For the quantitative determination of cross-linked fibrin degradation products (D-dimers) in human plasma on Siemens Healthcare Diagnostics and Sysmex® Coagulation Systems. The INNOVANCE® D-Dimer assay is intended for use in conjunction with a non-high clinical pretest probability (PTP) assessment model to exclude deep vein thrombosis (DVT) and pulmonary embolism (PE).

Device Description

Polystyrene particles covalently coated with a monoclonal antibody (8D3) are aggregated when mixed with samples containing D-dimer. The D-dimer crosslinkage region has a stereosymmetrical structure, i.e. the epitope for the monoclonal antibody occurs twice. Consequently, one antibody suffices in order to trigger an aggregation reaction, which is then detected turbidimetrically via the increase in turbidity.

AI/ML Overview

Here's a breakdown of the acceptance criteria and study information for the INNOVANCE® D-Dimer assay:

1. Table of Acceptance Criteria and Reported Device Performance

The acceptance criteria are not explicitly stated as distinct numerical targets in the provided text. However, the study aims to demonstrate that the device performs with sufficient sensitivity and Negative Predictive Value (NPV) to reliably exclude DVT, especially in patients with an unlikely pre-test probability. Based on the presented data, the implied acceptance criteria would be a sensitivity and NPV close to or at 100% for the intended use.

Metric	Acceptance Criteria (Implied)	Reported Device Performance (All Patients)	Reported Device Performance (Unlikely PTP Patients)
Sensitivity	≥ 96% (based on lower CL)	100.0% (96.1 – 100.0% CL)	100.0% (83.9 – 100.0% CL)
Specificity	Not directly, but >30% (for practical use)	34.5% (29.4 – 39.9% CL)	37.0% (31.0 – 43.4% CL)
NPV	≥ 96% (based on lower CL)	100.0% (96.8 – 100.0% CL)	100.0% (96.0 – 100.0% CL)

Study Proving Device Meets Acceptance Criteria:

The study referenced is a multi-center clinical evaluation evaluating the INNOVANCE® D-Dimer assay on the BCS® / BCS® XP System to exclude DVT.

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

Sample Size for Test Set:
- Total Patients: 455 consecutive patients initially enrolled.
- Patients for Final Analysis: 426 patients (29 were excluded)
- Patients with unlikely pre-test probability: 267 patients.
Data Provenance: The study was a "multi-center study," suggesting data was collected from multiple clinical sites. The text doesn't explicitly state the country of origin, but the manufacturer is German, and the contact information is for the US. It is a prospective study as it involved "consecutive patients presenting to the emergency department" and follow-up for three months.

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

The text does not specify the number of experts used or their qualifications to establish the ground truth for the test set.

4. Adjudication Method for the Test Set

The text does not explicitly state an adjudication method for the test set. The diagnostic certainty (ground truth) appears to have been established through a combination of imaging methods (compression ultrasound and/or venography) for positive D-dimer results, and a three-month follow-up for negative D-dimer and negative imaging results. This implicitly suggests that the attending clinicians/radiologists' assessments, informed by these methods, served as the ground truth.

5. If a Multi-Reader Multi-Case (MRMC) Comparative Effectiveness Study Was Done, and Effect Size

No, an MRMC comparative effectiveness study involving human readers with and without AI assistance was not done. This study focuses on the standalone performance of the D-dimer assay.

6. If a Standalone (Algorithm Only Without Human-in-the-Loop Performance) Was Done

Yes, a standalone performance study was done. The results presented (Sensitivity, Specificity, NPV) are for the INNOVANCE® D-Dimer assay performed at a specific cutoff, independent of human interpretation of the D-dimer value itself, other than applying the PTP model. The assay's performance is then compared to the established ground truth of DVT.

7. The Type of Ground Truth Used

The ground truth used was a combination of:

Imaging methods: Compression ultrasound and/or venography for patients with positive D-dimer results.
Outcomes data: Three-month follow-up for patients with negative D-dimer results and those with negative imaging results, to evaluate for the potential development of DVT.

8. The Sample Size for the Training Set

The document does not specify a separate training set or its sample size. The study described appears to be a validation study of the device against clinical outcomes, rather than a development and training study for an algorithm. D-dimer assays traditionally involve established biochemical principles and cutoffs, rather than machine learning algorithms that require explicit training sets.

