SIGMA DIAGNOSTICS ALEXIN LS, MODELS A1219, A1334 by SIGMA DIAGNOSTICS, INC.

Sigma Diagnostics ALEXIN™ LS is a device used for primary screening for coagulation Shina Diagnest of evaluation of the effect of therapy on procoagulant disorders, and as able mail.com factor deficiencies of the intrinsic coagulation pathway.

Device Description

Sigma Diagnostics ALEXIN™ LS contains purified rabbit brain and sov phospholipids with an ellagic acid activator for the determination of the activated partial thromboplastin time and related coagulation procedures in citrated plasma. This reagent has increased sensitivity to lupus anticoagulants.

AI/ML Overview

The provided document describes the safety and effectiveness study for the Sigma Diagnostics ALEXIN™ LS device, demonstrating its substantial equivalence to the Dade Actin-FSL device.

Here's a breakdown of the requested information:

1. Table of Acceptance Criteria and Reported Device Performance:

The primary acceptance criteria for this device appear to be a strong correlation and agreement with a legally marketed predicate device (Dade Actin-FSL). The precision data also represents performance within expected ranges for such assays.

Acceptance Criteria Category	Specific Criteria (Implied)	Reported Device Performance (ALEXIN™ LS vs. Dade Actin-FSL)
Correlation Coefficient	High correlation (e.g., > 0.90) between ALEXIN™ LS and predicate device	Optical Mode: 0.97
		Mechanical Mode: 0.98
		KC 4A Analyzer: 0.95
Regression Equation (Slope/Intercept)	Close agreement (slope near 1, intercept near 0)	Optical Mode: y = 0.91x + 0.10
		Mechanical Mode: y = 0.92x + 0.08
		KC 4A Analyzer: y = 0.86x + 0.15
Precision (Within-Run CV%)	Low variability (typically < 5-10% for APTT)	Control I: 1.51%
		Control II: 0.57%
		Control III: 0.74%
Precision (Total CV%)	Low variability (typically < 10-15% for APTT)	Control I: 2.87%
		Control II: 1.85%
		Control III: 2.50%

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

Sample Size:
- Substantial Equivalence Testing: 153 random frozen patient samples were used for comparison between ALEXIN™ LS and Dade Actin-FSL.
- KC 4A Analyzer Correlation: 98 random frozen samples were used for correlation on the KC 4A analyzer.
- Precision Testing: Not explicitly stated, but "plasma controls at three different APTT levels" were used. The number of replicates for each control is not specified.
Data Provenance: The samples were "random frozen patient samples." The country of origin is not specified, and it's implied these were retrospective samples as they were "frozen."

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

This type of study (comparative performance of a diagnostic reagent) typically does not rely on expert adjudication to establish a "ground truth" in the way an imaging AI algorithm might. Instead, the "ground truth" for the comparative effectiveness portion is established by an existing, legally marketed predicate device (Dade Actin-FSL), which is assumed to provide accurate results. The precision testing uses established control materials with known target values. Therefore, this question is not directly applicable in the same way it would be for a typical AI medical device. There were no human experts adjudicating individual patient cases in this study.

4. Adjudication Method for the Test Set:

Not applicable. As explained above, the "truth" for the comparative portion was the result produced by the predicate device, not an adjudicated expert consensus.

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

No, an MRMC comparative effectiveness study was not done. This study is focused on the analytical performance of a diagnostic reagent, not on the impact of a device on human reader performance.

6. Standalone (Algorithm Only Without Human-in-the-Loop Performance) Study:

Yes, in a sense, this is a standalone performance study of the ALEXIN™ LS reagent. Its performance is measured directly against a predicate device and against established precision metrics, without active human-in-the-loop interaction beyond running the assay and interpreting the numerical output. The device itself (the reagent) is the "algorithm" and its output is a direct assay result.

7. Type of Ground Truth Used:

For Substantial Equivalence: The "ground truth" was the results obtained from the legally marketed predicate device, Dade Actin-FSL. This is a common approach for demonstrating substantial equivalence for in vitro diagnostic devices.
For Precision Studies: The "ground truth" (or target values) were derived from plasma controls at three different APTT levels. These controls are manufactured to have specific, known ranges for APTT.

8. Sample Size for the Training Set:

This information is not provided because this is a diagnostic reagent, not an AI/ML algorithm that requires a "training set" in the conventional sense. The "development" of the reagent would involve chemical formulation and optimization, not machine learning training.

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

Not applicable, as there is no "training set" for this type of device.

Summary

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K 992712

DEC - 6 1999 SUMMARY OF SAFETY AND EFFECTIVENESS ALEXINTM LS (Catalog No. A 1219/A 1344)

The activated partial thromboplastin time (APTT) is a general screening procedure for the detection of coagulation abnormalities in the intrinsic pathway. This assay was developed from the plasma recalcification time (PRT) by the addition of a surface activator to a suspension of rabbit brain cephalin. The activator eliminates the effect of variable glass surfaces on coagulation assays.

The APTT is sensitive to deficiencies or abnormalities of factors VIII, IX, XI, XII, X, V and II, prekallikrein, high molecular weight kininogen (HMWK), fibrinogen and to inhibitors of blood coagulation such as lupus anticoagulants and fibrin/fibrinogen degradation products. The presence of non-specific inhibitors, such as lupus-anticoagulants may prolong the APTT. However, this effect is variable and related to the nature of the APTT reagent employed.4 The APTT assay has also been widely used to monitor the effectiveness of standard heparin therapy, where the clotting time is prolonged in proportion to the level of unfractionated heparin.56 In summary, the APTT is a clinically relevant screening test for the diagnosis of coagulant disorders and therapeutic monitoring of unfractionated heparin.

