HemosIL D-Dimer is an automated latex enhanced immunoassay for the quantitative determination of D-Dimer in human citrated plasma on IL Coagulation Systems for use in conjunction with a clinical pretest probability (PTP) assessment model to exclude venous thromboembolism (VTE) in outpatients suspected of deep venous thrombosis (DVT) and pulmonary cmbolism (PE).

Device Description

The D-Dimer Latex Reagent is a suspension of polystyrenc latex particles of uniform size coated with a monoclonal antibody highly specific for the D-Dimer domain included in fibrin soluble derivatives. When a plasma containing D-Dimer is mixed with the Latex Reagent and the Reaction Buffer included in the D-Dimer kit, the coated latex particles agglutinate. The degree of agglutination is directly proportional to the concentration of D-Dimer in the sample and is determined by measuring the decrease of the transmitted light at 405 nm caused by the aggregates (turbidimetric immunoassay).

AI/ML Overview

Here's a breakdown of the acceptance criteria and study findings for the HemosIL D-Dimer, based on the provided text:

Acceptance Criteria and Device Performance

The acceptance criteria for the HemosIL D-Dimer device are demonstrated through its clinical performance metrics, specifically focusing on its ability to exclude venous thromboembolism (VTE) in outpatients suspected of Deep Venous Thrombosis (DVT) and Pulmonary Embolism (PE), when used in conjunction with a clinical pretest probability (PTP) assessment model. The key performance metrics are Sensitivity and Negative Predictive Value (NPV), as a high value in these indicates the device's effectiveness in ruling out the condition.

The reported device performance aims to demonstrate that the HemosIL D-Dimer test effectively rules out DVT and PE when the D-Dimer result is negative and the PTP is low/moderate.

Table of Acceptance Criteria (Implied by Intended Use) and Reported Device Performance:

Performance Metric	Implied Acceptance Criteria (High for exclusion)	ACL TOP (Reported Performance - Low + Moderate PTP)	ACL ELITE (Reported Performance - Low + Moderate PTP)
DVT Sensitivity	High (e.g., >95%)	100.0% (32/32)	100.0% (32/32)
DVT Negative Predictive Value (NPV)	High (e.g., >95%)	100.0% (92/92)	100.0% (74/74)
PE Sensitivity	High (e.g., >95%)	100.0% (43/43)	97.6% (41/42)
PE Negative Predictive Value (NPV)	High (e.g., >95%)	100.0% (79/79)	99.1% (109/110)

Note on Implied Acceptance Criteria: The document does not explicitly state numerical acceptance criteria in a dedicated section. However, for a device intended to exclude a condition, high sensitivity and a high negative predictive value are critical to minimize false negatives and ensure patient safety. The reported 100% sensitivity and NPV (or very close to it) for low and moderate PTP groups are indicative of meeting the implicit requirement for a safe exclusion test.

Study Details:

Sample Size Used for the Test Set and Data Provenance:
- ACL TOP:
  - DVT Suspected Patients: 302 samples
  - PE Suspected Patients: 330 samples
- ACL ELITE:
  - DVT Suspected Patients: 298 samples
  - PE Suspected Patients: 331 samples
- Total Patients (ACL TOP & ELITE): 632 samples (ACL TOP) and 629 samples (ACL ELITE) according to the text, implying a total of approximately 1261 samples for the general study. The specific breakdown for DVT/PE cases are provided above.
- Data Provenance: The study was a "multi-center management study performed at four hospitals on patients admitted consecutively to the emergency unit." This indicates a prospective, real-world clinical study. The country of origin for the data is not explicitly stated, but the FDA submission and US regulatory context suggest a US-based or internationally recognized clinical trial standard.
Number of Experts Used to Establish the Ground Truth for the Test Set and Qualifications of Those Experts:
- The document does not specify the number or qualifications of experts used to establish the ground truth.
- It mentions that for patients with a positive D-Dimer test result or a high PTP score, they "underwent imaging techniques." For patients with negative D-Dimer and moderate PTP, "it was the physician's decision whether to follow-up after 3 months or to undergo imaging techniques." Finally, patients with a negative D-Dimer and low PTP "underwent no further diagnostic testing and were followed-up after 3 months for development of DVT or PE."
- This implies that the ground truth was established through a combination of:
  - Diagnostic Imaging (e.g., ultrasound, CT angiography): For "positive" cases or those requiring further investigation.
  - Clinical Follow-up (3 months): For "negative" cases, to confirm the absence of VTE.
  - Physician's Decision/Clinical Judgment: For moderate PTP cases.
Adjudication Method for the Test Set:
- The document does not explicitly detail an adjudication method in the typical sense of multiple readers reviewing results.
- However, the clinical pathway describes a form of outcome-based validation: "Patients with a negative D-Dimer test result and a low PTP score underwent no further diagnostic testing and were followed-up after 3 months for development of DVT or PE." This 3-month follow-up for outcomes serves as a de-facto adjudication for negative cases. Positive cases or those with high PTP were adjudicated by "imaging techniques."
If a Multi-Reader Multi-Case (MRMC) Comparative Effectiveness Study was done, and the effect size of how much human readers improve with AI vs without AI assistance:
- No, an MRMC comparative effectiveness study involving human readers and AI assistance was not done. This device is an in-vitro diagnostic (IVD) immunoassay, not an imaging-based AI diagnostic tool. The "AI" referred to in the question is not applicable to this type of device. The device itself performs the D-Dimer measurement.
If a Standalone (i.e., algorithm only without human-in-the-loop performance) was done:
- Yes, the performance data presented is for the HemosIL D-Dimer immunoassay in a standalone capacity (i.e., the algorithm/device only), to determine D-Dimer levels. The device itself is an automated laboratory test.
- However, its intended use is in conjunction with a clinical pretest probability (PTP) assessment model, which represents a human-in-the-loop component (the physician's clinical judgment to establish PTP). The reported sensitivity and NPV are for the D-Dimer test result within this clinical context (i.e., when combined with PTP).
The Type of Ground Truth Used:
- As inferred from point 2, the ground truth was established through a combination of:
  - Diagnostic imaging techniques (e.g., ultrasound, CT scans) to confirm or rule out DVT/PE in symptomatic patients or those with positive D-Dimer/high PTP.
  - Patient outcomes data (3-month follow-up) to confirm the absence of DVT/PE in patients with negative D-Dimer and low/moderate PTP.
The Sample Size for the Training Set:
- The document does not provide specific details on a dedicated "training set" for the HemosIL D-Dimer assay. This is typical for an immunoassay, where the assay's fundamental chemistry and measurement parameters (e.g., calibration, reagent concentrations, reaction times) are developed and optimized internally. The clinical study described is a validation study for the established assay, not a training phase for a machine learning model.
How the Ground Truth for the Training Set Was Established:
- Given that this is an immunoassay and not an AI/machine learning device, there isn't a "ground truth for a training set" in the same sense. The "ground truth" for developing such an assay would relate to internal analytical validation, where known concentrations of D-Dimer are used to establish a standard curve, linearity, precision, etc. These methods are typically internal to the manufacturer's development process and not part of the clinical validation described here.

Summary

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X073042

HemosIL D-Dimer 510(k) Summary (Summary of Safety and Effectiveness)

Applicant Contact Information:

Applicant:	Instrumentation Laboratory Co.
Address:	113 Hartwell AvenueLexington, MA 02421	JUL 31 2008
Contact Person:	Carol Marble, Regulatory Affairs Director
Phone Number:	781-861-4467
Fax Number:	781-861-4207
Preparation Date:	June 27, 2008

Device Trade Name:

HemosIL D-Dimer

Regulatory Information:

Classification Name:	Fibrinogen and Fibrin Split Products, Antigen, Antiserum, Control
Device Class:	Class II
Regulation No.:	864.7320
Product Code:	DAP
Panel:	Hematology

Predicate Device:

K070927 HemosIL D-Dimer HS

Device Intended Use:

Device Description:

Technological Characteristic Summary:

The HemosIL D-Dimer assay is equivalent to the currently marketed HemosIL D-Dimer assay (K050278), except for the Intended Use. For purposes of the Intended Use expansion, we also claim equivalence to the HemosIL D-Dimer HS assay (K070927).

