MDA® D-Dimer is a homogeneous latex particle based immunoassay for the quantitative determination of crosslinked fibrin degradation products containing the D-dimer domain in citrated human plasma. MDA D-Dimer is an assay for use in conjunction with a clinical Pre-test Probability Assessment (PTP) model in excluding deep vein thrombosis (DVT) in outpatients suspected of a first episode of DVT. MDA D-Dimer can also be used as and in the assessment and evaluation of patients suspected of pulmonary embolism (PE). The assay is designed for use on the MDA automated coagulation analyzers.

Device Description

bioMerieux Inc. MDA® D-Dimer is a homogeneous latex particle based immunoassay for the quatitative determination of cross-linked fibrin degradation products containing the D-dimer domain in citrated human plasma. These latex particles aggregate in the presence of fibrin derivatives containing the D-dimer domain. The rate of latex microparticle aggregation is proportional to the concentration of D-dimer in the sample. D-dimer concentration may be interpolated from a reference curve.

AI/ML Overview

This summary describes the acceptance criteria and the study proving the MDA® D-Dimer device meets these criteria.

Acceptance Criteria and Device Performance

Parameter	Acceptance Criteria	Reported Device Performance
Specificity	MDA D-Dimer Latex Reagent aggregates in the presence of cross-linked fibrin degradation products D-dimer and D-dimer E.	MDA D-Dimer Latex Reagent aggregates in the presence of cross-linked fibrin degradation products D-dimer and D-dimer E.
Accuracy (Correlation)	High correlation (r) to a commercially available assay. (Implicitly, the predicate device K000942's performance)	r = 0.91 (compared to Fibrinostika® FbDP EIA)
Accuracy (Slope)	Slope close to 1.0 (Implicitly, the predicate device K000942's performance)	Slope = 1.005 (compared to Fibrinostika® FbDP EIA)
Accuracy (Intercept)	Intercept close to 0.0 (Implicitly, the predicate device K000942's performance)	Intercept = 0.293 (compared to Fibrinostika® FbDP EIA)
Precision (Positive Control CV)	Low CV (total) for positive control. (Implicitly, the predicate device K000942's performance)	Positive Control: CV (total) = 6.67%
Precision (Normal Control CV)	Low CV (total) for normal control. (Implicitly, the predicate device K000942's performance)	MDA Verify 1 (Normal Control): CV (total) = 12.65%
Clinical Sensitivity	High clinical sensitivity for excluding DVT. (No explicit threshold, but clinical utility required)	98.2% (95% CI: 90-100%) for suspected DVT
Clinical Specificity	Reasonable clinical specificity for excluding DVT. (No explicit threshold, but clinical utility required)	60.4% (95% CI: 56-65%) for suspected DVT
Negative Predictive Value (NPV)	Very high NPV for excluding DVT. (No explicit threshold, but clinical utility required)	99.7% (95% CI: 98-100%) for suspected DVT

Study Details for Clinical Performance (DVT Exclusion)

Sample Size used for the test set and the data provenance:
- Sample Size: 556 consecutive eligible outpatients.
- Data Provenance: Multi-center, prospective cohort study conducted at three hospitals. The country of origin is not explicitly stated but is implied to be the USA given the submission to the FDA by a US-based company.
Number of experts used to establish the ground truth for the test set and the qualifications of those experts:
- The document does not explicitly state the number or qualifications of experts used to establish the ground truth. It mentions that an MDA D-Dimer test was performed on presentation without knowledge of the Pre-test Probability Assessment (PTP) results. The "ground truth" for DVT diagnosis in patients with a positive D-Dimer and/or high PTP was established through serial compression ultrasound (CUS). For patients with a negative D-Dimer and low/moderate PTP, they underwent no further diagnostic testing but were "followed up for 3 months for development of DVT," which implies clinical outcomes as part of the ground truth.
Adjudication method for the test set:
- The document does not explicitly describe a formal adjudication method (e.g., 2+1, 3+1 consensus) for the diagnosis of DVT. The ground truth appears to be based on a combination of diagnostic imaging (serial CUS for some) and clinical follow-up for outcomes.
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:
- No, a multi-reader multi-case (MRMC) comparative effectiveness study was not done. This device is an in-vitro diagnostic (IVD) assay, not an AI-assisted diagnostic imaging tool that would typically involve human readers.
If a standalone (i.e. algorithm only without human-in-the loop performance) was done:
- Yes, the clinical performance described ("The sensitivity, specificity and negative predictive value of the MDA D-Dimer assay for a clinical cut off of 0.50 µg FEU/n1") represents the standalone performance of the assay when used in conjunction with a clinical PTP model. The assay itself (MDA D-Dimer) generates a quantitative output. The clinical "human-in-the-loop" component is the interpretation of that output in the context of the PTP model, but the assay's performance metrics are standalone for its measurement capabilities.
The type of ground truth used:
- The ground truth for DVT diagnosis was a combination of:
  - Diagnostic Imaging: Serial compression ultrasound (CUS) for patients with a positive MDA D-Dimer and/or high Pre-test Probability (PTP).
  - Clinical Outcomes Data: 3-month follow-up for development of DVT in patients with a negative MDA D-Dimer test result and a low or moderate PTP.
The sample size for the training set:
- The document does not specify a training set for algorithm development for the MDA D-Dimer assay. As an immunoassay, its "training" pertains more to establishing its analytical performance parameters (linearity, precision, etc.) and defining a clinical cutoff value. It states that a "clinical cut off value of 0.50 ug FEU/ml previously validated in an accuracy study" was used, suggesting prior studies informed this threshold, but no sample size for that "accuracy study" is provided here.
How the ground truth for the training set was established:
- As noted above, a formal "training set" in the AI/machine learning sense is not applicable here for this immunoassay. However, the clinical cutoff value of 0.50 µg FEU/ml was "previously validated in an accuracy study." The mechanism for establishing ground truth within that prior accuracy study is not detailed in this document.

