(167 days)
HemosIL D-Dimer HS is an automated latex enhanced immunoassay for the quantitative determination of D-Dimer in human citrated plasma on the ACL TOP 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.
The D-Dimer HS 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)2 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 D-Dimer HS 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 caused by the aggregates (turbidimetric immunoassay).
The HemosIL D-Dimer HS device is designed to quantitatively determine D-Dimer in human citrated plasma using an automated latex-enhanced immunoassay on the ACL TOP system. It is intended 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).
Here's an analysis of its acceptance criteria and the study proving its performance:
1. Table of Acceptance Criteria and Reported Device Performance
The acceptance criteria for the HemosIL D-Dimer HS device are implicitly demonstrated through its performance in a clinical management study, aiming to show high sensitivity and Negative Predictive Value (NPV) for VTE exclusion. While explicit "acceptance criteria" in terms of target percentages are not stated as such in the provided summary, the reported performance demonstrates its suitability for the stated intended use. A reasonable interpretation of "acceptance criteria" for a diagnostic device intended for exclusion would be very high sensitivity and NPV.
| Performance Metric | Target (Implicit Acceptance Criteria for exclusion) | Reported Device Performance (95% CI) - All Samples (DVT) | Reported Device Performance (95% CI) - All Samples (PE) |
|---|---|---|---|
| Sensitivity | Very High (e.g., >95%, ideally 100%) | 100.0% (94.2%-100.0%) | 100.0% (93.8%-100.0%) |
| Specificity | (Not primary for exclusion, but clinically relevant) | 38.4% (32.2%-44.8%) | 35.6% (30.2%-41.3%) |
| Negative Predictive Value (NPV) | Very High (e.g., >95%, ideally 100%) | 100.0% (96.2%-100.0%) | 100.0% (96.6%-100.0%) |
| Positive Predictive Value (PPV) | (Clinically relevant) | 29.1% (23.1%-35.7%) | 22.9% (17.9%-28.6%) |
| Prevalence | (Contextual) | 20.2% (15.8%-25.1%) | 16.1% (12.4%-20.3%) |
2. Sample Size Used for the Test Set and Data Provenance
- Sample Size:
- DVT Study: 307 patients
- PE Study: 361 patients
- Total Patients: 668 patients
- Data Provenance:
- Country of Origin: Not explicitly stated, but the study was described as a "multi-center management study was performed at four hospitals," suggesting a clinical setting likely within the country of the applicant (USA, based on address) or a close region.
- Retrospective or Prospective: The study was prospective. Patients were "admitted consecutively to the emergency unit with suspected DVT or PE" and underwent a PTP assessment followed by D-Dimer testing and subsequent diagnostic or follow-up procedures based on the results. The 3-month follow-up for negative D-Dimer patients confirms a prospective design.
3. Number of Experts Used to Establish the Ground Truth for the Test Set and Their Qualifications
The ground truth was established through a clinical management study involving diagnostic testing and 3-month follow-up, rather than expert review of images or specific clinical data points in isolation.
- Number of Experts: Not applicable in the context of establishing a ground truth for a diagnostic test like DVT/PE in this manner. The "experts" were the treating physicians who made decisions based on PTP and D-Dimer results, and the diagnostic imaging specialists who confirmed or ruled out DVT/PE.
- Qualifications of Experts: Not explicitly stated for specific individuals involved in ground truth determination. However, the study involved "patients admitted consecutively to the emergency unit" and "physician's decision" for follow-up, implying that the diagnostic and follow-up procedures were managed by qualified medical professionals (e.g., emergency physicians, radiologists, vascular specialists).
4. Adjudication Method for the Test Set
The adjudication method was based on a clinical management algorithm:
- Negative D-Dimer + Low PTP: No further diagnostic testing, followed up after 3 months for development of DVT or PE.
- Negative D-Dimer + Moderate PTP: Physician's decision for 3-month follow-up or imaging techniques.
- Positive D-Dimer or High PTP: Underwent imaging techniques (e.g., ultrasound/venography for DVT, CTPA/V/Q scan for PE).
