Automated coagulation functional assay for the quantitative determination of free Protein S in human citrated plasma as an aid in the diagnosis of hereditary and acquired Protein S deficiency, on ACL TOP Family members.

Device Description

The HemosIL Protein S Activity assay determines the functional activity of free Protein S by measuring the degree of prolongation of prothrombin time in the presence of the human recombinant factor, phospholipids, calcium ions, and activated Protein C. The protein S activity is correlated with the prolongation of the clotting time of a Protein S deficient plasma to which a diluted sample has been added.

AI/ML Overview

The provided document describes the HemosIL® Protein S Activity Assay, a device designed for the quantitative determination of free Protein S in human citrated plasma, aiding in the diagnosis of hereditary and acquired Protein S deficiency. The submission is a 510(k) premarket notification, indicating the device is being compared to a legally marketed predicate device (HemosIL ProS Assay, K053499) to establish substantial equivalence.

Based on the provided text, here's an analysis of the acceptance criteria and study information:

1. Table of Acceptance Criteria and Reported Device Performance

The document does not explicitly state "acceptance criteria" for the performance metrics (precision and method comparison). Instead, it presents the results of internal and field-site studies and implies that these results demonstrate performance equivalent to the predicate device, thereby fulfilling the requirements for substantial equivalence.

However, we can infer performance ranges from the provided data:

Metric	Acceptance Criteria (Inferred from Predicate Equivalence)	Reported Device Performance (HemosIL Protein S Activity Assay)
Precision	Not explicitly stated as acceptance criteria, but results are compared to established levels for similar assays.	Within-Run CV%: 1.6 - 3.8% (for various controls/samples)
		Total CV%: 4.2 - 7.1% (for various controls/samples)
Method Comparison (In-House)	Not explicitly stated. Implied to show substantial equivalence to predicate.	Slope: 0.966 (for ACL TOP 700)
		Y-intercept: 0.000 (for ACL TOP 700)
Method Comparison (Field Site)	Not explicitly stated. Implied to show substantial equivalence to predicate.	Slope: 0.955 - 1.010 (across various systems)
		Y-intercept: Not explicitly stated/clear in presented data.

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

Precision Study:
- Sample Size: "n=80/ instrument/ lot" for each sample level (Normal Control, Low Abnormal Control, High Abnormal Control, Internal Control 1, Internal Control 2, High Plasma Sample). This means for each of the 3 lots and 3 instruments, there were 80 data points for each sample type. This is a total of (80 data points/sample type * 6 sample types * 3 lots * 3 instruments) = 4320 data points for precision (if all combinations were tested for each sample type). However, the table only shows data from a "representative lot" on "ACL TOP".
- Data Provenance: The study was conducted "in accordance with CLSI EP05-A2" and utilized "3 lots of reagent on 3 representative members of the ACL TOP Family (ACL TOP, ACL TOP 500 CTS and ACL TOP 700)". This indicates the data is prospective and generated during internal validation, likely at the manufacturer's facility. Country of origin is not specified but the manufacturer is based in Bedford, MA, USA.
Method Comparison - In-House:
- Sample Size: Not explicitly stated in the provided text. The table only shows results for "ACL TOP 700" but doesn't mention the number of samples used for the comparison between the new device and the predicate.
- Data Provenance: "An in-house comparison study was performed". This indicates prospective data generated internally, likely at the manufacturer's facility.
Method Comparison - Field Sites:
- Sample Size: Not explicitly stated in the provided text. The table shows results from "Two field site studies" but doesn't mention the number of samples used.
- Data Provenance: "Two field site studies were performed". This indicates prospective data collected from external laboratories, likely in different geographical locations (though country of origin is not specified).

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

This information is not applicable and therefore, not provided. The device is an in vitro diagnostic assay that measures analyte concentration (Protein S activity). The "ground truth" for such assays is typically established by the reference method or by the predicate device's performance, not by expert consensus in clinical interpretation of images or symptoms. The studies involve comparing the new assay's results to the predicate device's quantitative results, or evaluating its precision against statistical guidelines.

4. Adjudication Method for the Test Set

This information is not applicable and therefore, not provided. Adjudication methods are typically used in studies involving subjective interpretation (e.g., image reading) where multiple experts might disagree. For an analytical assay, the comparison is quantitative and statistical, not based on adjudication of expert opinions.

5. Multi Reader Multi Case (MRMC) Comparative Effectiveness Study

This information is not applicable and therefore, not provided. An MRMC study is relevant for diagnostic imaging devices where human readers interpret cases, and the effectiveness of AI assistance on their performance is evaluated. This device is an in-vitro diagnostic assay and does not involve human "readers" in the same context.

