K Number
K070005
Date Cleared
2007-08-15

(224 days)

Product Code
Regulation Number
864.7750
Reference & Predicate Devices
Predicate For
AI/MLSaMDIVD (In Vitro Diagnostic)TherapeuticDiagnosticis PCCP AuthorizedThirdpartyExpeditedreview
Intended Use

A high sensitivity thromboplastin reagent based on recombinant human tissue factor (RTF) for the quantitative in vitro diagnostic determination in human citrated plasma of Prothrombin Time (PT) on IL Coagulation and ELECTRA Systems and Fibrinogen on IL Coagulation Systems only. The product is used for the evaluation of the extrinsic coagulation pathway and the monitoring of Oral Anticoagulant Therapy (OAT).

Device Description

The RecombiPlasTin 2G reagent is formulated to be insensitive to therapeutic levels of heparin. In the PT test, the addition of the tissue thromboplastin (RecombiPlasTin 2G reagent) to the patient plasma in the presence of calcium ions initiates the activation of the extrinsic pathway. This results ultimately in the conversion of fibringen to fibrin, with formation of a solid gel. For the IL Coagulation Systems only, the Fibrinogen is quantitated (PT-based method) by relating the absorbance or light-scatter during clotting to a calibrator.

AI/ML Overview

Here's an analysis of the provided text regarding the acceptance criteria and supporting studies for the HemosIL RecombiPlasTin 2G device:

It is important to note that this document is a 510(k) Summary, which provides a high-level overview of the device and its performance data. It does not contain a formal table of "acceptance criteria" presented as specific numerical thresholds that must be met for success, but rather presents performance data and states that the device is "not materially different" from the predicate. The "acceptance criteria" are inferred from the reported performance outcomes that demonstrate substantial equivalence to the predicate.

Acceptance Criteria and Reported Device Performance

Inferred Acceptance Criteria: The primary acceptance criterion for this 510(k) appears to be demonstrating substantial equivalence to the predicate device (HemosIL RecombiPlasTin K043184) in terms of precision, method correlation, and expected values. For Daptomycin dose-response testing, specific performance specifications are provided.