Summary

{0}------------------------------------------------

AUG 0 7 2002

510(k) SUMMARY

MDA® D-Dimer

This summary of safety and effectiveness information is being submitted in accordance with the requirements of SMDA 1990 and the final rule under 21 CFR 807.92 published December 14, 1994.

The submitter's name, address, telephone number, a contact person, and the date the summary (۵) (1) was prepared;

Submitter's Name: Submitter's Address: bioMérieux Inc. 100 Rodolphe Street Durbam, North Carolina 27712, USA

Submitter's Telephone: Submitter's Fax: Submitter's Contact: Date 510(k) Summary Prepared: (919) 620-2373 (919) 620-2548 Ron Sanyal June 6, 2002

The name of the device, including the trade or proprietary name if applicable, the common or (a) (2) usual name, and the classification name, if known;
Trade/Proprietary Name: Common/ Usual Name: Classification Name:

MDA® D-Dimer Fibrin Degradation Product Fibrin Degradation Product

(a) (3) An identification of the legally marketed device to which the submitter claims substantial equivalence.
Device Equivalent to:

MDA® D-Dimer (K000492)

{1}------------------------------------------------

A description of the device(System) (a) (4)

D-dimer containing fibrin degradation products (FbDP) fragments are released when cross-linked fibrin is degraded by plasmin. Cross-linked fibrin is formed when fibrionogen is cleaved by thrombin to form fibrin monomers, which then spontaneously polymerize and are cross-linked by Factor XIIIa. Thrombin is required to cleave fibringen as well as to activate Factor XIII. Plasmin formation is triggered when a fibrin clot is formed. Plasmin degrades some of the cross-linked fibrin and the resulting level of D-dimer is, therefore, an indirect measure of thrombin generation and subsequent clot formation.

D-dimer is elevated in disseminated intravascular coagulation (DIC), deep vein thrombosis (DVT), pulmonary embolism (PE), sickle cell crisis, pre-eclampsia, some cause of unstable angina, myocardial infarction, some cancers, and following major surgery or trauma.

MDA D-Dimer is a quantitative homogeneous-phase immunoassay using latex microparticles to photo-optically detect binding of specific monoclonal antibody to D-dimer. These latex particles aggregate in the presence of fibrin derivatives containing the D-dimer domain. The rate of latex microparticle aggregation is proportional to the concentration of D-dimer in the sample. D-dimer concentration may be interpolated from a reference curve.

(a) (5) A statement of the intended use of the device.

MDA D-Dimer is a homogeneous latex particle based immunoassay for the quantitative determination of cross-linked fibrin degradation products containing the D-dimer domain in citrated human plasma. MDA D-Dimer is an assay for use in conjunction with a clinical Pre-test Probability Assessment (PTP) model in excluding deep vein thrombosis (DVT) in outpatients suspected of a first episode of DVT. MDA D-Dimer can also be used as an aid in the assessment and evaluation of patients suspected of pulmonary embolism (PE). The assay is designed for use on the MDA automated coagulation analyzers.

{2}------------------------------------------------

(a) (6) A summary of the technological characteristics of the new device in comparision to those of the predicate device.

The technological characteristics of the device MDA® D-Dlmer in comparison to those of the 510(k) cleared device MDA® D-Dimer assay (K000492) are given in the table 1 below.

