(107 days)
ACL AcuStar: Automated immunoassay analyzer designed specifically for in vitro diagnostic use in a clinical laboratory. The assay analysis is based on chemiluminescent technology. The system provides results for both direct measurements and calculated parameters.
HemosIL AcuStar D-Dimer: Fully automated chemiluminescent immunoassay for the quantitative determination of D-Dimer in human citrated plasma on the ACL AcuStar as an aid in the diagnosis of venous thromboembolism (VTE) [deep vein thrombosis (DVT) and pulmonary embolism (PE)].
HemosIL AcuStar D-Dimer Controls: For the quality control of D-Dimer assay performed on the ACL AcuStar.
ACL AcuStar: The AcuStar is an automated, bench-top system for lab use that measures the analyte amount in blood samples by: Subjecting the blood sample to reagents that cause a reaction with an antigen or antibody in the sample. Placing the cuvettes in a controlled environment to allow the reactants to bind into a complex. Separating out the complex from unused reactants. Treating this complex with a chemical that produces light in proportion to the analyte concentration. Measuring the light output to determine the amount of antibodies or antigens that were in the sample.
HemosIL AcuStar D-Dimer: The HemosIL AcuStar D-Dimer assay is a two-step immunoassay to quantify D-Dimer in human citrated plasma using magnetic particles as solid phase and a chemiluminescent detection system. In the first step, sample, anti-D-Dimer antibody coated magnetic particles, and assay buffer are combined, and the fibrin soluble derivatives containing the D-Dimer domain present in the sample bind to the anti-D-Dimer antibody coated magnetic particles. After magnetic separation and washing, an anti-XDP antibody labeled with isoluminol is added and incubated in a second step. After a new magnetic separation and washing, two triggers are added and the resulting chemiluminescent reaction is measured as relative light units (RLUs) by the ACL AcuStar optical system. The RLUs are directly proportional to the D-Dimer concentration in the sample. The ACL AcuStar D-Dimer assay utilizes a 4 Parameter Logistic Curve (4PLC) fit data reduction method to generate a Master Curve. The Master Curve is predefined lot dependent, and is stored in the instrument through the cartridge barcode. With the measurement of calibrators, the predefined Master Curve is transformed to a new, instrument specific 4PLC Working Curve. The concentration values of the calibrators are included in the calibrator plastic tube barcodes.
HemosIL AcuStar D-Dimer Controls: The Low, High, and Very High D-Dimer 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.
Here's a breakdown of the acceptance criteria and the study details for the ACL™ AcuStar™ HemosIL™ AcuStar™ D-Dimer, based on the provided 510(k) summary:
Acceptance Criteria and Reported Device Performance
| Acceptance Criteria Category | Specific Metric | Acceptance Criterion (Implicit) | Reported Device Performance |
|---|---|---|---|
| Precision | Coefficient of Variation (CV%) for D-Dimer Controls and Calibrator 1 | The document does not explicitly state numerical acceptance criteria for precision (e.g., CV% < X%). However, good precision is generally expected for diagnostic assays. The reported CV% values demonstrate the reproducibility and reliability of the assay across different D-Dimer concentrations. | Low D-Dimer Control:- Within run CV%: 4.0%- Total CV%: 6.8%High D-Dimer Control:- Within run CV%: 2.3%- Total CV%: 4.9%Very High D-Dimer Control:- Within run CV%: 2.5%- Total CV%: 5.6%Calibrator 1:- Within run CV%: 2.7%- Total CV%: 5.4% |
| Method Comparison | Correlation (r) and Slope when compared to predicate device (VIDAS) | Not explicitly stated as a numerical threshold in the document. However, a strong correlation (r close to 1) and a slope close to 1 (or a consistent proportionality) are generally expected to demonstrate substantial equivalence to the predicate device. | Slope: 1.16r (correlation coefficient): 0.888 |
| Clinical Performance | Sensitivity for VTE diagnosis | For a D-Dimer assay used as an aid in diagnosis and for ruling out VTE, high sensitivity is crucial to minimize false negatives. While no explicit numerical threshold is stated, 100% sensitivity is a highly desirable outcome for an exclusion assay, indicating that no true positive VTE cases were missed. | Sensitivity: 100% (95% CI: 96.3%-100.0%) |