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

Since no explicit training set or machine learning algorithm development is described, the method for establishing ground truth for a training set is not applicable in this context. The 0.50 mg/L (FEU) cutoff is a pre-established clinical cutoff for D-dimer assays.

Summary

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510(k) Summary for INNOVANCE® D-Dimer Assay

This summary of 510(k) safety and effectiveness information is being submitted in accordance with the requirements of SMDA 1990 and 21 CFR 807.92.

The assigned 510(k) number is:

Manufacturer's Name, Address, Telephone, and Contact Person, Date of 1. Preparation:
Manufacturer:

こ」

Siemens Healthcare Diagnostics Products GmbH Emil-von-Behring Str. 76 D-35001, Marburg Germany

Contact Information:

Siemens Healthcare Diagnostics Inc. Glasgow Site P.O. Box 6101 Newark, Delaware 19714 Attn: Kathleen Dray-Lyons Tel: 781-826-4551 Fax: 781-826-2497

Preparation date:

November 23, 2009

1. Device Name/ Classification: INNOVANCE® D-Dimer
  Class:

Panel:

Fibrinogen and Fibrin Split Product, Antigen, Antiserum and controls, Class II 21 CFR 864.7320 Hematology (HE) DAP

1. Identification of the Legally Marketed Device:
  VIDAS® D-Dimer Exclusion™ - K040882
1. Device Description:
  Product Code:

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ട. Device Intended Use:

INNOVANCE® D-Dimer:

For the quantitative determination of cross-linked fibrin degradation products (D-dimers) in human plasma on Siemens Healthcare Diagnostics and Sysmex® Coagulation Systems. The INNOVANCE® D-Dimer assay is intended for use in coniunction with a non-high clinical pretest probability (PTP) assessment model to exclude deep vein thrombosis (DVT) and pulmonary embolism (PE).

6. Medical device to which equivalence is claimed and comparison information:

The INNOVANCE® D-Dimer is substantially equivalent to the VIDAS® D-Dimer Exclusion™ (K040882) assay. The INNOVANCE® D-Dimer method, like the VIDAS® D-Dimer Exclusion™ method, is intended for use in conjunction with a clinical pretest probability (PTP) assessment model to exclude deep vein thrombosis (DVT) and pulmonary embolism (PE) disease.

7. Device Performance Characteristics:

Clinical Performance of the INNOVANCE® D-Dimer assay to exclude DVT

The INNOVANCE® D-Dimer assay was evaluated on the BCS® / BCS® XP System in a multi-center study to validate the exclusion of DVT using fresh specimens collected from 455 consecutive patients presenting to the emergency department with suspected DVT. Of these 455 patients, 29 were excluded for a total of 426 patients available for final analysis.

All patients were evaluated using the Wells' rules to estimate a likely or unlikely pre-test probability (PTP) of DVT. Patient specimens were tested with the INNOVANCE® D-Dimer assay and results were compared to a cutoff 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.

Patients with a positive D-dimer result were evaluated by imaging methods, e.g. compression ultrasound and/or venography. Patients with a negative D-dimer, as well as those with negative imaging results, were followed for three months to evaluate potential development of DVT. All patients were subject to imaging at the physician's discretion.

The overall prevalence of DVT in those patients available for final analysis was 21.8 % (93/426). The following instrument-specific sensitivity, specificity and negative predictive value (NPV) with upper and lower 95% confidence limits (CL) were obtained with the INNOVANCE® D-Dimer clinical cutoff of 0.50 mg/L (FEU).

All Patients
Instrument	DVTPatients(n)	Cutoffmg/LFEU	Sensitivity(CL) %	Specificity(CL) %	NPV(CL) %
BCS®/BCS®XPSystem	426	0.50	100.0(96.1 –100.0)	34.5(29.4 –39.9)	100.0(96.8 –100.0)

All Patients

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Instrument	DVTPatients(n)	Cutoffmg/LFEU	Sensitivity(CL) %	Specificity(CL) %	NPV(CL) %
BCS ®/BCS®XPSystem	267	0.50	100.0(83.9 –100.0)	37.0(31.0 –43.4)	100.0(96.0 –100.0)

. . . .

