HemosIL D-Dimer HS 500 is an automated latex enhanced immunoassay for the quantitative determination of D-Dimer in human citrated plasma on the ACL TOP® Family 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).

HemosIL D-Dimer HS 500 Controls are intended for the quality control of the D-Dimer HS 500 assay performed on the ACL TOP® Family Systems.

For in vitro diagnostic use.

Device Description

HemosIL D-Dimer HS 500: The D-Dimer HS 500 Latex Reagent is a suspension of polystyrene latex particles of uniform size coated with the F(ab')2 fragment of a monoclonal antibody highly specific for the D-Dimer domain included in fibrin soluble derivatives. The use of the F(ab'), fragment allows a more specific D-Dimer detection avoiding the interference of some endogenous factors like the Rheumatoid Factor. When a plasma containing D-Dimer is mixed with the Latex Reagent and the Reaction Buffer included in the HemosIL D-Dimer HS 500 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 transmitted light caused by the aggregates (turbidimetric immunoassay).

HemosIL D-Dimer HS 500 Controls: The Low and High D-Dimer HS 500 Controls are prepared by means of a dedicated process and contain different concentrations of partially purified D-Dimer obtained by digestion of Factor XIIIa cross-linked human fibrin with human plasmin.

AI/ML Overview

Here's an analysis of the provided text, outlining the acceptance criteria and the study data that supports the device's performance, as requested:

1. Table of Acceptance Criteria and Reported Device Performance

The acceptance criteria for the HemosIL D-Dimer HS 500 assay are primarily focused on its sensitivity and negative predictive value (NPV) for excluding 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 reported performance from the outcome study and multi-center management study directly addresses these criteria.

Acceptance Criteria (Implied for VTE Exclusion)	Reported Device Performance (95% CI) - Overall Population
For Exclusion of DVT:
High Sensitivity	100.0% (96.0%-100.0%)
High Negative Predictive Value (NPV)	100.0% (97.2%-100.0%)
For Exclusion of PE:
High Sensitivity	100.0% (93.2%-100.0%)
High Negative Predictive Value (NPV)	100.0% (97.4%-100.0%)
Precision:	ACL TOP Family (Mean/CV%)
Acceptable precision (low CV%) for controls	Low Control: 877 U/mL (2.9% within-run, 8.9% total)
	High Control: 2469 U/mL (2.5% within-run, 7.3% total)
Acceptable precision for plasma pool	Plasma Pool: 423 U/mL (7.2% within-run, 9.5% total)
Method Comparison:	n=100
Good correlation with predicate device (VIDAS)	Slope: 1.00, r: 0.981

Study Proving Device Meets Acceptance Criteria:

The device's ability to meet the acceptance criteria is demonstrated through two primary clinical studies and supporting analytical studies:

"Outcome Study" (Section 2, paragraph 3)
"Multi-center Management Study" (Section 3, paragraph 1)
"Precision" study (Section 2, paragraph 1)
"Method Comparison" study (Section 2, paragraph 2)

These studies collectively show that the HemosIL D-Dimer HS 500, with a clinical cut-off of 500 ng/mL, consistently achieved 100% sensitivity and 100% negative predictive value for both DVT and PE in the studied outpatient populations when used in conjunction with a PTP assessment. This indicates that no VTE events were missed by the test, effectively "excluding" the condition when the D-Dimer result was negative. The precision and method comparison studies demonstrate the analytical reliability and equivalence to existing commercial methods.

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

Due to the nature of this in-vitro diagnostic device (IVD), there isn't a traditional "test set" in the sense of a medical imaging AI algorithm. Instead, there are clinical samples used in performance evaluations.

Outcome Study (Clinical Performance):
- Sample Size: 295 frozen samples.
- Data Provenance: Patients admitted consecutively to an emergency unit with suspected PE or DVT. The country of origin is not explicitly stated but implies a clinical setting. The samples are retrospective as they were "frozen samples" from past admissions.
Multi-center Management Study (Clinical Performance):
- Sample Size: 747 samples (401 suspected DVT, 346 suspected PE).
- Data Provenance: Patients admitted consecutively to the emergency unit with suspected DVT or PE at four hospitals. The country of origin is not explicitly stated. This appears to be a prospective study because it describes patient management pathways and follow-up, indicating data collected as patients were presented.
Precision and Method Comparison Studies: These appear to be in-house laboratory studies using controls, plasma pools, and patient samples (n=100 for method comparison). Further specifics on provenance are not detailed.