- 3-Month Follow-up: "As of the 3 month followup, none of the patients that were negative through D-Dimer testing had developed DVT or PE," which serves as a crucial part of the ground truth confirmation for the exclusion criteria.
This is a treatment-based or outcome-based adjudication that integrates diagnostic test results with clinical assessment and subsequent diagnostic pathways/follow-up.
5. Multi-Reader Multi-Case (MRMC) Comparative Effectiveness Study
- No, an MRMC comparative effectiveness study was not done. This is a diagnostic immunoassay, not an imaging device that typically requires human reader interpretation. The device's output is a quantitative D-Dimer value. The study evaluated the device's effectiveness within a clinical management pathway, not how human readers improve with or without AI assistance.
6. Standalone (Algorithm Only) Performance
- Yes, standalone performance was done. The reported sensitivity, specificity, and NPV values reflect the performance of the HemosIL D-Dimer HS assay at its clinical cut-off (230 ng/mL) within the context of a PTP model. The device itself generates the D-Dimer value, and the study assesses how that value performs in conjunction with PTP to exclude VTE. It's the performance of the assay in combination with PTP that is being evaluated in a standalone manner from further human interpretation of the D-Dimer value itself.
7. Type of Ground Truth Used
- The ground truth was a combination of definitive diagnostic imaging (e.g., ultrasound, CTPA) and 3-month clinical outcome data.
- Patients with positive D-Dimer or high PTP were sent for imaging, which is considered a definitive diagnostic method.
- Patients with negative D-Dimer and low/moderate PTP were followed up for 3 months to confirm the absence of VTE. If VTE didn't develop, that confirmed the initial exclusion. This integrates clinical outcomes into the ground truth.
8. Sample Size for the Training Set
- Not explicitly stated in the provided text. The summary focuses on the clinical validation study to support the intended use expansion. For immunoassay devices, "training sets" are typically used during assay development and optimization (e.g., establishing calibrator curves, cut-offs, interference profiles), which occurred before this 510(k) submission. The provided performance data (Sensitivity, Specificity, NPV) is from the test set (668 patients).
9. How the Ground Truth for the Training Set Was Established
- Not explicitly stated. As noted above, the concept of a "training set" and "ground truth establishment" for it is less applicable in the same way as for AI/ML algorithms in imaging. For a diagnostic immunoassay, the "ground truth" for developing the assay and establishing initial cut-offs (like the 230 ng/mL) would typically involve:
- Known positive and negative samples: Panels of samples from individuals definitively diagnosed with and without DVT/PE (e.g., confirmed by imaging or long-term follow-up).
- Correlation with predicate devices or established methods: Comparing results from the developing assay with well-established D-Dimer assays or gold-standard diagnostic procedures.
- Repeatability and reproducibility studies: Using control materials to ensure consistent performance.
The 230 ng/mL clinical cut-off is mentioned as "previously established," indicating it was determined prior to this specific multi-center management study. The details of how this initial cut-off was established and what data was used are not provided in this 510(k) summary.
{0}------------------------------------------------
HemosIL D-Dimer HS 510(k) Summary (Summary of Safety and Effectiveness)
Applicant Contact Information:
| Applicant: | Instrumentation Laboratory Co. | |
|---|---|---|
| Address: | 113 Hartwell Avenue | |
| Lexington, MA 02421 | SEP 17 2007 | |
| Contact Person: | Carol Marble, Regulatory Affairs Director | |
| Phone Number: | 781-861-4467 | |
| Fax Number: | 781-861-4207 | |
| Preparation Date: | August 13, 2007 |
Device Trade Name:
HemosIL D-Dimer HS
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:
Biomerieux Vidas® D-Dimer Exclusion Assay
Device Intended Use:
HemosIL D-Dimer HS is an automated latex enhanced immunoassay for the quantitative determination of D-Dimer in human citrated plasma on the ACL TOP 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).
Device Description:
The D-Dimer HS 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)2 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 D-Dimer HS 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 caused by the aggregates (turbidimetric immunoassay).
Technological Characteristic Summary:
The HemosIL D-Dimer HS assay is equivalent to the currently marketed HemosIL D-Dimer HS assay, except for the Intended Use. For purposes of the Intended Use expansion, we also claim equivalence to the Biomerieux Vidas® D-Dimer Exclusion Assay, cleared under K040882.