Category	MDA® D-Dimer assay (K000942)	MDA® D-Dimer
Medical Device	Yes	Yes
Intended Use	MDA® D-Dimer is a homogeneous latexparticle based immunoassay for thequantitative determination of cross-linkedfibrin degradation products containing theD-dimer domain in citrated humanplasma. MDA D-Dimer can be used toaid in the assessment and evaluation ofpatients suspected of venousthromboembolism (VTE), which iscomprised of deep vein thrombosis(DVT) and pulmonary embolism (PE).The assay is designed for use on theMDA automated coagulation analyzers.	MDA® D-Dimer is a homogeneous latexparticle based immunoassay for thequantitative determination of cross-linkedfibrin degradation products containing theD-dimer domain in citrated humanplasma. MDA D-Dimer can be used to aidin the assessment and evaluation ofpatients suspected of venousthromboembolism (VTE), which iscomprised of deep vein thrombosis(DVT) and pulmonary embolism (PE).The assay is designed for use on the MDAautomated coagulation analyzers.
Regulatory Class	Class II	Class II
Product Code	DAP	DAP
Classification Panel	Hematology	Hematology
C.F.R. Section	21 CFR 864.7320	21 CFR 864.7320
Presentation	Automated Latex Immunoassay	Automated Latex Immunoassay
Format	Quantitative	Quantitative
Instrument	MDA® automated coagulation analyzers	MDA® automated coagulation analyzers
Reagents	Same	Same
Principle of theprocedure	Same	Same
Quality Control	Same	Same
Test Procedure	Same	Same
Reference CurveRange	0-4.0 µg FEU/ml	0-4.0 µg FEU/ml

Table 1

{3}------------------------------------------------

(b) (1) A brief discussion of the nonclinical tests submitted, reference, or relied on in the premarket notification submission for a determination of substantial equivalency.
Not Applicable

A brief discussion of the clinical tests submitted, reference, or relied on in the premarket (b)(2) notification submission for a determination of substantial equivalency.

Comparison Data:

Performance Characteristics

Specificity

MDA D-Dimer Latex Reagent aggregates in the presence of cross-linked fibrin degradation products D-dimer and D-dimer E.

Accuracy

Results from MDA D-Dimer reagents obtained on an MDA were compared with a commercially available assay (Fibrinostika® FbDP EIA)for detection of crosslinked and non-crosslinked fibrin degradation product containing the D-dimer. Specimens were tested in duplicate according to NCCLS Approved Guideline EP9-A. " The following results for slope, intercept and correlation were observed for linear least squares regression comparing MDA D-Dimer (y-axis) and the reference method (x-axis):

Reference Method	n	Slope	Intercept	r
Fibrinostika® FbDP EIA	175	1.005	0.293	0.91

Precision

Total precision and within-run precision for the MDA D-Dimer assay were determined in accordance with NCCLS Tentative Guideline EPS-T2.30 Controls were tested in duplicate on an MDA instrument twice daily. Data were collected for 20 days, with a minimum of 40 runs and 80 measurements at each control level. The following precision was observed:

Sample	Mean(ug FEU/ml)	SD (within-run)(ug FEU/ml)	CV (within-run)(%)	SD(total)(ug FEU/ml)	CV(total)(%)
Positive Control	1.51	0.06	3.83	0.10	6.67
MDA Verify 1(Normal Control)	0.28	0.02	6.97	0.04	12.65

Image /page/3/Picture/13 description: The image contains a handwritten symbol that resembles a figure eight with a loop at the top. The symbol is drawn with thick, dark lines, giving it a bold appearance. The overall impression is that of a quick, stylized sketch of the number eight.

{4}------------------------------------------------

Clinical Performance

A multi-center, prospective cohort study was designed to validate the diagnostic utility of the MDA D-Dimer assay to exclude a diagnosis of deep vein thrombosis (DVT).» Consecutive eligible outpatients (n = 556) with a first suspected DVT episode were evaluated at three hospitals. Using a previously validated standardized clinical model » to estimate the probability of DVT, patients were classified as having a high, moderate, or low pre-test- probability -(PTP) of DVT, and had an MDA D-Dimer test performed on presentation.

The D-Dimer assay was performed without knowledge of the PTP assessment results. A clinical cut off value of 0.50 ug FEU/ml previously validated in an accuracy study. A D-Dimer result of >0.50 µg FEU/ml was considered positive, and a result of <0.50 µg FEU/ml was considered negative.

The overall prevalence of DVT in the total population studied was 10.1% (56/556). The sensitivity, specificity and negative predictive value of the MDA D-Dimer assay for a clinical cut off of 0.50 µg FEU/n1 are summarized below with the corresponding 95% confidence interval (CI).