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

The concept of "experts" establishing ground truth in this context is different from image-based AI where radiologists annotate images. Here, the ground truth for VTE (DVT and PE) status was established through "standard objective tests" and clinical follow-up, not by a panel of human reviewers interpreting the D-Dimer test itself.

Outcome Study: VTE positive cases (75 samples) were confirmed by "standard objective tests." VTE negative cases (220 samples) were also confirmed. The specific tests (e.g., ultrasound, CT angiography) are not detailed, nor are the number or qualifications of the clinicians/technicians who performed or interpreted these objective tests.
Multi-center Management Study: VTE status for DVT and PE was confirmed through a combination of imaging techniques (for positive D-Dimer or high PTP patients) and importantly, 3-month clinical follow-up for patients with negative D-Dimer and low/moderate PTP. Again, the number and specific qualifications of the clinicians involved in these diagnostic methods or follow-ups are not specified.

4. Adjudication Method for the Test Set

Not applicable in the conventional sense of human reviewers adjudicating results. The "adjudication" of definitive VTE status relied on a combination of objective diagnostic tests and clinical follow-up, which are the accepted standards for determining the presence or absence of DVT/PE. The clinical pretest probability (PTP) assessment using the Wells model served as an initial clinical judgment tool, guiding further diagnostic pathways, but the ultimate ground truth was based on objective methods and patient outcomes.

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

No, a Multi-Reader Multi-Case (MRMC) comparative effectiveness study was not done as described for AI assistance. This device is an in-vitro diagnostic (IVD) assay, a lab test intended to provide quantitative results directly, not to assist human readers in interpreting complex images or data in the same way an AI algorithm might augment a radiologist. The study evaluates the assay's performance in a clinical pathway, not the improvement of human readers with AI assistance.

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

Yes, the performance data presented is for the standalone performance of the HemosIL D-Dimer HS 500 assay, specifically the quantitative determination of D-Dimer. The "human-in-the-loop" aspect here refers to the physician integrating the D-Dimer result with the clinical pretest probability (PTP) assessment model. The device itself (the assay) provides a direct quantitative reading (e.g., 500 ng/mL) without human interpretation to arrive at that numerical value. The clinical utility is then determined by how this standalone result integrates into a diagnostic algorithm. The sensitivity and NPV reported are based on the assay's output.

7. The Type of Ground Truth Used

The ground truth used for the clinical studies (Outcome Study and Multi-center Management Study) was primarily:

Objective Diagnostic Tests: For confirmed VTE cases (DVT and PE), standard objective tests (e.g., imaging techniques like ultrasound for DVT, CT angiography for PE) were used. These are considered highly definitive.
Outcomes Data (Clinical Follow-up): Crucially, for patients with negative D-Dimer and low/moderate PTP, the absence of VTE was confirmed by 3-month clinical follow-up where the development of DVT or PE was monitored. This represents outcomes data as ground truth, which is a very strong form of evidence for exclusion criteria.

8. The Sample Size for the Training Set

The provided summary does not explicitly mention a "training set" in the context of machine learning. This is an in-vitro diagnostic device, which is typically developed through analytical validation (reagent formulation, calibration, interference studies) and clinical validation.

The "Method Comparison" study (n=100) could be considered part of the validation data used to refine or confirm equivalence, but it's not a training set for an algorithm in the AI sense.
The "Precision" study uses controls and a plasma pool, which are analytical samples for assessing assay performance, not a training set.

If earlier development involved optimizing the assay's parameters (e.g., antibody concentration, reaction conditions), that would have used various experimental samples, but a defined "training set" like in AI is not applicable here.

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

As there isn't a "training set" in the AI sense for this IVD, this question is not directly applicable. For analytical development and validation, the "ground truth" would be established through:

Defined D-Dimer concentrations: For calibrators and controls used in precision studies.
Comparison to established reference methods: For method comparison, the predicate device (VIDAS D-Dimer Exclusion Assay) served as the reference for comparison. The ground truth for the samples tested would be their D-Dimer concentration as determined by the predicate device.