Attachment B

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Characteristic	Modified Device:HemosIL D-Dimer	Predicate Device:Current HemosIL D-Dimer(K050278)	Predicate Device:HemosIL D-Dimer HS(K070927)
Indications for use	HemosIL D-Dimer is an automated latexenhanced immunoassay for thequantitative determination of D-Dimer inhuman citrated plasma on IL CoagulationSystems for use in conjunction with aclinical pretest probability (PTP)assessment model to exclude venousthromboembolism (VTE) in outpatientssuspected of deep venous thrombosis(DVT) and pulmonary embolism (PE).	HemosIL D-Dimer is an automatedlatex enhanced immunoassay for thequantitative determination ofD-Dimer in human citrated plasmaon IL Coagulation Systems as an aidin the diagnosis of venousthromboembolism (VTE) [deepvenous thrombosis (DVT) andpulmonary embolism (PE)].	HemosIL D-Dimer HS is anautomated latex enhancedimmunoassay for the quantitativedetermination of D-Dimer in humancitrated plasma on the ACL TOP foruse in conjunction with a clinicalpretest probability (PTP) assessmentmodel to exclude venousthromboembolism (VTE) [deepvenous thrombosis (DVT) andpulmonary embolism (PE)].
Assay principle	Latex-enhancedimmunoturbidmetric assay	Same	Same
Instruments	IL Coagulation Systems	Same	ACL TOP instruments only
Sample type	Citrated plasma	Same	Same
Calibrator	Kit Calibrator	Same	Same
Quality Control	HemosIL D-Dimer Controls	Same	Same
Measuring Range	200 - 5250 ng/mLwith automatic rerun	Same	150 - 69000 ng/mLwith automatic rerun
Detection Limit	ACL FamilyACL Futura/ACL AdvanceACL TOP	Same	21 ng/mLACL TOP
	140 ng/mL156 ng/mL69 ng/mL
Characteristic	Modified Device:HemosIL D-Dimer	Predicate Device:HemosIL D-Dimer(K050278)	Predicate Device:HemosIL D-Dimer HS(K070927)
Within-runPrecision (% CV)	ACL Family:4.5% at 246 ng/mL 6.01% at 310 ng/mL 2.42% at 732 ng/mL ACL Futura/ACL Advance: 11.82% at 304 ng/mL 3.59% at 813 ng/mL ACL TOP: 6.8% at 282 ng/mL 4.6% at 340 ng/mL 2.5% at 729 ng/mL	Same	ACL TOP: 8.3% at 180 ng/mL 3.7% at 314 ng/mL 2.0% at 677 ng/mL
Interferences	ACL Family andACL Futura/ACL Advance Systems: Hemoglobin up to 50 mg/dL Bilirubin up to 5 mg/dL Lipids up to 1000 mg/dL Rheumatoid Factor up to 60 IU/mL ACL TOP Hemoglobin up to 100 mg/dL Bilirubin up to 10 mg/dL Triglycerides up to 1500 mg/dL The presence of Rheumatoid Factor may produce an overestimation of the test result	Same	ACL TOP: Hemoglobin up to 500 mg/dL Bilirubin up to 18 mg/dL Triglycerides up to 1327 mg/dL Rheumatoid Factor up to 1400 UI/mL
Clinical Cut-off	230 ng/mL	Same	Same

Substantial Equivalence Comparison Table

Attachment B

Page 2 of 5

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Substantial Equivalence Comparison Table (Cont.)