Attachment B
{1}------------------------------------------------
| Characteristic | Modified Device:HemosIL D-Dimer HS | Predicate Device:HemosIL D-Dimer HS(K050544) | Predicate Device: BiomerieuxVidas® D-Dimer Exclusion Assay(K040882) |
|---|---|---|---|
| cions for use | HemosIL D-Dimer HS is anautomated latex enhancedimmunoassay for thequantitative determination ofD-Dimer in human citratedplasma on the ACL TOP foruse in conjunction with aclinical pretest probability(PTP) assessment model toexclude venousthromboembolism (VTE) [deepvenous thrombosis (DVT) andpulmonary embolism (PE)]. | HemosIL D-Dimer HS is anautomated latex enhancedimmunoassay for the quantitativedetermination of D-Dimer inhuman citrated plasma on the ACLTOP as an aid in the diagnosis ofvenous thromboembolism (VTE)[deep venous thrombosis (DVT)and pulmonary embolism (PE)]. | For use in conjunction with a clinicalPre-test Probability (PTP)assessment model to exclude deepvenous thrombosis (DVT) andpulmonary embolism (PE) inoutpatients suspected of DVT andPE. |
| principle | Same as K050544 | Latex-enhancedimmunoturbidmetric assay | Two-step enzyme immunoassaysandwich method with a finalfluorescent detection. |
| nent | Same as K050544 | ACL TOP instruments | VIDAS instruments |
| type | Same as K050544 | Citrated plasma | Citrated plasma |
| ator | Same as K050544 | D-Dimer Calibrator | DD2 Calibrators |
| Characteristic | Modified Device:HemosIL D-Dimer HS | Predicate Device:HemosIL D-Dimer HS(K050544) | Predicate Device: BiomerieuxVidas® D-Dimer Exclusion Assay(K040882) |
| Measuring Range | Same as K050544 | 150 - 69000 ng/mLwith automatic rerun | 45 - 10000 ng/mL (FEU) |
| Detection Limit | Same as K050544 | 21 ng/mL | 45 ng/mL (FEU) |
| Within-run Precision (% CV) | Same as K050544 | • 8.3% at 180 ng/mL• 3.7% at 314 ng/mL• 2.0% at 677 ng/mL | • 5.0% at 264 ng/mL (FEU)• 3.9% at 549 ng/mL (FEU)• 5.3% at 7283 ng/mL (FEU) |
| Total Precision (% CV) | Same as K050544 | • 11.0% at 180 ng/mL• 7.0% at 314 ng/mL• 7.0% at 677 ng/mL | • 5.7% at 264 ng/mL (FEU)• 5.8% at 549 ng/mL (FEU)• 7.1% at 7283 ng/mL (FEU) |
| Interferences | Same as K050544 | • Hemoglobin up to 500 mg/dL• Bilirubin up to 18 mg/dL• Triglycerides up to 1327 mg/dL• FDP up to 10 µg/mL• Rheumatoid Factor up to 1400 UI/mL | None of the following factors havebeen found to significantly influencethis assay: hemolysis, lipemia,bilirubinemia, rheumatoid factor.It is recommended not to usesamples that appear to be clearlyhemolyzed, lipemic, or icteric. |
| Clinical Cut-off | Same as K050544 | 230 ng/mL | 500 ng/mL (FEU) |
Substantial Equivalence Comparison Table
Attachment B
Page 2 of 4
emosIL D-Dimer HS 510(k)
{2}------------------------------------------------
Substantial Equivalence Comparison Table (Cont.)