Summary

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510(k) Summary

Applicant Contact Information:

Applicant:	Instrumentation Laboratory Co.
Address:	113 Hartwell AvenueLexington, MA 02421	FEB - 5 2010
Contact Person:	Carol Marble, Regulatory Affairs Director
Phone Number:	781-861-4467
Fax Number:	781-861-4207
Revision Date:	August 12, 2009

Device Trade Names:

HemosIL® D-Dimer HS 500 HemosIL® D-Dimer HS 500 Controls

Device Regulatory Information:

Regulation Nos.:	21 CFR 864.7320 (Assay); 21 CFR 864.5425 (Controls)
Regulation Names:	Fibrinogen and Fibrin Split Products, Antigen, Antiserum, Control (Assay)Plasma, Coagulation Controls (Controls)
Regulatory Class:	Class II
Product Codes:	DAP (Assay) and GGN (Controls)
Panel:	Hematology

Predicate Devices:

K040882	VIDAS® D-Dimer Exclusion™ Assay
K070927	HemosIL® D-Dimer HS
K972696	HemosIL® D-Dimer Controls

Device Descriptions:

Device Intended Uses:

HemosIL D-Dimer HS 500: Automated latex enhanced immunoassay for the quantitative determination of D-Dimer in human citrated plasma on the ACL TOP® Family 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).

HemosIL D-Dimer HS 500 Controls: For the quality control of the D-Dimer HS 500 assay performed on the ACL TOP® Family Systems.

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510(k) Summary (Cont.)

Substantial Equivalence

Differences andSimilarities	New Device:HemosIL D-Dimer HS 500	Predicate Device (K070927):HemosIL D-Dimer HS	Predicate Device (K040882):VIDAS D-Dimer Exclusion Assay
Indications for Use	HemosIL D-Dimer HS 500 is an automatedlatex enhanced immunoassay for thequantitative determination of D-Dimer inhuman citrated plasma on the ACL TOPFamily Systems for use in conjunction witha clinical pretest probability (PTP)assessment model to exclude venousthromboembolism (VTE) in outpatientssuspected of deep venous thrombosis(DVT) and pulmonary embolism (PE).	Same	VIDAS D-Dimer Exclusion assay is anautomated quantitative test for use on theVIDAS analyzers for the immunoenzymaticdetermination of fibrin degradation products(FbDP) in citrated human plasma using theELFA techniques (Enzyme LinkedFluorescent Assay). The VIDAS D-DimerExclusion assay is indicated for use inconjunction with a clinical pretest probability(PTP) assessment model to exclude deepvenous thrombosis (DVT) and pulmonaryembolism (PE) in outpatients suspected ofDVT and PE.
Physical Format	Liquid Latex Reagent	Lyophilized Latex Reagent	Ready-to-use strips
Assay Principle	Latex-enhanced immunoturbidimetric assay	Same	Two-step enzyme immunoassay sandwichmethod with a final fluorescent detection
Instrument Platforms	ACL TOP family of analyzers	Same	VIDAS instruments
Sample Type	Citrated Plasma	Same	Same
Calibrator	Same as K070927 (included in kit)	D-Dimer Calibrator (included in kit)	D-Dimer Calibrator (included in kit)
Quality Controls	HemosIL D-Dimer HS 500 Controls(sold separately)	HemosIL D-Dimer Controls(sold separately)	Vidas D-Dimer Controls C1 and C2(included in kit)
Detection Limit	203 ng/mL	21 ng/mL	45 ng/mL (FEU)
Linear Range	215-128000 ng/mL with Auto Rerun	150 - 69000 ng/mL with Auto Rerun	45-10000 ng/mL (FEU)
Clinical Cut-off	500 ng/mL	230 ng/mL	500 ng/mL (FEU)

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510(k) Summary (Cont.)

Summary Performance Data:

Precision

Within run (repeatability) and total (within device) precision was assessed over multiple runs using the two levels of HemosIL D-Dimer HS 500 Controls and a low D-Dimer plasma pool on an ACL TOP instrument:

ACL TOP Family	Mean (U/mL)	CV % (Within run)	CV % (Total)
D-Dimer Plasma Pool	423	7.2	9.5
Low D-Dimer HS 500 Control	877	2.9	8.9
High D-Dimer HS 500 Control	2469	2.5	7.3

Method Comparison

An in-house method comparison study was performed to compare the performance of HemosIL D-Dimer HS 500 on an ACL TOP instrument versus the VIDAS D-Dimer Exclusion Assay with the following results:

n	Slope	r
100	1.00	0.981

Outcome Study

An outcome study was performed on 295 frozen samples from patients admitted consecutively to an emergency unit with suspected PE or DVT (frequency of venous thromboembolic disease: 25.4%). Of the 295 samples, 75 were confirmed as VTE positive (47 PE and 28 DVT) by standard objective tests and the remaining 220 were confirmed as negative.