Attachment B

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Performance Data:

A multi-center management study was performed at four hospitals on patients admitted consecutively to the emergency unit with suspected DVT or PE using representative IL Coagulation Systems: an ACL TOP (632 samples) and an ACL ELITE (629 samples). 302 patients on the ACL TOP and 298 patients on an ACL ELITE were suspected of DVT; 330 patients on the ACL TOP and 331 patients on the ACL ELITE were suspected of PE. As part of the study, patients underwent a PTP (pretest probability) assessment using the Wells model and were classified as having a high, moderate, or low probability of DVT or PE. Patients with a negative D-Dimer test result and a low PTP score underwent no further diagnostic testing and were followed-up after 3 months for development of DVT or PE. For patients with a negative D-Dimer test result and a moderate PTP, it was the physician's decision whether to follow-up after 3 months or to undergo imaging techniques. Patients with a positive D-Dimer test result or a high PTP score underwent imaging techniques.

There was one case during the study where a patient with a moderate PTP score and a negative D-Dimer test result on the ACL ELITE was confirmed for PE through imaging techniques. This same sample gave a positive D-Dimer test result on the ACL TOP.

The overall prevalence of DVT in the total population of samples was 19.5% (59/302) on the ACL TOP and 20.5% (61/298) on the ACL ELITE. The overall prevalence of PE in the total population of samples was 15.2% (50/330) on the ACL. TOP and 15.1% (50/331) on the ACL ELITE.

The sensitivity, specificity and negative predictive value (NPV) of HemosIL D-Dimer on the ACL. TOP and ACL ELITE for DVT and PE using the previously established clinical cut-off of 230 ng/mL is summarized below with the corresponding 95% confidence intervals (CI):

ACL TOP
DVT Performance	All samples	High PTP	Low + ModeratePTP
n	302	53	249
Sensitivity	100.0% (59/59)(93.9%-100.0%)	100.0% (27/27)(87.2%-100.0%)	100.0% (32/32)(89.1%-100.0%)
Specificity	41.6% (101/243)(35.3%-48.0%)	34.6% (9/26)(17.2%-55.7%)	42.4% (92/217)(35.7%-49.3%)
NegativePredictive value	100.0% (101/101)(96.4%-100.0%)	100.0% (9/9)(66.4%-100.0%)	100.0% (92/92)(96.1%-100.0%)
PositivePredictive value	29.4% (59/201)(23.2%-36.2%)	61.4% (27/44)(45.5%-75.6%)	20.4% (32/157)(14.4%-27.5%)
Prevalence	19.5% (59/302)(15.2%-24.5%)	50.9% (27/53)(36.8%-64.9%)	12.9% (32/249)(9.0%-17.7%)
PE Performance	All samples	High PTP	Low + ModeratePTP
n	330	24	306
Sensitivity	100.0% (50/50)(92.9%-100.0%)	100.0% (7/7)(59.0%-100.0%)	100.0% (43/43)(91.8%-100.0%)
Specificity	29.3% (82/280)(24.0%-35.0%)	17.6% (3/17)(3.8%-43.4%)	30.0% (79/263)(24.6%-36.0%)
NegativePredictive value	100.0% (82/82)(95.6%-100.0%)	100.0% (3/3)(29.2%-100.0%)	100.0% (79/79)(95.4%-100.0%)
PositivePredictive value	20.2% (50/248)(15.4%-25.7%)	33.3% (7/21)(14.6%-57.0%)	18.9% (43/227)(14.1%-24.7%)
	15.2% (50/330)	29.2% (7/24)	14.1% (43/306)

HemosIL D-Dimer 510(k) Response (06/27/08)

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Performance Data (Cont.):