Performance MetricInferred Acceptance CriteriaReported Device Performance
Precision (PT - CV%)Maintain low coefficient of variation (CV%) for within-run and total precision across normal, low abnormal, and high abnormal samples, comparable to the predicate. (Quantitative thresholds are not explicitly stated as "acceptance criteria" but are demonstrated by the predicate.)ELECTRA: Normal 1.3% (within), 1.9% (total); Low Abnormal 1.2% (within), 2.6% (total); High Abnormal 1.3% (within), 3.4% (total). ACL Family: Normal 0.6% (within), 1.5% (total); Low Abnormal 1.0% (within), 1.9% (total); High Abnormal 1.1% (within), 2.6% (total). ACL Futura/Advance: Normal 1.1% (within), 1.9% (total); Low Abnormal 1.6% (within), 1.9% (total); High Abnormal 1.8% (within), 2.4% (total). ACL TOP: Normal 0.8% (within), 2.2% (total); Low Abnormal 0.8% (within), 3.1% (total); High Abnormal 0.9% (within), 3.1% (total).
Precision (Fibrinogen - CV%)Maintain low CV% for within-run and total precision across normal and low fibrinogen control samples, comparable to the predicate.ACL Family: Normal 4.2% (within), 5.0% (total); Low Control 5.9% (within), 6.9% (total). ACL Futura/Advance: Normal 3.0% (within), 3.1% (total); Low Control 3.7% (within), 4.5% (total). ACL TOP: Normal 1.4% (within), 2.4% (total); Low Control 2.9% (within), 3.6% (total).
Method Comparison (Correlation)High correlation (r-value close to 1) with the predicate device on various systems.PT: r-values ranging from 0.9789 to 0.9934 (In-house) and 0.9887 to 0.9945 (Field Site) against the predicate. Fibrinogen: r-values ranging from 0.9783 to 0.9969 (In-house) and 0.9832 to 0.9946 (Field Site) against the predicate.
Method Comparison (Slope/Intercept)Slope close to 1 and intercept close to 0 when compared to the predicate, indicating minimal bias.PT: Slopes ranging from 0.7637 to 0.8137 (In-house/Field Site). Intercepts ranging from 2.7138 to 4.0035. Fibrinogen: Slopes ranging from 0.9350 to 1.0129 (In-house/Field Site). Intercepts ranging from -3.6298 to 10.933.
Expected Values (Normal Range)Establish a normal range for PT and Fibrinogen, consistent with expected physiological values and comparable to the predicate (though the note states labs should establish their own).PT (seconds): ELECTRA: 9.8 - 12.2 (N=130); ACL Family: 9.1 - 12.1 (N=130); ACL Futura/Advance: 9.9 - 12.9 (N=130); ACL TOP: 9.4 - 12.5 (N=130). Fibrinogen (mg/dL): ACL Family: 308 - 613 (N=129); ACL Futura/Advance: 222 - 340 (N=129); ACL TOP: 276 - 471 (N=129).
CUBICIN Dose-Response (Normal PT)Normal Sample: ± 1 second from unspiked sample.Achieved: E.g., for ACL 6000, 100 µg/mL showed +0.4 sec change, 125 µg/mL showed +0.5 sec change. For ACL 10000, 100 µg/mL showed +0.7 sec change, 125 µg/mL showed +0.7 sec change. All reported changes were within the ±1 second specification.
CUBICIN Dose-Response (Coumadin PT)Coumadin Sample: ± 10% recovery of the unspiked sample.Achieved: E.g., for ACL 6000, 100 µg/mL showed 107% recovery, 125 µg/mL showed 110% recovery. For ACL 10000, 100 µg/mL showed 107% recovery, 125 µg/mL showed 110% recovery. All reported recoveries were within the ±10% specification (assuming "±10% recovery" implies a range of 90-110% or indicates that the value itself is 100±10, which matches the data). For example, 110% recovery is within the ±10% variation from the unspiked sample (100%).

Study Details

The provided document describes various analytical performance studies. It does not describe a clinical study in the typical sense for a medical device (e.g., involving human patients, multi-reader multi-case studies, or traditional test set/training set breakdowns for AI algorithms). This device is a reagent for an in vitro diagnostic (IVD) test, and the studies focus on laboratory performance characteristics.

  1. Sample Size used for the test set and the data provenance:

    • Precision: Not explicitly stated, but typically involves multiple replicates of control plasmas. "Over multiple runs using three levels of control plasma for PT and two levels of control plasma for fibrinogen" suggests sufficient replicates to calculate CVs.
    • Method Comparison (In-house & Field Site): Not explicitly stated, but typically involves a sufficient number of patient samples (e.g., 50-100+) to establish correlation and agreement.
    • Expected Values (Normal Range):
      • PT: N = 130 per system (ELECTRA, ACL Family, ACL Futura/Advance, ACL TOP).
      • Fibrinogen: N = 129 per system (ACL Family, ACL Futura/Advance, ACL TOP).
    • CUBICIN Dose-Response Testing: Not explicitly stated how many individual "Normal Sample" or "Coumadin Sample" plasma units were used, but multiple concentrations of CUBICIN were tested on each system. Two types of samples (normal and coumadin plasma) were spiked.
    • Data Provenance: Not explicitly stated, but an "in-house" study and "two field site" studies are mentioned, implying a mix of internal lab data and potentially external lab data. Given it's a 510(k) for an IVD, the data would typically be derived from laboratory measurements, likely from the US or international sites where the manufacturer operates. The data is retrospective in the sense that the measurements were likely taken prior to the 510(k) submission as part of development and validation.
  2. Number of experts used to establish the ground truth for the test set and the qualifications of those experts:

    • Not applicable. This is an IVD reagent, not an image-based or diagnostic device requiring expert interpretation for ground truth. The "ground truth" for these studies is the actual quantitative measurement of PT and Fibrinogen by the predicate device and the new device.
  3. Adjudication method for the test set:

    • Not applicable. As described above, this is an IVD reagent and does not involve human interpretation or adjudication for ground truth.
  4. 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. This is not an AI-assisted diagnostic device, and therefore, an MRMC study is not relevant or performed.
  5. If a standalone (i.e. algorithm only without human-in-the loop performance) was done:

    • Yes, in a sense. The "device" here is the reagent itself, and its performance is evaluated in a standalone manner on automated coagulation analyzers (IL Coagulation and ELECTRA Systems) without a human "interpretation" in the loop beyond operating the instrument and ensuring quality control. The reported performance refers to the analytical performance of the combined reagent and instrument system.
  6. The type of ground truth used (expert consensus, pathology, outcomes data, etc):

    • The "ground truth" in these studies is the quantitative analytical measurement provided by:
      • The predicate device (HemosIL RecombiPlasTin) for method comparison studies.
      • Reference materials/control plasmas with known target values for precision studies.
      • Healthy plasma samples for establishing normal ranges.
      • Spiked plasma samples (with CUBICIN) for dose-response testing where the known concentration of the drug and the baseline readings serve as the reference.
  7. The sample size for the training set:

    • Not applicable. This is not a machine learning or AI device that requires a distinct "training set" in the context of algorithm development. The development and optimization of the reagent formulation itself would involve extensive R&D, but not a formally defined "training set" for an algorithm.
  8. How the ground truth for the training set was established:

    • Not applicable, as there is no traditional "training set" for an algorithm in this context.

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KO70005

510(k) Summary (Summary of Safety and Effectiveness)

Submitted by:

Instrumentation Laboratory Company 113 Hartwell Avenue Lexington, MA 02421

Contact Person:

Carol Marble, Regulatory Affairs Director Phone No .: 781-861-4467 Fax No .: 781-861-4207

Prepared:

June 28, 2007

Device Name:

HemosIL RecombiPlasTin 2G

Regulatory Information:

864.7750Prothrombin Time TestClass II
81GJSTest, Time, Prothrombin
864.7340Fibrinogen Determination SystemClass II
81GISTest, Fibrinogen

Predicate Device:

HemosIL RecombiPlasTin K043184

Device Description:

The RecombiPlasTin 2G reagent is formulated to be insensitive to therapeutic levels of heparin. In the PT test, the addition of the tissue thromboplastin (RecombiPlasTin 2G reagent) to the patient plasma in the presence of calcium ions initiates the activation of the extrinsic pathway. This results ultimately in the conversion of fibringen to fibrin, with formation of a solid gel. For the IL Coagulation Systems only, the Fibrinogen is quantitated (PT-based method) by relating the absorbance or light-scatter during clotting to a calibrator.

Device Intended Use:

HemosIL RecombiPlasTin 2G is a high sensitivity thromboplastin reagent based on recombinant human tissue factor (RTF) for the quantitative determination in human citrated plasma of Prothrombin Time (PT) on IL Coagulation and ELECTRA Systems and Fibrinogen on IL Coagulation Systems only.

The product is used for the evaluation of the extrinsic coagulation pathway and the monitoring of Oral Anticoagulant Therapy (OAT).

Statement of Technological Characteristics of the Device Compared to Predicate Device:

The performance of HemosIL RecombiPlasTin 2G with a modified phospholivid ratio is not materially different from the FDA cleared device: HemosIL RecombiPlasTin (K043184).

Attachment D

AUG 1 5 2007

Page 1 of 5

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510(k) Summary (Cont.)

Summary of Performance Data:

Precision

Within run and total precision assessed over multiple runs using three levels of control plasma for PT and two levels of control plasma for fibrinogen gave the following results:

ELECTRAMean (PT seconds)CV % (Within run)CV % (Total)
Normal12.21.31.9
Low Abnormal21.11.22.6
High Abnormal31.31.33.4
ACL FamilyMean (PT seconds)CV % (Within run)CV % (Total)
Normal11.70.61.5
Low Abnormal21.61.01.9
High Abnormal32.91.12.6
ACL Futura/ACL AdvanceMean (PT seconds)CV % (Within run)CV % (Total)
Normal12.51.11.9
Low Abnormal23.81.61.9
High Abnormal36.01.82.4
ACL TOPMean (PT seconds)CV % (Within run)CV % (Total)
Normal11.90.82.2
Low Abnormal22.00.83.1
High Abnormal34.00.93.1
ACL FamilyMean (Fibrinogen mg/dL)CV % (Within run)CV % (Total)
Normal3194.25.0
Low Fibrinogen Control1495.96.9
ACL Futura/ACL AdvanceMean (Fibrinogen mg/dL)CV % (Within run)CV % (Total)
Normal2293.03.1
Low Fibrinogen Control1573.74.5
ACL TOPMean (Fibrinogen mg/dL)CV % (Within run)CV % (Total)
Normal2961.42.4
Low Fibrinogen Control1352.93.6

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510(k) Summary (Cont.)

Summary of Performance Data (Cont.):

Method Comparison - In-house

An in-house method comparison study was performed with modified RecombiPlasTin 2G versus the current HemosIL RecombiPlasTin:

SystemAssaySlopeInterceptrReference Method
ELECTRAPT(Seconds)0.76373.04270.9789HemosIL RTF on ELECTRA
ACL Family0.79102.78600.9885HemosIL RTF on ACL Family
ACL Futura/ACL Advance0.80752.88990.9913HemosIL RTF on ACL Advance
ACL TOP0.80102.71380.9916HemosIL RTF on ACL TOP
ACL FamilyFibrinogen(mg/dL)0.93506.10430.9866Fibrinogen (PT-Fib based) onACL Family
ACL Futura/ACL Advance0.971110.9330.9783Fibrinogen (PT-Fib based) onACL Advance
ACL TOP1.0129-3.62980.9969Fibrinogen (PT-Fib based) onACL TOP

Method Comparison - Field Site

Two field site method comparison studies were performed with modified RecombiPlasTin 2G versus the current HemosIL RecombiPlasTin:

SystemAssaySlopeInterceptrReference Method
ACL TOPPT (Sec.)0.81374.00350.9934
ACL TOPPT INR1.0838-0.10710.9945HemosIL RTF on ACL TOP
ACL TOPFibrinogen (mg/dL)0.98055.34660.9946
SystemAssaySlopeInterceptrReference Method
ACL 10000PT (Sec.)0.79352.17330.9887
ACL 10000PT INR0.94460.03670.9881HemosIL RTF on ACL 10000
ACL 10000Fibrinogen (mg/dL)0.94317.57630.9832

Expected Values

A normal range study was performed using the modified RecombiPlasTin 2G reagent:

PTNRange
• ELECTRA1309.8 - 12.2 (seconds)
• ACL Family1309.1 - 12.1 (seconds)
• ACL Futura/ACL Advance1309.9 - 12.9 (seconds)
• ACL TOP1309.4 - 12.5 (seconds)
FibrinogenNRange
• ACL Family129308 - 613 (mg/dL)
• ACL Futura/ACL Advance129222 - 340 (mg/dL)
• ACL TOP129276 - 471 (mg/dL)

*NOTE: The product insert advises customers that "These results were obtained using a specific lot of reagent. Due to many variables which may affect clotting times, each laboratory should establish its own normal range."

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510(k) Summary (Cont.) (Summary of Safety and Effectiveness)

Summary of Performance Data (Cont.):

CUBICIN (Daptomycin for injection) Dose-Response Testing

An in vitro study indicated no clinically significant CUBICIN (Daptomycin for injection) dose response with the modified HemosIL RecombiPlasTin 2G using the following specifications:

  • NOTE: The expected peak dosing for CUBICIN (Daptomycin for injection) in circulating blood is 75μg/mL.
    • Normal Sample ± 1 second from unspiked sample .
    • . Coumadin Sample ± 10% recovery of the unspiked sample

Data from this testing on representative IL Coagulation Systems are provided below:

ACL 6000 Coagulation Analyzer
CUBICINConcentration(µg/mL)Normal Sample(PT Seconds)Change inSecondsCoumadin Sample(PT Seconds)% Recovery
010.5--22.5--
110.50.022.7101%
1010.60.123.0102%
2510.50.023.4104%
5010.60.124.0107%
10010.90.424.8110%
12511.00.524.7110%
ACL 10000 Coagulation Analyzer
CUBICINConcentration(µg/mL)Normal Sample(PT Seconds)Change inSecondsCoumadin Sample(PT Seconds)% Recovery
011.7--25.1--
111.70.025.3101%
1011.80.125.7102%
2511.90.225.9103%
5012.00.326.4105%
10012.40.726.9107%
12512.40.727.5110%

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510(k) Summary (Cont.) (Summary of Safety and Effectiveness)

Summary of Performance Data (Cont.):

ACL Advance Coagulation Analyzer
CUBICINConcentration(µg/mL)Normal Sample(PT Seconds)Change inSecondsCoumadin Sample(PT Seconds)% Recovery
012.7--26.9--
112.80.126.8100%
1012.60.127.6103%
2512.80.127.3101%
5012.80.128.4106%
10013.20.529.2109%
12513.20.529.5110%

CUBICIN (Daptomycin for injection) Dose-Response Testing (Cont.)

ACL TOP Coagulation Analyzer
CUBICINConcentration(µg/mL)Normal Sample(PT Seconds)Change inSecondsCoumadin Sample(PT Seconds)% Recovery
012.3--27.3--
112.30.027.4100%
1012.30.027.8102%
2512.50.227.8102%
5012.60.328.4104%
10012.80.529.3107%
12512.90.629.7109%
ELECTRA 1600C Coagulation Analyzer
CUBICINConcentration(µg/mL)Normal Sample(PT Seconds)Change inSecondsCoumadin Sample(PT Seconds)% Recovery
012.2--23.1--
112.40.223.6102%
1012.30.122.095%
2512.60.424.0104%
5012.40.224.2105%
10012.80.623.4101%
12512.70.524.6106%

Attachment D

HemosIL RecombiPlasTin 2G 510(k)

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Image /page/5/Picture/1 description: The image shows the logo for the U.S. Department of Health & Human Services. The logo consists of a stylized eagle with three stripes representing the three levels of government: federal, state, and local. The eagle is enclosed in a circle with the text "DEPARTMENT OF HEALTH & HUMAN SERVICES - USA" around the perimeter.

Food and Drug Administration 2098 Gaither Road Rockville MD 20850

AUG 1 5 2007

Carol Marble Regulatory Affairs Director Instrumentation Laboratory Company 113 Hartwell Avenue Lexington, Massachusetts 02421

Re: K070005

Trade/Device Name: HemosIL RecombiPlasTin 2G Regulation Number: 21 CFR 864.7750 Regulation Name: Prothrombin Time Test Regulatory Class: Class II Product Code: GJS, GIS Dated: March 22, 2007 Received: March 23, 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

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

Page 2 -

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 Compliance 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.

Robert H. Becker/

Robert L. Becker, Jr., MD, PhD Director Division of Immunology and Hematology 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 RecombiPlasTin 2G

Indications for Use:

A high sensitivity thromboplastin reagent based on recombinant human tissue factor (RTF) for the quantitative in vitro diagnostic determination in human citrated plasma of Prothrombin Time (PT) on IL Coagulation and ELECTRA Systems and Fibrinogen on IL Coagulation Systems only.

The product is used for the evaluation of the extrinsic coagulation pathway and the monitoring of Oral Anticoagulant Therapy (OAT).

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 Sign-Off
-------------------

Office of In Vitro Diagnostic Device
Evaluation and SafetyHemosIL RecombiPlasTin 2G 510(k)

§ 864.7750 Prothrombin time test.

(a)
Identification. A prothrombin time test is a device used as a general screening procedure for the detection of possible clotting factor deficiencies in the extrinsic coagulation pathway, which involves the reaction between coagulation factors III and VII, and to monitor patients receiving coumarin therapy (the administration of one of the coumarin anticoagulants in the treatment of venous thrombosis or pulmonary embolism).(b)
Classification. Class II (performance standards).