® FSL
. Fibrinogen (Fbq) 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:

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Device Comparison Table

Similarities to the Predicate Device

Similarities between Sysmex CS-2100i and Sysmex CA®-1500
Analyzer Component	Proposed DevicePredicate Device
	Sysmex CS-2100i	Sysmex CA®-1500
RegulatoryClassification	JPA Class 2System, Multipurpose for in vitrocoagulation studies	Same
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 clinicallaboratory.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 theSysmex CA®-1500 is asa fully automated,computerized bloodplasma coagulationanalyzer for in vitrodiagnostic use in clinicallaboratories.The instrument usescitrated human plasmato perform the followingparameters andcalculated parameters:Clotting AnalysisPrameters: ProthrombinTime (PT); ActivatedPartial ThromboplastinTime (APTT); Fibrinogen(Clauss); BatroxobinTime; Extrinsic Factors(II, V, VII, X); IntrinsicFactors (VIII, IX, XI, XII);Protein C.Chromogenic AnalysisParameters:Antithrombin III; FactorVIII; Plasminogen;Heparin; Protein C; α2-Antiplasmin.
Similarities between Sysmex CS-2100i and Sysmex CA®-1500
Analyzer Component	Proposed DeviceSysmex CS-2100i	Predicate DeviceSysmex CA®-1500
		Parameters: D-dimer.Calculated Parameters:PT Ratio; PT INR; PT %;Derived Fibrinogen;Factor Assays % Activity
Application	Immuno-chemical Application:D-dimerwith INNOVANCE® D-Dimer	Same
Sample Type	Human plasma,3.2% sodium citrate	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	D-dimer with INNOVANCE® D-Dimer 13 µL	Same
Differences between Sysmex CS-2100i and Sysmex CA®-1500
Analyzer Component	Proposed DeviceSysmex CS-2100i	Predicate DeviceSysmex CA®-1500
Operating Principle	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
Wavelengths* used inAnalysis	*The default wavelengthis normally used togenerate the reportedvalue of themeasurement. The sub-wavelength is run inparallel. If a light intensityerror occurs by using thedefault wavelength thevalue from the sub-wavelength is usedautomatically.	D-dimer with INNOVANCE® D-Dimer (Default = 660 nm; Sub-Wavelength= none)	D-dimer with INNOVANCE® D-Dimer (Default = 800 nm; Sub-Wavelength= none)
Light Source	Clotting	Halogen Lamp	Light Emitting Diode
Cap Piercing	Cap Piercer only	Both options available:Cap Piercer and No-Cap Piercer
Temperature Control	-Detector : 37 °C ± 0.5 °C-Reagent incubation probe :37.5 °C ± 0.5 °C	-Detector: 37°C ± 1.0°C-Reagent incubation probe: 37°C± 1.0°C
Analyzer Component	Proposed DeviceSysmex CS-2100i	Predicate DeviceSysmex CA®-1500
Reagent Cooling	10°C ± 2°C, when ambienttemperature is 20°C - 28°C.During operation 4°C -15°C, whenambient temperature is 15°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
Sample Volumes inMicro Mode (Plasma)	15 μL	13 μL
Bidirectional Interfacecommunicationprotocols	CA-, ASTM-, CS- Protocol	CA-, ASTM-Protocol

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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:

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The above described differences do not raise new questions as to safety and effectiveness of the new device.

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7. Performance Data

Performance Data: Extended indication for the exclusion of deep vein thrombosis (DVT). See original submission (K151259) for previously conducted analytical and clinical studies:

-Method comparison
-Reproducibility
-Detection Capability
Linearity & Measuring Range
-Reference Interval
-D-dimer PE exclusion validation

7.1 D-Dimer DVT Exclusion Validation Study

The INNOVANCE® D-Dimer assay was evaluated on the Sysmex CS-2100i System in a multicenter study to validate the exclusion of a first event of Deep Vein Thrombosis (DVT) using frozen specimens collected prospectively from 1907 consecutive outpatients presenting to the emergency or ambulatory department with suspected DVT. Of these 1907 patients, 368 were excluded from analysis (including 213 patients reported to have a previously documented or chronic DVT) resulting in a total of 1539 patients. All potentially eligible patients were evaluated using the Wells' rules to estimate their pre-test probability (PTP) with regard to DVT, and then categorized into likely or unlikely, or alternatively as high, intermediate or low PTP. Patients with a high PTP score were excluded from enrollment. Patients with no or a positive D-dimer result with the D-dimer assay used at the respective study center were evaluated by imaging methods, e.g. ultrasound. 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 clinical diagnosis of DVT at presentation were followed up after three months to evaluate potential development of DVT. Patients with unobtainable follow-up data were excluded from analysis resulting in n= 1317 patients available for final analysis. The overall prevalence of DVT in the 1317 patients was 6.1 % (80 of 1317) with 7.0 % in the US population and 4.7 % 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, specificity, negative predictive value (NPV) and positive value (PPV) with lower bound (LCL) of a two-sided 95 % confidence interval were calculated. Results obtained for each study population are detailed below.

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US sites DVT		Reference (Imaging and 3-month follow-up)
		Positive	Negative	Total
INNOVANCE®D-Dimer on CS-2100i	Positive	55	450	505
	Negative	1	297	298
	Total	56	747	803
Sensitivity %=	98.2	95% LCL=	90.4
Specificity %=	39.8	95% LCL=	36.2
NPV %=	99.7	95% LCL=	98.1
NPV* %=	99.2	95% LCL=	95.7
PPV %=	10.9	95% LCL=	8.5
PPV* %=	22.3	95% LCL=	17.9

*standardized to a prevalence of 15%

OUS sites DVT		Reference (Imaging and 3-month follow-up)
		Positive	Negative	Total
INNOVANCE®D-Dimer on CS-2100i	Positive	23	217	240
	Negative	1	273	274
	Total	24	490	514

*standardized to a prevalence of 15%

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US and OUS sites DVT		Reference (Imaging and 3-month follow-up)
		Positive	Negative	Total
NNOVANCE®D-Dimer on CS-2100i	Positive	78	667	745
D-Dimer on CS-2100i	Negative	2	570	572
D-Dimer on CS-2100i	Total	80	1237	1317
Sensitivity %=	97.5	95% LCL=	91.3
Specificity %=	46.1	95% LCL=	43.3
NPV %=	99.7	95% LCL=	98.7
NPV* %=	99.1	95% LCL=	96.6
PPV %=	10.5	95% LCL=	8.5
PPV* %=	24.2	95% LCL=	20.2

*standardized to a prevalence of 15%

Note:

For the exclusion of deep vein thrombosis (DVT) the diagnostic performance was assessed in a population of patients with the suspicion of a first event of DVT. For other patient populations (e. g. with recurrent or chronic DVT) the effectiveness of the device to exclude DVT has not been verified.

8. Conclusion

The modified Sysmex CS-2100i Coagulation Analyzer, with the expanded indication of the INNOVANCE® D-Dimer for the exclusion of Deep Vein Thrombosis, is substantially equivalent to the legally marketed predicate device FDA cleared under K011235.

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.