| Specificity for VTE diagnosis | While not as critical as sensitivity for exclusion assays, reasonable specificity helps reduce unnecessary further testing. No explicit numerical threshold is provided, but the reported specificity provides insight into the assay's ability to correctly identify true negatives. | Specificity: 55.5% (95% CI: 49.0%-61.8%) | |
| Negative Predictive Value (NPV) for VTE diagnosis | High NPV is paramount for an exclusion assay, as it indicates the probability that a patient truly does not have the condition if the test result is negative. Similar to sensitivity, 100% NPV is an ideal outcome for an exclusion assay. | NPV: 100% (95% CI: 97.3%-100.0%) | |
| Detection Limit | Lower limit of D-Dimer concentration that can be reliably detected | The detection limit is an inherent performance characteristic. A lower detection limit can offer more sensitive assessment. The document compares this to predicate devices. | 6.51 ng/mL |
| Linear Range | Range of D-Dimer concentrations over which the assay provides accurate | This defines the measurable range of the assay. A wide linear range with auto-rerun capability is advantageous. The document compares this to predicate devices. | 54.3 - 1110000 ng/mL with Auto Rerun |
Study Information
2. Sample size used for the test set and the data provenance:
- Test Set Sample Size (Clinical Management Study): 344 frozen citrated plasma samples.
- Data Provenance: From patients admitted to an emergency unit with suspected PE or DVT. The country of origin is not explicitly stated, but the context generally implies a clinical setting in a developed country (e.g., US or EU) for regulatory submissions of this type. The samples were retrospective, as they were "frozen citrated plasmas from patients."
3. 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 of experts or their qualifications.
- Ground Truth Establishment: "97 were confirmed as VTE positive (64 PE and 33 DVT) by standard objective tests and the remaining 247 were confirmed as negative." The "standard objective tests" would typically be interpreted and confirmed by medical specialists (e.g., radiologists for imaging, clinical physicians for diagnosis confirmation), but this is not detailed.
4. Adjudication method for the test set:
- The document does not specify an explicit adjudication method (e.g., 2+1, 3+1). The ground truth was established by "standard objective tests" and clinical confirmation.
5. If a multi-reader multi-case (MRMC) comparative effectiveness study was done:
- No, an MRMC comparative effectiveness study was not done. This submission focuses on the performance of a diagnostic instrument and assay (ACL AcuStar D-Dimer) as a standalone test, and its clinical utility for exclusion of VTE, rather than human reader improvement 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 device (ACL AcuStar D-Dimer assay and instrument) without human-in-the-loop assistance in its interpretation. The results (sensitivity, specificity, NPV) directly reflect the device's diagnostic capability.
7. The type of ground truth used:
- The ground truth was established by outcomes data and expert diagnosis based on standard objective tests:
- VTE positive cases (PE and DVT) were "confirmed ... by standard objective tests." These typically include imaging studies (e.g., CT pulmonary angiography for PE, ultrasound for DVT) and clinical assessment.
- VTE negative cases were "confirmed as negative" also presumably by the absence of findings on standard objective tests and clinical follow-up.
8. The sample size for the training set:
- The document does not specify a separate "training set" in the context of machine learning. This is a traditional in-vitro diagnostic device submission for an immunoassay. The concept of a training set for an algorithm is not directly applicable here. The "training" in this context refers to the development and optimization of the assay and its reagents during product development, which is typically done with various in-house samples and analytical studies.
9. How the ground truth for the training set was established:
- As noted above, the concept of a separate "training set" with ground truth in the machine learning sense is not explicitly present. For an immunoassay, the "ground truth" during development (analogous to training) would involve using characterized samples with known D-Dimer concentrations or clinical status, and optimizing the assay's reagents and calibration curve to achieve accurate measurements and clinical cut-offs. This development process for assays does not typically involve the formal "ground truth establishment" and "adjudication" methods seen in AI/ML validation studies.