The safety and effectiveness of Sigma Diagnostics ALEXIN LS has been demonstrated by showing its substantial equivalence to Dade Actin-FSL. One hundred fifty-three random frozen patient samples were assayed in both the optical and mechanical modes with the described ALEXIN LS reagent (y) and with Dade Actin-FSL (x). Comparison of the results yielded a correlation coefficient of 0.97 and regression equation of y = 0.91 x + 0.10 using the optical mode and a correlation coefficient of 0.98 and regression equation of y = 0.92 x + 0.08 using the mechanical mode. When 98 random frozen samples were correlated on the KC 4A analyzer , correlation coefficient was 0.95 and the regression equation was y = 0.86 x + 0.15. All regression results were assessed using logarithmically transformed data.

Sample	Control I	Control II	Control III
Mean, seconds	25.0	40.8	55.9
Within-Run
1 SD, seconds	0.38	0.23	0.41
CV %	1.51	0.57	0.74
Total
1 SD, seconds	0.72	0.75	1.40
CV%	2.87	1.85	2.50

Precision was determined on the KC 4A according to the NCCLS publication EP5-A using plasma controls at three different APTT levels. The following data were obtained:

REFERENCES

1. Manual of Hemostasis and Thrombosis, 3rd ed. AR Thompson, LA Harker, Editors, Davis Company, Philadelphia, 1983
1. Human Blood Coagulation, Haemostasis and Thrombosis, 3rd ed. R Biggs, CR Rizza, Editors, Blackwell Scientific Publications London, 1984
1. Surdsmo JS, Fair DS: Relationship among the complement, kinin, coagulation and fibrinolytic systems in the inflammatory reaction. Clin Physiol Biochem 1:225, 1983.

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1. Forastiero RR, Cerrato GS, Carreras LO: Evaluation of Recently Described Tests for Detection of the Lupus Anticoagulant. Throm. Haem. 72(5):728,1994.
Basu D, Gallus MB, Hirsh J, Cade J: A prospective study of the value of monitoring heparin 5. treatment with the activated partial thromboplastin time. N Engl J Med 287:324, 1972
Deykin D: Regulation of heparin therapy. N Engl J Med 287:355, 1972 6.
National Committee for Clinical Laboratory Standards. Evaluation of Precision Performance of 7. Clinical Chemistry Devices; Approved Guideline. NCCLS Publication EP5-A, Villanova, PA, 1999

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Food and Drug Administration 2098 Gaither Road Rockville MD 20850

DEC - 6 1999

William R. Gilbert, Ph.D. Manager, Scientific Affairs Sigma Diagnostics, Inc. 545 South Ewing Avenue St. Louis, Missouri 63103

Re: K992712 Trade Name: Sigma Diagnostics ALEXIN™ LS Regulatory Class: II Product Code: GFO Dated: October 14, 1999 Received: October 15, 1999

Dear Dr. Gilbert:

We have reviewed your Section 510(k) notification of intent to market the device referenced above and we 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). 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 (Premarket Approval), it may be subject to such additional controls. Existing major regulations affecting your device can be found in the Code of Federal Regulations. Title 21, Parts 800 to 895. A substantially equivalent determination assumes compliance with the Current Good Manufacturing Practice requirements, as set forth in the Quality System Regulation (OS) for Medical Devices: General regulation (21 CFR Part 820) and that, through periodic OS inspections, the Food and Drug Administration (FDA) will verify such assumptions. Failure to comply with the GMP regulation may result in regulatory action. In addition, FDA may publish further announcements concerning your device in the Federal Register. Please note: this response to your premarket notification submission does not affect any obligation you might have under sections 531 through 542 of the Act for devices under the Electronic Product Radiation Control provisions, or other Federal laws or regulations.

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Under the Clinical Laboratory Improvement Amendments of 1988 (CLIA-88), this device may require a CLIA complexity categorization. To determine if it does, you should contact the Centers for Disease Control and Prevention (CDC) at (770)488-7655.

This letter will allow you to begin marketing your device as described in your 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 and additionally 809.10 for in vitro diagnostic devices), please contact the Office of Compliance at (301) 594-4588. Additionally, for questions on the promotion and advertising of your device, please contact the Office of Compliance at (301) 594-4639. Also, please note the regulation entitled, "Misbranding by reference to premarket notification" (21 CFR 807.97). Other general information on your responsibilities under the Act may be obtained from the Division of Small Manufacturers Assistance at its toll free number (800) 638-2041 or at (301) 443-6597 or at its internet address "http://www.fda.gov/cdrh/dsmamain.html"

Sincerely vours.

Steven Butman

Steven I. Gutman, M.D., M.B.A. Director Division of Clinical Laboratory Devices Office of Device Evaluation Center for Devices and Radiological Health

Enclosure

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510(k) Number (if known): رق ال 19927)

Device Name: Sigma Diagnostics ALEXIN™ LS

Indications For Use:

(PLEASE DO NOT WRITE BELOW THIS LINE-CONTINUE ON ANOTHER PAGE IF NEEDED)

Concurrence of CDRH, Office of Device Evaluation (ODE)

Luta E. Make
(Division Sign-Off)
Division of Clinical Laboratory Devices K992712
510(k) Number

Prescription Use ✓
(Per 21 CFR 801.109)
OR
Over-The-Counter Use __

Regulation Number and Section

§ 864.7925 Partial thromboplastin time tests.

(a)
Identification. A partial thromboplastin time test is a device used for primary screening for coagulation abnormalities, for evaluation of the effect of therapy on procoagulant disorders, and as an assay for coagulation factor deficiencies of the intrinsic coagulation pathway.(b)
Classification. Class II (performance standards).