IemosIL D-Dimer HS 510(k)
Page 3 of 4
Attachment B
{3}------------------------------------------------
Performance Data:
A multi-center management study was performed at four hospitals on 668 samples from patients admitted consecutively to the emergency unit with suspected DVT or PE. 307 patients were suspected of DVT and 361 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 of DVT in the total population of samples was 20.2% (62/307). The overall prevalence of PE in the total population of samples was 16.1% (58/361). As of the 3 month followup, 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 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):
| DVT Performance | All samples | High PTP | Low + ModeratePTP |
|---|---|---|---|
| n | 307 | 54 | 253 |
| Sensitivity | 100.0% (62/62)(94.2%-100.0%) | 100.0% (28/28)(87.7%-100.0%) | 100.0% (34/34)(89.7%-100.0%) |
| Specificity | 38.4% (94/245)(32.2%-44.8%) | 34.6% (9/26)(17.2%-55.7%) | 38.8% (85/219)(32.3%-45.6%) |
| NegativePredictive value | 100.0% (94/94)(96.2%-100.0%) | 100.0% (9/9)(66.4%-100.0%) | 100.0% (85/85)(95.8%-100.0) |
| PositivePredictive value | 29.1% (62/213)(23.1%-35.7%) | 62.2% (28/45)(46.5%-76.2%) | 20.2% (34/168)(14.4%-27.1%) |
| Prevalence | 20.2% (62/307)(15.8%-25.1%) | 51.9% (28/54)(37.8%-65.7%) | 13.4% (34/253)(9.5%-18.3%) |
| PE Performance | All samples | High PTP | Low + ModeratePTP |
|---|---|---|---|
| n | 361 | 28 | 333 |
| Sensitivity | 100.0% (58/58) | 100.0% (10/10) | 100.0% (48/48) |
| (93.8%-100.0%) | (69.2%-100.0%) | (92.6%-100.0%) | |
| Specificity | 35.6% (108/303) | 16.7% (3/18) | 36.8% (105/285) |
| (30.2%-41.3%) | (3.6%-41.4%) | (31.2%-42.7%) | |
| NegativePredictive value | 100.0% (108/108) | 100.0% (3/3) | 100.0% (105/105) |
| (96.6%-100.0%) | (29.2%-100.0%) | (96.5%-100.0%) | |
| PositivePredictive value | 22.9% (58/253) | 40.0% (10/25) | 21.1% (48/228) |
| (17.9%-28.6%) | (21.1%-61.3%) | (15.9%-26.9%) | |
| Prevalence | 16.1% (58/361) | 35.7% (10/28) | 14.4% (48/333) |
| (12.4%-20.3%) | (18.6%-55.9%) | (10.8%-18.7%) |
{4}------------------------------------------------
Image /page/4/Picture/1 description: The image shows the logo for the Department of Health & Human Services (HHS). The logo features a stylized caduceus, a symbol often associated with medicine and healthcare, with three swooping lines representing the wings of the staff. The text "DEPARTMENT OF HEALTH & HUMAN SERVICES - USA" is arranged in a circular fashion around the caduceus.
Food and Drug Administration 2098 Gaither Road Rockville MD 20850
SEP 17 2007
Carol Marble Regulatory Affairs Director Instrumentation Laboratory Company 113 Hartwell Avenue Lexington, Massachusetts 02421
Re: K070927
Trade/Device Name: HemosIL D-Dimer HS Regulation Number: 21 CFR 864.7320 Regulation Name: Fibrinogen/Fibrin Degradation Product Assay Regulatory Class: Class II Product Code: DAP Dated: March 30, 2007 Received: April 3, 2007
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
{5}------------------------------------------------
Page 2 – Carol Marble
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), 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 vours.
Robert J. Boctor
Robert L. Becker, M.D., Ph.D. Director Division of Immunology and Hematology Office of In Vitro Diagnostic Device Evaluation and Safety Center for Devices and Radiological Health
Enclosure
{6}------------------------------------------------
Page 3 -- Carol Marble
cc: HFZ-401 DMC HFZ-404 510(k) Staff HFZ- Division D.O.
{7}------------------------------------------------
Indications for Use Statement
510(k) Number (if known): K070921
Device Name: HemosIL D-Dimer HS
Indications for Use:
HemosIL D-Dimer HS is an automated latex enhanced immunoassay for the quantitative determination of D-Dimer in human citrated plasma on the ACL TOP 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) Division Sig
Office of In Vitro Diagnostic Device Evaluation and Safety
510(k) K070927
HemosIL D-Dimer HS 510(k)
§ 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).