Patients with unlikely pre-test probability

CL = lower and upper 95 % confidence limits

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Image /page/3/Picture/1 description: The image shows the logo for the U.S. Department of Health & Human Services. The logo consists of a circular border with the text "DEPARTMENT OF HEALTH & HUMAN SERVICES USA" arranged around the perimeter. Inside the circle is an abstract symbol resembling an eagle or bird in flight, composed of three curved lines.

Food and Drug Administration 10903 New Hampshire Avenue Silver Spring, MD 20993-0002

Siemens Healthcare Diagnostics c/o Ms. Kathleen Ann Dray-Lyons Manager, Regulatory Affairs 500 GBC Drive P.O. Box 6101 Newark, DE 19714-6101

NOV 2 9 2010

Re: K093626

Trade/Device Name: INNOVANCE® D-Dimer Regulation Number: 21 CFR 864.7320 Regulation Name: Fibrinogen/Fibrin Degradation Products Assay Regulatory Class: Class II Product Code: DAP Dated: October 26, 2010 Received: October 27, 2010

Dear Ms. Dray-Lyons:

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 class II (Special Controls), it may be subject to such additional controls. Existing major regulations affecting your device can be found in Title 21, Code of Federal Regulations (CFR), Parts 800 to 895. 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 CFR Part 807); labeling (21 CFR Parts 801 and 809); medical device reporting (reporting of medical device-related adverse events) (21 CFR 803); and good manufacturing practice

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Page 2 - Ms. Kathleen Ann Dray-Lyons

requirements as set forth in the quality systems (QS) regulation (21 CFR Part 820). This letter will allow you to begin marketing your device as described in your Section 510(k) premarket notification. The FDA finding of substantial equivalence of your device to a legally marketed predicate device results in a classification for your device and thus, permits your device to proceed to the market.

If you desire specific advice for your device on our labeling regulation (21 CFR Parts 801 and 809), please contact the Office of In Vitro Diagnostic Device Evaluation and Safety at (301) 796-5450. Also, please note the regulation entitled, "Misbranding by reference to premarket notification" (21 CFR 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 Small Manufacturers, International and Consumer Assistance at its toll-free number (800) 638-2041 or (301) 796-7100 or at its Internet address http://www.fda.gov/cdrh/industry/support/index.html.

Sincerely yours,

m. Chan

Maria M. Chan, Ph.D. Director Division of Immunology and Hematology Devices Office of In Vitro Diagnostic Device Evaluation and Safety Center for Devices and Radiological Health

Enclosure

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Indications for Use

510(k) Number (if known):

Device Name: INNOVANCE® D-Dimer

NUV 2 9 2010

Indications For Use:

INNOVANCE® D-Dimer:

For the quantitative determination of cross-linked fibrin degradation products (Ddimers) in human plasma on Siemens Healthcare Diagnostics and Sysmex® Coagulation Systems. The INNOVANCE® D-Dimer assay is intended for use in conjunction with a non-high clinical pretest probability (PTP) assessment model to exclude deep vein thrombosis (DVT) and pulmonary embolism (PE).

Prescription Use × (Per 21 CFR 801 Subpart D) Over-The-Counter-Use (21 CFR 801 Subpart C)

(PLEASE DO NOT WRITE BELOW THIS LINE - CONTINUE ON ANOTHER PAGE IF NEEDED)

AND/OR

Concurrence of CDRH, Office of Device Evaluation

Page 1 of

Maria McChan

Division Sign-Off

Office of In Vitro Diagnostic
Device Evaluation and Safety

Regulation Number and Section

§ 864.7320 Fibrinogen/fibrin degradation products assay.

(a)
Identification. A fibrinogen/fibrin degradation products assay is a device used to detect and measure fibrinogen degradation products and fibrin degradation products (protein fragments produced by the enzymatic action of plasmin on fibrinogen and fibrin) as an aid in detecting the presence and degree of intravascular coagulation and fibrinolysis (the dissolution of the fibrin in a blood clot) and in monitoring therapy for disseminated intravascular coagulation (nonlocalized clotting in the blood vessels).(b)
Classification. Class II (performance standards).