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 pulmonary embolism (PE) disease and as an aid in the diagnosis of venous thromboembolism (VTE) [deep vein thrombosis (DVT) or pulmonary embolism (PE)].

Device Description

Polystyrene particles covalently coated with a monoclonal antibody (8D3) are aggreated 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

The INNOVANCE® D-Dimer assay was evaluated in a multicenter clinical study to validate its ability to assist in the exclusion of pulmonary embolism (PE).

Here's a breakdown of the acceptance criteria and study details:

1. Acceptance Criteria and Reported Device Performance:

The document doesn't explicitly state quantitative acceptance criteria in a dedicated section. However, the performance is reported as key metrics (Sensitivity, Specificity, and Negative Predictive Value) with 95% Confidence Limits (CL), which are typically compared against pre-defined thresholds for acceptance in clinical trials. Given the context of a 510(k) submission for exclusion of PE, a high Negative Predictive Value (NPV) is crucial.

Metric	Acceptance Criteria (Implied)	Reported Device Performance (All Patients)	Reported Device Performance (Low/Moderate PTP Patients)
Sensitivity	High (especially for PE exclusion)	98.9% (93.9 - 100.0%)	98.6% (92.5 - 100.0%)
Specificity	Adequate (to avoid unnecessary imaging)	39.6% (35.5 - 43.8%)	40.4% (36.3 - 44.7%)
NPV	Very High (critical for rule-out)	99.6% (97.5 - 100.0%)	99.6% (97.5 - 100.0%)

Note: The "Acceptance Criteria (Implied)" column reflects the expected performance for a D-dimer assay used to exclude PE. A very high NPV is generally the primary focus for such an exclusion test.

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

Sample Size:
- Initial patients presenting: 701
- Patients available for final analysis (test set): 647
Data Provenance: The study was a multicenter study, suggesting data was collected from multiple clinical sites. It was a prospective study, as patients were "consecutive patients presenting to the emergency department with suspected PE." The country of origin is not explicitly stated, but the manufacturer is based in Germany and the contact information is in the US, indicating an international context or a US-based multicenter study.

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

This information is not explicitly stated in the provided text. The document mentions that "Patients with a positive D-dimer result and/or a high PTP were evaluated by imaging methods, e.g. spiral CT and/or VQ scan." It also states, "Patients with a negative D-dimer result and a low or moderate PTP (these patients underwent imaging at the physician's discretion), and patients with negative imaging results, were followed for three months to evaluate potential development of PE." This implies that the ultimate diagnosis of PE (the ground truth) was established through a combination of imaging, clinical follow-up for events, and physician assessment, but the number or specific qualifications of experts involved in reviewing these results are not detailed.

4. Adjudication Method for the Test Set:

The document does not explicitly describe an adjudication method for conflicting interpretations of imaging or follow-up results. The ground truth seems to be derived from a combination of recognized medical diagnostic procedures (imaging, follow-up) as performed by attending physicians, rather than a separate, blinded expert adjudication panel of the test results themselves.

5. If a Multi Reader Multi Case (MRMC) Comparative Effectiveness Study was done, If so, what was the effect size of how much human readers improve with AI vs without AI assistance:

This was not an MRMC comparative effectiveness study in the context of human readers vs. AI. The device is an in-vitro diagnostic (IVD) assay (D-dimer blood test), not an AI imaging or diagnostic algorithm designed to assist human readers. Therefore, this section is not applicable.

6. If a Standalone (i.e. algorithm only without human-in-the-loop performance) was done:

Yes, this was a standalone performance study of the INNOVANCE® D-Dimer assay. The study evaluated the direct output of the assay (D-dimer levels) in conjunction with clinical pretest probability (PTP) assessment, without explicit human-in-the-loop performance comparison for the assay itself. The physician's role was to use the assay's results as part of a diagnostic algorithm (along with PTP).

7. The Type of Ground Truth Used:

The ground truth for the presence or absence of PE was established through a combination of:

Imaging methods: e.g., spiral CT and/or VQ scan for patients with positive D-dimer and/or high PTP, and for some patients with negative D-dimer and low/moderate PTP at physician's discretion.
Outcomes data/Clinical Follow-up: Three-month follow-up for patients with negative D-dimer and low or moderate PTP (and those with negative imaging) to evaluate potential development of PE.

This is a robust method leveraging established clinical diagnostic pathways for PE.