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510(k) Summary
Applicant Contact Information:
MAR 1 3 2009
| Applicant: | Instrumentation Laboratory Co. |
|---|---|
| Address: | 113 Hartwell Avenue |
| Lexington, MA 02421 | |
| Contact Person: | Carol Marble, Regulatory Affairs Director |
| Alternate Contact: | Gabriella Erdosy, Regulatory Affairs Associate |
| Phone Number: | 781-861-4467 |
| Fax Number: | 781-861-4207 |
| Preparation Date: | February 26, 2009 |
Device Trade Names:
ACL™ AcuStar™ HemosIL™ AcuStar™ D-Dimer HemosIL™ AcuStar™ D-Dimer Controls
Device Regulatory Information:
| Regulation Nos.: | 21 CFR 864.7320 (Assay); 21 CFR 864.5425 (Instrument and Controls) |
|---|---|
| Regulation Names: | Multipurpose System for In Vitro Coagulation StudiesFibrinogen and Fibrin Split Products, Antigen, Antiserum, Control (Assay)Plasma, Coagulation Controls (Controls) |
| Regulatory Class: | Class II |
| Product Codes: | JPA (Instrument), DAP (Assay) and GGN (Controls) |
| Panel: | Hematology |
Predicate Devices:
| K891385 | VIDAS Instrument |
|---|---|
| K040882 | VIDAS D-Dimer Exclusion Assay |
| K073377 | ACL TOP |
| K070927 | HemosIL D-Dimer HS |
| K972696 | HemosIL D-Dimer Controls |
Device Indications for Use:
·
- . ACL AcuStar: Automated immunoassay analyzer designed specifically for in vitro diagnostic use in a clinical laboratory. The assay analysis is based on chemiluminescent technology. The system provides results for both direct measurements and calculated parameters.
- HemosIL AcuStar D-Dimer: Fully automated chemiluminescent immunoassay for the quantitative . determination of D-Dimer in human citrated plasma on the ACL AcuStar as an aid in the diagnosis of venous thromboembolism (VTE) [deep vein thrombosis (DVT) and pulmonary embolism (PE)].
- . HemosIL AcuStar D-Dimer Controls: For the quality control of D-Dimer assay performed on the ACL AcuStar.
Attachment B K083518: ACL AcuStar, HemosIL AcuStar D-Dimer and Controls Page 1 of 4
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510(k) Summary (Cont.)
Device Descriptions:
ACL AcuStar: .
The AcuStar is an automated, bench-top system for lab use that measures the analyte amount in blood samples by:
- Subjecting the blood sample to reagents that cause a reaction with an antigen or antibody in the � sample.
- Placing the cuvettes in a controlled environment to allow the reactants to bind into a complex. . Q
- . Separating out the complex from unused reactants.
- . Treating this complex with a chemical that produces light in proportion to the analyte concentration.
- Measuring the light output to determine the amount of antibodies or antigens that were in the � sample.
. HemosIL AcuStar D-Dimer:
The HemosIL AcuStar D-Dimer assay is a two-step immunoassay to quantify D-Dimer in human citrated plasma using magnetic particles as solid phase and a chemiluminescent detection system. In the first step, sample, anti-D-Dimer antibody coated magnetic particles, and assay buffer are combined, and the fibrin soluble derivatives containing the D-Dimer domain present in the sample bind to the anti-D-Dimer antibody coated magnetic particles. After magnetic separation and washing, an anti-XDP antibody labeled with isoluminol is added and incubated in a second step. After a new magnetic separation and washing, two triggers are added and the resulting chemiluminescent reaction is measured as relative light units (RLUs) by the ACL AcuStar optical system. The RLUs are directly proportional to the D-Dimer concentration in the sample. The ACL AcuStar D-Dimer assay utilizes a 4 Parameter Logistic Curve (4PLC) fit data reduction method to generate a Master Curve. The Master Curve is predefined lot dependent, and is stored in the instrument through the cartridge barcode. With the measurement of calibrators, the predefined Master Curve is transformed to a new, instrument specific 4PLC Working Curve. The concentration values of the calibrators are included in the calibrator plastic tube barcodes.