6. Standalone Performance

Yes, a standalone performance study was done for the algorithm (the assay). The entire document describes the standalone performance of the HemosIL Protein S Activity assay. It characterizes the assay's precision (within-run and total CV%) and its correlation with a legally marketed predicate device through method comparison studies. The performance reported in section "VII. Summary of Performance Data" are characteristics of the device itself (the "algorithm only" if the assay method is considered analogous to an algorithm).

7. Type of Ground Truth Used

The ground truth used for performance evaluation is derived from:

Precision: Statistical measures of reproducibility, comparing the device's own measurements across repeated tests.
Method Comparison: The results obtained from the predicate device (HemosIL ProS). The new device's performance is established by demonstrating substantial equivalence to the predicate device's quantitative results. This means the predicate device's measurements serve as the referent or "ground truth" for comparison to establish equivalence.

8. Sample Size for the Training Set

This information is not applicable and not provided. The HemosIL Protein S Activity assay is a reagent-based assay for laboratory testing, not an AI/ML algorithm that requires a "training set" in the conventional sense of machine learning. The "training" for such an assay involves the development and optimization of the reagents and methodology, which is a chemical and biological process, not a computational one with a distinct training dataset.

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

This information is not applicable and not provided for the reasons stated in point 8.

Summary

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MAR 1 7 2011

510(k) Summary

(per 21 CFR 807.92)

781-861-4350

781-861-4207

July 28, 2010

jemery@ilww.com

HemosIL® Protein S Activity

l. Applicant Contact Information

Applicant:	Instrumentation Laboratory Co.
Address:	180 Hartwell Road
	Bedford, MA 01730
Contact Person:	Jacqueline Emery, BS EE

Phone Number: Fax Number: Email: Preparation Date:

Device Trade Name

II. Device Regulatory Information

Regulatory Section	21 CFR 864.7290
Classification	Class II
Common Name:	Protein S Test
Classification Name:	Factor Deficiency Test
Product Code:	GGP
Panel:	81 (hematology)

III. Identification of Legally Marketed Device

K053499

HemosIL® ProS

IV. Device Description

V. Device Indications/ Intended Use

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HemosIL® Protein S Activity Assay

VI. Comparison of Technological Characteristics of the Device

Similarities

ﺘ

The HemosIL Protein S Activity Assay is Substantially Equivalent to its predicate, the HemosIL ProS Assay (K053499), in both intended use and performance:

TABLE 1:	Table of Similarity and Differences
----------	-------------------------------------

Item	Predicate Device	New Device
K#	K053499	TBD
Device Name	HemosIL ProS	HemosIL Protein SActivity
Manufacturer	Instrumentation Laboratory Co. (self)	Same
Indications for Use	Automated coagulation functional assayfor the quantitative determination offree Protein S in human citrated plasmaas an aid in the diagnosis of hereditaryand acquired Protein S deficiency, onthe ACL TOP® Family of analyzers.	Same
Sample Type	citrated plasma	Same
Test Principle	Functional Clotting Assay	Same
Methodology	The test is based on the ability ofendogenous protein S as a cofactor ofactivated protein C to prolong theclotting time. Protein S levels in patientplasma are measured automatically onthe ACL TOP® Family of analyzers.The test determines the functionalactivity of free protein S by measuringthe degree of prolongation of aprothrombin time in the presence ofthe recombinant tissue factor,phospholipids, calcium ions, andactivated protein C.The protein S activity is correlated withthe prolongation of the clotting time ofa Protein S deficient plasma to whichdiluted sample has been added.	Same
Calibration	HemosIL Calibration plasma values areassigned for Protein S Activity and usedfor calibrating the standard curve.	Same
Item	Predicate Device	New Device
K#	K053499	TBD
Device Name	HemosIL ProS	HemosIL Protein SActivity
Kit Composition
- Protein S reagent	- Lyophilized preparationcontaining recombinant tissuefactor, synthetic phospholipids,activated protein C, Polybrene,buffer, stabilizers &preservatives.- Includes calcium ions.- Rabbit Tissue Factor	- Lyophilizedpreparationcontainingrecombinanttissue factor,syntheticphospholipids,activated protein. C, Polybrene,buffer, stabilizers& preservatives.- Calcium is addedseparately toimprove shelf life.- Human TissueFactor
- Calcium Reagent	- Calcium is included in the ProteinS reagent vial.	- Calcium isincluded in aseparate vial.
- Protein S deficientplasma	- Lyophilized human plasma whichhas been artificially depleted ofprotein S.	- Same except forvial size.
- Protein S controlplasma	- Lyophilized human plasmacontaining a low level of protein S.	- Not sold with thisproduct.

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TABLE 2: Table of Similarity and Differences (continued)

Differences

. . .

There are 2 main differences between the 2 products; the HemosIL Protein S Activity Assay, the subject of this submission, and its HemosIL ProS assay predicate: the applicant contains human tissue factor, whereas the predicate utilizes rabbit tissue factor.