ACL ELITE
DVT Performance	All samples	High PTP	Low + ModeratePTP
n	298	54	244
Sensitivity	100.0% (61/61)(94.1%-100.0%)	100.0% (29/29)(88.1%-100.0%)	100.0% (32/32)(89.1%-100.0%)
Specificity	33.8% (80/237)(27.8%-40.2%)	24.0% (6/25)(9.4%-45.1%)	34.9% (74/212)(28.5%-41.7%)
Negative Predictive Value	100.0% (80/80)(95.5%-100.0%)	100.0% (6/6)(54.1%-100.0%)	100.0% (74/74)(95.1%-100.0%)
Positive Predictive Value	28.0% (61/218)(22.1%-34.4%)	60.4% (29/48)(45.3%-74.2%)	18.8% (32/170)(13.2%-25.5%)
Prevalence	20.5% (61/298)(16.0%-25.5%)	53.7% (29/54)(39.6%-67.4%)	13.1% (32/244)(9.1%-18.0%)
PE Performance	All samples	High PTP	Low + ModeratePTP
n	331	25	306
Sensitivity	98.0% (49/50)(89.4%-99.9%)	100.0% (8/8)(63.1%-100.0%)	97.6% (41/42)(87.4%-99.9%)
Specificity	41.3% (116/281)(35.5%-47.3%)	41.2% (7/17)(18.4%-67.1%)	41.3% (109/264)(35.3%-47.5%)
Negative Predictive Value	99.1% (116/117)(95.3%-100.0%)	100.0% (7/7)(59.0%-100.0%)	99.1% (109/110)(95.0%-100.0%)
Positive Predictive Value	22.9% (49/214)(17.4%-29.1%)	44.4% (8/18)(21.5%-69.2%)	20.9% (41/196)(15.4%-27.3%)
Prevalence	15.1% (50/331)	32.0% (8/25)	13.7% (42/306)

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DEPARTMENT OF HEALTH & HUMAN SERVICES

Image /page/5/Picture/1 description: The image shows the logo for the U.S. Department of Health and Human Services. The logo consists of a stylized eagle or bird-like figure with three curved lines representing its wings or body. The text "DEPARTMENT OF HEALTH & HUMAN SERVICES USA" is arranged in a circular pattern around the bird-like figure.

Food and Drug Administration 2098 Gaither Road Rockville MD 20850

JUL 31 2008

Instrumentation Laboratory c/o Carol Marble Regulatory Affairs Director 113 Hartwell Avenue Lexington, Massachusetts 02421

Re: K073042

Trade/Device Name: Hemosil D-Dimer Regulation Number: 21 CFR 864.7320 Regulation Name: Fibrinogen/Fibrin Degradation Product Assay Regulatory Class: Class II Product Code: DAP Dated: June 27, 2008 Received: June 30, 2008

Dear Ms. Marble:

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 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 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); and good manufacturing practice 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

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Page 2 - Instrumentation Laboratory

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), please contact the Office of In Vitro Diagnostic Device Evaluation and Safety at (240) 276-0450. Also, please note the regulation entitled, "Misbranding by reference to premarket notification" (21CFR Part 807.97). For questions regarding postmarket surveillance, please contact CDRH's Office of Surveillance and Biometric's (OSB's) Division of Postmarket Surveillance at (240) 276-3474. For questions regarding the reporting of device adverse events (Medical Device Reporting (MDR)), please contact the Division of Surveillance Systems at (240) 276-3464. 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 (240) 276-3150 or at its Internet address http://www.fda.gov/cdrh/industry/support/index.html.

Sincerely yours.

Mana In Chan

Maria M. Chan, Ph.D. Acting 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 Statement

510(k) Number (if known): ____________________________________________________________________________________________________________________________________________________

Device Name: HemosIL D-Dimer

Indications for Use:

HemosIL D-Dimer is an automated latex enhanced immunoassay for the quantitative determination of D-Dimer in human citrated plasma on II. Coagulation Systems for use in conjunction with a clinical pretest probability (PTP) assessment model to exclude venous thromboembolism (VTE) in outpatients suspected of deep venous thrombosis (DVT) and pulmonary embolism (PE).

For in vitro diagnostic use.

Prescription Use (Part 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 In Vitro Diagnostic Devices (OIVD)

Josephine Bautista
Division Sign Off

Office of In Vitro Diagnostic Device Evaluation and Safety

510(k) K073042

HemosIL D-Dimer 510(k)

(2) -- (2)

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).