(114 days)
Sigma Diagnostics ACCUCLOT™ Thrombin Time Reagent (A8713/A4589) is a device intended to measure fibrinogen concentration and to detect fibrin or fibrinogen split products for the evaluation of bleeding disorders.
Sigma Diagnostics' ACCUCLOT™ Thrombin Time Reagent is intended for use as a screening procedure to detect functional fibrinogen and thrombin inhibitors such as heparin, in citrated plasma. The ACCUCLOT™ Thrombin Time Reagent provides thrombin for fibrinogen hydrolysis and is able to detect normal fibrinogen function even in the presence of severe coagulation abnormalities such as hemophilia (Factor VIII or Factor IX deficiency) or a decrease in factor levels associated with vitamin K deficiency.
The provided text describes the safety and effectiveness of the Sigma Diagnostics' ACCUCLOT™ Thrombin Time Reagent, primarily by demonstrating its substantial equivalence to a legally marketed predicate device, Organon's Thromboquik™ Thrombin Time Reagent.
1. Table of Acceptance Criteria and Reported Device Performance:
| Acceptance Criteria Category | Acceptance Criteria (Predicate Equivalent) | Reported Device Performance (ACCUCLOT™ Thrombin Time Reagent) |
|---|---|---|
| Correlation with Predicate Device (Organon Thromboquik™) on Different Instruments | High correlation (r² close to 1) with the predicate device across various coagulation analyzers. No specific numerical threshold for r² is given as an acceptance criterion, but the provided r² values indicate strong correlation. | AMAX Optical: Y = 2.11x - 13.33, r² = 0.978 (N=101) AMAX Mechanical: Y = 2.87x - 18.10, r² = 0.972 (N=101) KC4a: Y = 1.95x - 7.26, r² = 0.959 (N=49) |
| Precision (Within-run CV) | Less than 7% | Less than 7% |
| Precision (Total Precision) | Less than 6% | Less than 6% |
| Heparin Sensitivity | Detect heparin levels corresponding to 0.2 U/mL and up to at least 0.8 U/mL (implied equivalence to predicate's performance in detecting these levels) | Sensitive to heparin levels corresponding to 0.2 heparin U/mL and up to at least 0.8 heparin U/mL. |
| Fibrinogen Sensitivity | Detect abnormal low fibrinogen levels (implied for equivalence). No specific numerical threshold is given for the predicate, but ACCUCLOT™ shows sensitivity starting at 98 mg/dL. | Demonstrated sensitivity for abnormal low fibrinogen levels starting at 98 mg/dL fibrinogen. |
Study Proving Acceptance Criteria:
The study proving the device meets the acceptance criteria is a substantial equivalence study comparing the Sigma Diagnostics' ACCUCLOT™ Thrombin Time Reagent to Organon's Thromboquik™ Thrombin Time Reagent (the predicate device).
2. Sample Sizes Used for the Test Set and Data Provenance:
- Correlation Study:
- AMAX Optical & AMAX Mechanical: N = 101 plasma samples (normal and abnormal)
- KC4a: N = 49 plasma samples (normal and abnormal)
- Precision Study: Normal and abnormal control plasmas were used, but the specific number of samples or replicates is not explicitly stated, only that the "within run CV" and "total precision" were measured.
- Heparin/Fibrinogen Sensitivity: The text states the reagent's sensitivity but does not provide specific sample sizes for these evaluations.
- Data Provenance: The document does not specify the country of origin of the data. The study appears to be retrospective in the sense that existing plasma samples (normal and abnormal) were used to compare the new device against the predicate.
3. Number of Experts Used to Establish Ground Truth for the Test Set and Qualifications:
Not applicable. This study does not involve expert interpretation of results to establish ground truth in the way medical imaging or clinical diagnostics typically would. The "ground truth" for the correlation study is the result obtained from the legally marketed predicate device (Organon's Thromboquik™). For precision, it's the expected value of the control plasmas.
4. Adjudication Method for the Test Set:
Not applicable. This is a quantitative comparison against a predicate device, not an interpretation task requiring adjudication.
5. If a Multi-Reader Multi-Case (MRMC) Comparative Effectiveness Study Was Done:
No, an MRMC comparative effectiveness study was not done. This study focuses on the analytical performance of the new reagent compared to a predicate, not on human reader performance with or without AI assistance.
6. If a Standalone (i.e., algorithm only without human-in-the-loop performance) Was Done:
Yes, the studies described are essentially "standalone" in nature, comparing the performance of the ACCUCLOT™ reagent (the "algorithm" or test method) directly against the predicate Thromboquik™ reagent. There is no human-in-the-loop component described for interpreting the results beyond standard laboratory technician procedures.
7. The Type of Ground Truth Used:
The primary "ground truth" used for substantial equivalence is the results obtained from the legally marketed predicate device (Organon's Thromboquik™ Thrombin Time Reagent). For the precision studies, the ground truth would be the known values of the normal and abnormal control plasmas.
8. The Sample Size for the Training Set:
Not applicable. This study does not describe a machine learning model with a separate training set. The "training" in this context refers to the development and optimization of the reagent itself, not an algorithm.