In addition the HemosiL Protein S Activity assay kit composition has changed as compared to its predicate: the calcium ions required for the reaction, which were previously included in the predicate's Protein S reagent vial, are now offered as a separate component. The test results demonstrate that these changes do not adversely affect the product's performance.

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VII. Summary of Performance Data

. Precision

Performance characteristics were assessed utilizing 3 lots of reagent on 3 representative members of the ACL TOP Family (ACL TOP, ACL TOP 500 CTS and ACL TOP 700). Precision was evaluated in accordance with CLSI EP05-A2-, for 20 days, with 2 runs per day and 2 replicates per run, for each sample level (n=80/ instrument/ lot). Data from a representative lot is included below:

ACL TOP	Mean (% PS)	CV% (Within run)	CV% (Total)
· Normal Control	94.2	2.5	4.9
Low Abnormal Control	33.6	3.8	7.1
High Abnormal Control	19.3	1.19(SD)	2.23 (SD)
Internal Control 1	44.5	2.9	6.2
Internal Control 2	67.2	1.7	4.7
High Plasma Sample	128	1.6	4.2

. Method Comparison - In-House
An in-house comparison study was performed in accordance with CLSI EPO9-A2; Method Comparison and Bias Estimation, 200 Edition, 2002, to compare the performance of HemoslL Protein S Activity versus the predicate device (HemoslL ProS) on representative ACL TOP Family members with the following results:

TABLE 3: METHOD COMPARISON RESULTS IN-HOUSE

System	Canada Canada Cara Cara Cara Cara Cara Cara Cara Cara Cara Cara Cara Cara Cara Cara Cara Cara Cara Cara Cara Cara Cara Cara Cara Cara Cara Cara Cara Cara Cara Cara Cara Cara	1Slope	E & TE I RE IN MIN LA MINING BANK
------------------------------------		10.966	------------------------------------------------------------------------------------------------------------------------------------------------------------------------------Achieves and color de control controlled and contraction of the contribution0 000
CI TOP SOO CTS		BALL BROOM STATIST A--------OACA AND A AND A Comen	1975=44-46-140------------------------------------------------------------------------------------------------------------------------------------------------------------------------------

CLSI EP5-A2: Evaluation of Precision Performance of Quantitative Measurement Methods; Approved Guideline, 2" edition.

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Method Comparison – Field Sites .

Two field site studies were performed to compare the performance of the HemosIL Protein S Activity assay versus the predicate device (HemosIL ProS) on the ACL TOP with the following 1 results:

	TABLE 4:	METHOD COMPARISON RESULTS FIELD SITE
--	----------	--------------------------------------

System		Slope	-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------
ﻟ44 1	A A C1	0000	Address StatesU OCC
11 mt	A 1999 199Acres of the comments of the closed on the comments of the contributed to the coursesA ANNUAL AND AND AND A	1 010	10 955ما تي مل هال

VIII. Conclusion

Based on the device's similarity in intended use, technology characteristics and performance data, it is determined that the IL HemosIL Protein S Activity assay is substantially equivalent to its predicate, the HemosIL ProS assay.

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Image /page/5/Picture/1 description: The image shows the logo for the Department of Health & Human Services USA. The logo features a stylized eagle with three lines representing its body and wings. The words "DEPARTMENT OF HEALTH & HUMAN SERVICES USA" are arranged in a circular pattern around the eagle.

Food and Drug Administration 10903 New Hampshire Avenue Document Mail Center - WO66-0609 Silver Spring, MD 20993-0002

Instrumentation Laboratory Co. c/o Ms. Jacqueline Emery Regulatory Affairs Manager 180 Hartwell Rd. Bedford, MA 01730

MAR 1 7 2011

Re: K102164 Trade/Device Name: HemosIL® Protein S Activity Regulation Number: 21 CFR 864.7290 Regulation Name: Test Qualitative and Quantitative Factor Deficiency Regulatory Class: Class II Product Code: GGP Dated: March 4, 2011 Received: March 7, 2011

Dear Ms. Emery,

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. Jacqueline Emery

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,

Maria M. Khan

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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K102164 - HemosIL® Protein S Activity Assay

09/28/2010 Request for Additional Information-Response

Indications for Use Statement

102164 510(k) Number (if known):

Device Name: HemosIL Protein S Activity

Indications for Use:

V 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)

Lenck

Division Sign-Off Office of In Vitro Diagnostic Device Evaluation and Safety

510(k) K102164

COMPANY CONFIDENTIAL

Regulation Number and Section

§ 864.7290 Factor deficiency test.

(a)
Identification. A factor deficiency test is a device used to diagnose specific coagulation defects, to monitor certain types of therapy, to detect coagulation inhibitors, and to detect a carrier state (a person carrying both a recessive gene for a coagulation factor deficiency such as hemophilia and the corresponding normal gene).(b)
Classification. Class II (performance standards).