HemosIL AcuStar D-Dimer Controls: .
The Low, High, and Very High D-Dimer 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.
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10(k) Summary (Cont
| Substantial Equivalence:Differences andSimilarities | New Device:ACL AcuStar andHemosIL AcuStar D-Dimerand HemosIL AcuStar D-Dimer Ctrls | Predicate Devices:ACL TOP (K073377) withHemosIL D-Dimer HS (K070927)and HemosIL D-Dimer Controls(K972696) | Predicate Devices:VIDAS Instrument (K891385) withVIDAS D-Dimer Exclusion Assay(K040882) |
|---|---|---|---|
| Indications for Use | Fully automated chemiluminescentimmunoassay for the quantitativedetermination of D-Dimer in humancitrated plasma on the ACL AcuStar as anaid in the diagnosis of venousthromboembolism (VTE) [deep veinthrombosis (DVT) and pulmonaryembolism (PE)]. | Automated latex enhancedimmunoassay for the quantitativedetermination of D-Dimer in humancitrated plasma on the ACL TOPFamily Systems for use in conjunctionwith a clinical pretest probability (PTP)assessment model to exclude venousthromboembolism (VTE) in outpatientssuspected of deep venous thrombosis(DVT) and pulmonary embolism (PE). | Automated 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 VIDASD-Dimer Exclusion assay is indicated foruse in conjunction with a clinical Pre-testProbability (PTP) assessment model toexclude deep venous thrombosis (DVT) andpulmonary embolism (PE) in outpatientssuspected of DVT and PE. |
| Physical Format | Single cartridge containing reagents | Lyophilized Latex Reagent | Ready-to-use strips |
| Assay Principle | Two-step chemiluminescent immunoassay | Latex-enhanced immunoturbidmetricassay | Two-step enzyme immunoassay sandwichmethod with a final fluorescent detection |
| Instrument Platform | ACL AcuStar | ACL TOP family of analyzers | VIDAS instruments |
| Sample Type | Citrated Plasma | Same | Same |
| Calibrator | D-Dimer Calibrator (included in kit) | D-Dimer Calibrator (included in kit) | D-Dimer Calibrator (included in kit) |
| Quality Controls | AcuStar D-Dimer Controls,Low, High and Very High (soldseparately) | HemosIL D-Dimer Controls,Low and High (sold separately) | D-Dimer Controls (included in kit) |
| Detection Limit | 6.51 ng/mL | 21 ng/mL | 45 ng/mL (FEU) |
| Linear Range | 54.3 - 1110000 ng/mL with Auto Rerun | 150 - 69000 ng/mL with Auto Rerun | 45-10000 ng/mL (FEU) |
| Clinical Cut-off | 500 ng/mL (FEU) | 230 ng/mL (D-Dimer Units) | 500 ng/mL (FEU) |
83518: ACL AcuStar, HemosIL AcuStar D-Dimer and Contro
Attachment B
Page 3 of 4
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510(k) Summary (Cont.)
Summary Performance Data:
Precision
Precision was assessed over multiple runs using the three levels of HemosIL AcuStar D-Dimer Controls and the kit Calibrator Level 1 on an ACL AcuStar instrument:
| ACL AcuStar | Mean (ng/m L) | CV% (Within run) | CV% (Total) |
|---|---|---|---|
| Low D-Dimer Control | 234 | 4.0% | 6.8% |
| High D-Dimer Control | 841 | 2.3% | 4.9% |
| Very High D-Dimer Control | 8467 | 2.5% | 5.6% |
| Calibrator 1 | 358 | 2.7% | 5.4% |
Method Comparison
An in-house method comparison study was performed to compare the performance of HemosIL AcuStar D-Dimer on an ACL AcuStar versus the VIDAS D-Dimer Exclusion Assay with the following results:
| n | Slope | r |
|---|---|---|
| 179 | 1.16 | 0.888 |
Management Study
A management study was performed on 344 frozen citrated plasmas from patients admitted to an emergency unit with suspected PE or DVT (frequency of venous thrombosis disease 28.2%). Of the 344 samples, 97 were confirmed as VTE positive (64 PE and 33 DVT) by standard objective tests and the remaining 247 were confirmed as negative.
