Sysmex Automated Blood Coagulation Analyzer CS-2100i

K161312 · Siemens Healthcare Diagnostics Products GmbH · JPA · Sep 1, 2016 · Hematology

Device Facts

• Record ID: K161312
• Device Name: Sysmex Automated Blood Coagulation Analyzer CS-2100i
• Applicant: Siemens Healthcare Diagnostics Products GmbH
• Product Code: JPA · Hematology
• Decision Date: Sep 1, 2016
• Decision: SESE
• Submission Type: Traditional
• Regulation: 21 CFR 864.5425
• Device Class: Class 2

Intended Use

The Sysmex CS-2100i is a fully automated blood coagulation analyzer intended for in vitro diagnostic use using venous blood samples collected 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 Story

Sysmex CS-2100i is an automated, random-access blood coagulation analyzer for clinical laboratories. It processes venous plasma samples (3.2% sodium citrate) using clotting, chromogenic, and immunoassay methods. The system performs automated pipetting, dilution, and analysis of samples in normal or micro-sample modes. It utilizes mechanical, hydraulic, and electrical systems to measure coagulation parameters. Results are displayed on an integrated Information Processing Unit (IPU), printable, or transmittable to a host computer. The device aids clinicians in diagnosing coagulation disorders and excluding DVT/PE when used with non-high PTP assessment models. By providing rapid, quantitative D-dimer results, it assists in clinical decision-making regarding the necessity of further imaging, potentially reducing unnecessary diagnostic procedures for patients suspected of DVT or PE.

Clinical Evidence

Multicenter study (n=1317) evaluated INNOVANCE D-Dimer assay on Sysmex CS-2100i for exclusion of first-event DVT. Patients with suspected DVT were categorized by Wells' rules; high PTP patients excluded. Performance compared to imaging/3-month follow-up. Results: Sensitivity 97.5% (95% LCL 91.3%), Specificity 46.1% (95% LCL 43.3%), NPV 99.7% (95% LCL 98.7%).

Technological Characteristics

Automated coagulation analyzer; mechanical, hydraulic, and electrical sensing. Uses 3.2% sodium citrate venous plasma. Halogen lamp light source (660 nm for D-dimer). Random access, cap-piercing capability. Temperature control: 37°C ± 0.5°C (detector). Connectivity: Bidirectional interface (CA, ASTM, CS protocols). Automated calibration and QC (X-Bar, Levey-Jennings).

Indications for Use

Indicated for use in clinical laboratories to analyze venous plasma samples (3.2% sodium citrate) for coagulation parameters including PT, APTT, Fibrinogen, Antithrombin, and D-dimer. D-dimer assay is indicated for use in conjunction with a non-high clinical pre-test probability (PTP) assessment model to exclude deep vein thrombosis (DVT) and pulmonary embolism (PE). Not established for neonate or pediatric populations.

Regulatory Classification

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.

Special Controls

*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.

Predicate Devices

• Sysmex® CA-1500 (K011235)

Submission Summary (Full Text)

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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 [phone] or [phone] 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 [phone] or [phone] 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)

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)

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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: | [e-mail] |
| 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 CFR<br>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<br>864.5425) |
| 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

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
- 트 Calibrators
- I 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.

## 5. Intended Use / Indications for Use

The Sysmex CS-2100i is a fully automated blood coagulation analyzer intended for in vitro diagnostic use using plasma collected from venous blood samples in 3.2% sodium citrate tubes to analyze clotting, chromogenic and immunoassay methods in the clinical laboratory.

For determination of:

- . Prothrombin Time (PT) seconds and PT INR with Dade® Innovin®
- . Activated Partial Thromboplastin Time (APTT) with Dade® Actin® FSL
- . Fibrinogen (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 Device<br>Predicate Device | | |
| | Sysmex CS-2100i | Sysmex CA®-1500 | |
| Regulatory<br>Classification | JPA Class 2<br>System, Multipurpose for in vitro<br>coagulation studies | Same | |
| Intended Use<br>Statement | The Sysmex CS-2100i is a fully<br>automated blood coagulation<br>analyzer intended for in vitro<br>diagnostic use using plasma<br>collected from venous blood<br>samples in 3.2% sodium citrate<br>tubes to analyze clotting,<br>chromogenic and immunoassay<br>methods in the clinical<br>laboratory.<br><br>For determination of:<br>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<br>Sysmex CA®-1500 is as<br>a fully automated,<br>computerized blood<br>plasma coagulation<br>analyzer for in vitro<br>diagnostic use in clinical<br>laboratories.<br><br>The instrument uses<br>citrated human plasma<br>to perform the following<br>parameters and<br>calculated parameters:<br><br>Clotting Analysis<br>Prameters: Prothrombin<br>Time (PT); Activated<br>Partial Thromboplastin<br>Time (APTT); Fibrinogen<br>(Clauss); Batroxobin<br>Time; Extrinsic Factors<br>(II, V, VII, X); Intrinsic<br>Factors (VIII, IX, XI, XII);<br>Protein C.<br><br>Chromogenic Analysis<br>Parameters:<br>Antithrombin III; Factor<br>VIII; Plasminogen;<br>Heparin; Protein C; α2-<br>Antiplasmin. | |
| Similarities between Sysmex CS-2100i and Sysmex CA®-1500 | | | |
| Analyzer Component | Proposed Device<br>Sysmex CS-2100i | Predicate Device<br>Sysmex CA®-1500 | |
| | | Parameters: D-dimer.<br>Calculated Parameters:<br>PT Ratio; PT INR; PT %;<br>Derived Fibrinogen;<br>Factor Assays % Activity | |
| Application | Immuno-chemical Application:<br><br>D-dimer<br>with INNOVANCE® D-Dimer | Same | |
| Sample Type | Human plasma,<br>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 in<br>Normal Mode | D-dimer with INNOVANCE® D-<br>Dimer 13 µL | Same | |
| Differences between Sysmex CS-2100i and Sysmex CA®-1500 | | | |
| Analyzer Component | Proposed Device<br>Sysmex CS-2100i | Predicate Device<br>Sysmex CA®-1500 | |
| Operating Principle | Immuno-chemical | Transmitted Light Detection<br>(Absorbance) at 340, 405, 575,<br>660 or 800 nm. Wavelengths 340,<br>405, 575, and 800 are technically<br>available but not validated in<br>combination with the intended<br>applications. | Optical Density at 405, 575, or<br>800 nm |
| Wavelengths* used in<br>Analysis | *The default wavelength<br>is normally used to<br>generate the reported<br>value of the<br>measurement. The sub-<br>wavelength is run in<br>parallel. If a light intensity<br>error occurs by using the<br>default wavelength the<br>value from the sub-<br>wavelength is used<br>automatically. | D-dimer with INNOVANCE® D-<br>Dimer (Default = 660 nm; Sub-<br>Wavelength= none) | D-dimer with INNOVANCE® D-<br>Dimer (Default = 800 nm; Sub-<br>Wavelength= none) |
| Light Source | Clotting | Halogen Lamp | Light Emitting Diode |
| Cap Piercing | Cap Piercer only | Both options available:<br>Cap Piercer and No-Cap Piercer | |
| Temperature Control | -Detector : 37 °C ± 0.5 °C<br><br>-Reagent incubation probe :<br>37.5 °C ± 0.5 °C | -Detector: 37°C ± 1.0°C<br><br>-Reagent incubation probe: 37°C<br>± 1.0°C | |
| Analyzer Component | Proposed Device<br>Sysmex CS-2100i | Predicate Device<br>Sysmex CA®-1500 | |
| Reagent Cooling | 10°C ± 2°C, when ambient<br>temperature is 20°C - 28°C.<br>During operation 4°C -15°C, when<br>ambient temperature is 15°C – 30°C | 15°C ± 2°C, when ambient<br>temperature is 15°C – 30°C | |
| Pipetting Capabilities | Reagent probe:<br>20 – 200 μL<br><br>Sample probe:<br>4 – 270 μL | Reagent probe:<br>3 – 200 μL<br><br>Sample probe:<br>5 – 450 μL | |
| Sample Volumes in<br>Micro Mode (Plasma) | 15 μL | 13 μL | |
| Bidirectional Interface<br>communication<br>protocols | 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®<br>D-Dimer on CS-<br>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®<br>D-Dimer on CS-<br>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®<br>D-Dimer on CS-<br>2100i | Positive | 78 | 667 | 745 |
| D-Dimer on CS-<br>2100i | Negative | 2 | 570 | 572 |
| D-Dimer on CS-<br>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.