8. The Sample Size for the Training Set:

The document does not provide information about a separate training set. This study describes the clinical validation of the INNOVANCE® D-Dimer assay, implying that the assay itself (and its cutoff values) were already developed and "trained" (if applicable to the assay's development process) prior to this multicenter clinical validation. IVD assays typically undergo extensive R&D and analytical validation before clinical studies like this for regulatory submission.

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

As no specific training set is detailed for this 510(k) submission, the method for establishing its ground truth is not provided.

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: ________________K091916

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

Manufacturer:

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

Contact Information:

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

Preparation date:

September 22, 2009

Device Name/ Classification: INNOVANCE® D-Dimer 2.

Class:

Panel:

Product Code:

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

Identification of the Legally Marketed Device: 3.

VIDAS® D-Dimer Exclusion™ - K040882

4. Device Description:

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5. Device Intended Use:

INNOVANCE® D-Dimer:

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

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 pulmonary embolism (PE) disease.

7. Device Performance Characteristics:

Comparative Method	Slope	Intercept(mg/L FEU)	CorrelationCoefficient	n
VIDAS® D-Dimer Exclusion™	1.11	-0.075	0.96	265

The range of D-dimer values in the correlation studies was 0.17 to 4.17 mg/L FEU.

Clinical Study Summary

The INNOVANCE® D-Dimer assay was evaluated on the BCS® / BCS® XP System in a multicenter study to validate the exclusion of PE using fresh specimens collected from 701 consecutive patients presenting to the emergency department with suspected PE. Of these 701 patients, 54 were excluded for a total of 647 patients available for final analysis.

All patients were evaluated using the Wells' rules to estimate a high, moderate or low pre-test probability (PTP) of PE. Patient specimens were tested with the INNOVANCE® D-Dimer assay and results were compared to a cutoff value of 0.5 mg/L (FEU). A D-dimer result <0.5 mg/L (FEU) was considered negative and a D-dimer result ≥0.5 mg/L (FEU) was considered positive.

Patients with a positive D-dimer result and/or a high PTP were evaluated by imaging methods, e.g. spiral CT and/or VQ scan. Patients with a negative D-dimer result and a low or moderate PTP (these patients underwent imaging at the physician's discretion), and patients with negative imaging results, were followed for three months to evaluate potential development of PE.

The overall prevalence of PE in those patients available for final analysis was 13.8% (89/647). 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 0.5 mg/L (FEU).

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All Patients

Instrument	PEPatients(n)	Cutoffmg/L FEU	Sensitivity(CL) %	Specificity(CL) %	NPV(CL) %
BCS ®/BCS®XPSystem	647	0.5	98.9(93.9 - 100.0)	39.6(35.5 - 43.8)	99.6(97.5 - 100.0)

Patients with low and moderate pre-test probability

. . . . . . . . .

Instrument	PEPatients(n)	Cutoffmg/L FEU	Sensitivity(CL) %	Specificity(CL) %	NPV(CL) %
BCS®/BCS®XPSystem	616	0.5	98.6(92.5 - 100.0)	40.4(36.3 - 44.7)	99.6(97.5 - 100.0)

、

. . . . .

CL = lower and upper 95 % confidence limits

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Image /page/3/Picture/1 description: The image shows the seal of the U.S. Department of Health & Human Services. The seal features a stylized caduceus, a symbol often associated with medicine and healthcare, with three lines forming the snake and staff. The text "DEPARTMENT OF HEALTH & HUMAN SERVICES - USA" is arranged in a circular pattern around the caduceus.

Food and Drug Administration 10903 New Hampshire Avenue Document Mail Center - WO66-0609 Silver Spring, MD 20993-0002

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

OCT 2 9 2009

Re: K091916

Trade/Device Namc: INNOVANCE® D-Dimer Regulation Number: 21 CFR 864.7320 Regulation Name: Fibrinogen/fibrin degradation product assays Regulatory Class: Class II Product Code: DAP Dated: October 28, 2009 Received: October 29, 2009

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.

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 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,

Mana m chen

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):

INNOVANCE® D-Dimer Device Name:

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 pulmonary embolism (PE) disease and as an aid in the diagnosis of venous thromboembolism (VTE) [deep vein thrombosis (DVT) or pulmonary embolism (PE)].

Prescription Use × (Per 21 CFR 801 Subpart D) AND/OR

Over-The-Counter-Use (21 CFR 801 Subpart C)

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

Concurrence of CDRH, Office of Device Evaluation

Page 1 of

Maria Mchan

Division Sign-Off

Office of In Vitro Diagnostic Device Evaluation and Safety

510(k) - K091916

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).