| Instrument | N | Cut-off | % Sensitivity(95% CI) | % Specificity(95% CI) | % NPV(95% CI) |
|---|---|---|---|---|---|
| ACL AcuStar | 344 | 500 ng/mL | 100%(96.3%-100.0%) | 55.5%(49.0%-61.8%) | 100%(97.3%-100.0%) |
Attachment B K083518: ACL AcuStar, HemosIL AcuStar D-Dimer and Controls
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Image /page/4/Picture/1 description: The image shows the seal of the Department of Health & Human Services (HHS). The seal features a stylized eagle with three stripes forming its wing, and the text "DEPARTMENT OF HEALTH & HUMAN SERVICES . USA" encircles the eagle. The text is arranged in a circular fashion around the eagle, with the words "DEPARTMENT OF HEALTH & HUMAN SERVICES" at the bottom and ". USA" at the top.
Food and Drug Administration 2098 Gaither Road Rockville MD 20850
MAR 1 3 2009
Instrumentation Laboratory Co. c/o Ms. Carol Marble Regulatory Affairs Director 113 Hartwell Avenue Lexington, MA 02421
Re: K083518
Trade/Device Name: ACL™ AcuStar™, HemosIL™ AcuStar™ D-Dimer and HemsIL™ AcuStar™ D-Dimer Controls
Regulation Number: 21 CFR 864.7320 Regulation Name: Fibrinogen/Fibrin Degradation Product Assay Regulatory Class: Class II Product Code: JPA, DAP, GGN Dated: February 26, 2009 Received: February 27, 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 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
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Page 2 - Ms. Carol Marble
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 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,
ia m chan
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 Statement
510(k) Number (if known):
Devices Name: ACL™ AcuStar™ HemosIL™ AcuStar™ D-Dimer HemosIL™ AcuStar™ D-Dimer Controls
Indications for Use:
- ACL AcuStar: Automated immunoassay analyzer designed specifically for in vitro . diagnostic use in a clinical laboratory. The assay analysis is based on chemiluminescent The system provides results for both direct measurements and calculated technology. parameters.
- HemosIL AcuStar D-Dimer: Fully automated chemiluminescent immunoassay for the . quantitative determination of D-Dimer in human citrated plasma on the ACL AcuStar as an aid in the diagnosis of venous thromboembolism (VTE) [deep vein thrombosis (DVT) and pulmonary embolism (PE)].
- HemosIL AcuStar D-Dimer Controls: For the quality control of D-Dimer assay performed . on the ACL AcuStar.
Prescription Use
(Part 21 CFR 801 Subpart D) √
AND/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)
Josephine Bautista
Division Sign-Off
Office office office official official official official official official official official official official official official official official official official official In Vitro Diagnostic Device Evaluation and Safety
510(k) K083518
Section 4
ACL AcuStar, HemosIL AcuStar D-Dimer and Controls 510(k)
Page 1 of 1
§ 864.5425 Multipurpose system for in vitro coagulation studies.
(a)
Identification. A multipurpose system for in vitro coagulation studies is a device consisting of one automated or semiautomated instrument and its associated reagents and controls. The system is used to perform a series of coagulation studies and coagulation factor assays.(b)
Classification. Class II (special controls). A control intended for use with a multipurpose system for in vitro coagulation studies is exempt from the premarket notification procedures in subpart E of part 807 of this chapter subject to the limitations in § 864.9.