Instrument	N	Cut-off	% Sensitivity(95% CI)	% Specificity(95% CI)	% NPV(95% CI)
ACL TOP	295	500 ng/mL	100%(95.2% to 100%)	42.3%(35.7% - 49.1%)	100%(96.1% to 100%)

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510(k) Summary (Cont.)

Summary Performance Data (Cont.):

A multi-center management study was performed at four hospitals on 747 samples from patients admitted consecutively to the emergency unit with suspected DVT or PE . 401 patients were suspected of DVT and 346 patients 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.

The overall prevalence DVT in the total population of samples was 22.4% (90/401). The overall prevalence of PE in the total population of samples was 15.0% (52/346). As of the 3 month follow-up, none of the patients that were negative through D-Dimer testing had developed DVT or PE.

The sensitivity, specificity and negative predictive value (NPV) of HemosIL D-Dimer HS 500 for DVT and PE using the previously established clinical cut-off of 500 ng/mL is summarized below with the corresponding 95% confidence intervals (CI):

DVT Performance	All samples	High PTP	Low + ModeratePTP
n	401	79	322
Sensitivity	100.0% (90/90)(96.0%-100.0%)	100.0% (45/45)(92.1%-100.0%)	100.0% (45/45)(92.1%-100.0%)
Specificity	42.1% (131/311)(36.6%-47.8%)	32.4% (11/34)(17.4%-50.5%)	43.3% (120/277)(37.4%-49.4%)
NegativePredictive value	100.0% (131/131)(97.2%-100.0%)	100.0% (11/11)(71.5%-100.0%)	100.0% (120/120)(97.0%-100.0%)
PositivePredictive value	33.3% (90/270)(27.7%-39.3%)	66.2% (45/68)(53.7%-77.2%)	22.3% (45/202)(16.7%-28.6%)
Prevalence	22.4% (90/401)(18.5%-26.8%)	57.0% (45/79)(45.3%-68.1%)	14.0% (45/322)(10.4%-18.2%)

PE Performance	All samples	High PTP	Low + ModeratePTP
n	346	24	322
Sensitivity	100.0% (52/52)(93.2%-100.0%)	100.0% (9/9)(66.4%-100.0%)	100.0% (43/43)(91.8%-100.0%)
Specificity	48.3% (142/294)(42.5%-54.2%)	33.3% (5/15)(11.8%-61.6%)	49.1% (137/279)(43.1%-55.1%)
NegativePredictive value	100.0% (142/142)(97.4%-100.0%)	100.0% (5/5)(47.8%-100.0%)	100.0% (137/137)(97.3%-100.0%)
PositivePredictive value	25.5% (52/204)(19.7%-32.0%)	47.4% (9/19)(24.4%-71.1%)	23.2% (43/185)(17.4%-30.0%)
Prevalence	15.0% (52/346)(11.4%-19.2%)	37.5% (9/24)(18.8%-59.4%)	13.4% (43/322)(9.8%-17.6%)

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Image /page/4/Picture/1 description: The image shows the logo for the U.S. Department of Health & Human Services. The logo consists of a stylized depiction of an 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 fashion around the bird-like figure.

Food and Drug Administration 10903 New Hampshire Avenue Document Mail Center - WO66-G609 Silver Spring, MD 20993-0002

FEB 0 5 2010

Instrumentation Laboratory Co. c/o Ms. Carol Marble, Regulatory Affairs Director 113 Hartwell Avenue Lexington, MA 02421

Re: K090264

Trade/Device Name: HemosIL D-Dimer HS 500 and HemosIL D-Dimer HS 500 Controls Regulation Number: 21 CFR 864.7320 Regulation Name: Fibrinogen/fibrin degradation products assay Regulatory Class: Class II Product Code: DAP, GGN Dated: August 12, 2009 Received: August 13, 2009

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 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. Carol Marble

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/ReportalProblem/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,

Lenek. S.

Maria M. Chan, Ph.D. Director Division 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): K090264

HemosIL® D-Dimer HS 500 Device Names: HemosIL® D-Dimer HS 500 Controls

Indications for Use:

HemosIL D-Dimer HS 500 Controls are intended for the quality control of the D-Dimer HS 500 assay performed on the ACL TOP® Family Systems.

For in vitro diagnostic use.

V Prescription Use (Part 21 CFR 801 Subpart D) OR

Over-The-Counter Use (21 CFR 807 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)

Division Sign-Off

Office of In Vitro Diagnostic Device Evaluation and Safety

51000 K090264

HemosIL D-Dimer HS 500 Kit and Controls 510(k)

Page 1 of 1

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).