Patients	N	% Clinical Sensitivity(95% CI)	% Clinical Specificity(95% CI)	% Negative PredictiveValue (95% CI)
Suspected DVT	556	98.2(90-100 CI)	60.4(56-65 CI)	99.7(98-100 CI)

This study was designed as a management clinical trial and patients were grouped according to PTP. Those patients having a negative MDA D-Dimer test result and a low or moderate PTP of DVT underwent no further diagnostic testing and were followed up for 3 months for development of DVT. Patients with a positive MDA D-Dimer and/or high PTP underwent serial compression ultrasound (CUS).

The results of this study suggest that a negative MDA D-Dimer test result in conjunction with Wells clinical Pre-test probability Assessnent (PTP) model excludes clinically significant DVT in out patients with a first suspected episode. In addition, this test provides a rapid, automated diagnostic tool and eliminates the need to expose patients to invasive procedures or unnecessary treatment.

The conclusion drawn from the nonclinical and clinical tests that demonstrate that the device is (b) (3) as safe, as effective, and performed as well or better than the legally marketed device identified in (a) (3).

In conclusion, the MDA® D-Dimer has successfully met all aspects of non-clinical and clinical testing and have demonstrated that the device is safe and effective and has performed well and is substantially equivalent to the legally marketed device MDA® D-Dimer assay (K000492),

{5}------------------------------------------------

Image /page/5/Picture/0 description: The image shows the text "DEPARTMENT OF HEALTH & HUMAN SERVICES" in a bold, sans-serif font. The text is black and appears to be on a white background. The words are all capitalized and evenly spaced.

Image /page/5/Picture/1 description: The image is a black and white logo for the U.S. Department of Health & Human Services. The logo features a stylized image of an eagle with three lines forming its body and wings. The words "DEPARTMENT OF HEALTH & HUMAN SERVICES - USA" are arranged in a circular pattern around the eagle.

Food and Drug Administration 2098 Gaither Road Rockville MD 20850

Mr. Ron Sanyal, M. Pharm, COE, RAC Acting Head of Regulatory Affairs BioMerieux, Inc. 100 Rodolphe Street Durham, North Carolina 27712

Re: K021877

Trade/Device Name: MDA® D-Dimer Regulation Number: 21 CFR § 864.7320 Regulation Name: Fibrin Degradation Product Regulatory Class: II Product Code: GHH Dated: June 6, 2002 Received: June 7, 2002

Dear Mr. Sanyal:

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.

AUG 0 7 2002

If your device is classified (see above) into either class II (Special Controls) or class III (PMA), it may be subject to such 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 CFR Part 807); labeling (21 CFR Part 801); 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.

{6}------------------------------------------------

Page 2

This letter will allow you to begin marketing your device as described in your 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 Part 801 and additionally 809.10 for in vitro diagnostic devices), please contact the Office of Compliance at (301) 594-4588. Additionally, for questions on the promotion and advertising of your device, please contact the Office of Compliance at (301) 594-4639. Also, please note the regulation entitled, "Misbranding by reference to premarket notification" (21CFR 807.97). Other general information on your responsibilities under the Act may be obtained from the Division of Small Manufacturers International and Consumer Assistance at its toll-free number (800) 638-2041 or (301) 443-6597 or at its internet address "http://www.fda.gov/cdrh/dsma/dsmamain.html".

Sincerely yours,

Steven Sutman

Steven I. Gutman, M.D., M.B.A. Director Division of Clinical Laboratory Devices Office of Device Evaluation Center for Devices and Radiological Health

Enclosure

{7}------------------------------------------------

Page

page 1 of 1

(IF KNOWN): 510 (K) NUMBER DEVICE NAME:

5.0 INDICATIONS FOR USE:

MDA® D-Dimer is a homogeneous latex particle based immunoassay for the quantitative determination of crosslinked fibrin degradation products containing the D-dimer domain in citrated human plasma. MDA D-Diner is an assay for use in conjunction with a clinical Pre-test Probability Assessment (PTP) model in excluding deep vein thrombosis (DVT) in outpatients suspected of a first episode of DVT. MDA D-Dimer can also be used as and in the assessment and evaluation of patients suspected of pulmonary embolism (PE). The assay is designed for use on the MDA automated coagulation analyzers.

Josephine Bautista

(Division Sign-Off)
Division of Clinical Laboratory Devices

510(k) Number.

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

Concurrence of CDRH, Office of Device Evaluation (ODE)

Prescription Use (Per 21 CFR 801.109) OR

Over-The-Counter-Use (Optional Format 1.- 2-96)

GAY

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).