9. How the Ground Truth for the Training Set Was Established:
Not applicable, as there's no machine learning training set described. The "ground truth" for the development of the reagent would stem from established scientific principles of coagulation testing and chemical reactions.
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OCT 1 5 1998
Summarv of Safety and Effectiveness
ACCUCLOT™ Thrombin Time Reagent (Product No. A8713, A4589)
Sigma Diagnostics' ACCUCLOT™ Thrombin Time Reagent is intended for use as a screening procedure to detect functional fibrinogen and thrombin inhibitors such as heparin, in citrated plasma.
The thrombin clotting time (TT) is an important screening procedure for disorders of thrombosis and hemostasis as well as the presence of heparin.1-3 Thrombin Time testing is a rapid assay procedure that measures the polymerization of fibrinogen to fibrin. Any interference with this conversion will be reflected in a prolongation in the clotting time of the test procedure.
The ACCUCLOT™ Thrombin Time Reagent provides thrombin for fibrinogen hydrolysis and is able to detect normal fibrinogen function even in the presence of severe coagulation abnormalities such as hemophilia (Factor VIII or Factor IX deficiency) or a decrease in factor levels associated with vitamin K deficiency. Abnormal thrombin clotting times occur in cases of hypofibrinogenemia. afibrinogenemia, or dysfibrinogenemia. The TT is also prolonged in the presence of inhibitors such as heparin, myeloma proteins and fibrin/fibrinogen degradation products, which block either thrombin cleavage of fibrinopeptides or fibrin monomer polymerization. 3-5
Sigma Diagnostics' ATROXIN® assay (Catalog # 845-2) can provide data to rule out the presence of heparin in samples with elongated thrombin clotting times.
The safety and effectiveness of the Sigma Diagnostics' ACCUCLOT™ Thrombin Time Reagent has been demonstrated by showing its substantial equivalence to Organon's Thromboquik™ Thrombin Time Reagent. Both Thrombin Time reagents were compared using normal and abnormal plasma samples. Sigma's ACCUCLOT™ Thrombin Time Reagent (y) was used on an Amelung KC-4A, an CS-190 (optically and mechanically) and Organon Teknika's AMAX Thromboquik™ (x) was used on a photo-optical analyzer, the Coag-A-Mate X2. Results of these correlation studies are presented in the table below.
| Instrument | Equation | r2 | N |
|---|---|---|---|
| AMAX Optical | Y=2.11x-13.33 | 0.978 | 101 |
| AMAX Mechanical | Y=2.87x-18.10 | 0.972 | 101 |
| KC4a | Y=1.95x-7.26 | 0.959 | 49 |
Precision studies demonstrated a within run CV of less than 7% and a total
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precision of less than 6%, using normal and abnormal control plasmas. Sigma Diagnostics' ACCUCLOT™ Thrombin Time Reagent is sensitive to heparin levels corresponding to 0.2 heparin U/mL and up to at least 0.8 heparin U/mL. The reagent also, demonstrated sensitivity for abnormal low fibrinogen levels starting at 98 mg/dL fibrinogen.
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- Coleman RW, Hirsh J. Marder VJ, Salzman EW: Hemostasis and Thrombosis_2nd ed. J B Lippincott Co., Philadelphia, 1987
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- Jarret L. Sonnenworth AC: Gradwohl's Clinical Laboratory Methods and Diagnosis, Vol 1, 2nd ed. C V Mosby Co., St. Louis (MO), 1977
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- Miale JB: Laboratory Medicine Hematology, 5th ed. C V Mosby Co., St. Louis (MO), 1977
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- Williams WT, Beutler E, Erslev AJ, Rundles RW: Hematology, 2nd ed. _McGraw-Hill, New York, 1977
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- Wintrobe MM, Lee GR, Boggs DR, Bitchell JC, Foerster J, Athens JW, Lukens JN: Clinical Hematology, 8th ed. Lea & Febiger, Philadelphia, 1981
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OCT 1 5 1998
Food and Drug Administration 2098 Gaither Road Rockville MD 20850
William R. Gilbert, Ph.D. Manager, Scientific Affairs Siqma Diagnostics 545 South Ewing Avenue St. Louis, Missouri 63103
Re: K982209/S1 Trade Name: ACCUCLOT Thrombin Time Reagent Regulatory Class: II Product Code: GJA Dated: September 17, 1998 Received: September 18, 1998
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 A substantially equivalent determination assumes compliance to 895. with the Current Good Manufacturing Practice requirements, as set forth in the Quality System Regulation (QS) for Medical Devices: General requlation (21 CFR Part 820) and that, through periodic QS inspections, the Food and Drug Administration (FDA) will verify such assumptions. Failure to comply with the GMP regulation may result in requlatory 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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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 requlation (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 (301) 443-6597, or at its internet address "http://www.fda.gov/cdrh/dsma/dsmamain.html".
Sincerely yours,
Steven Putman
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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Page ! of I
510(k) Number (if known): ___
Device Name: _ Sigma Diagnostics ACCUCLOT™ Thrombin Time Reagent (A8713/A4589)
Indications For Use:
Sigma Diagnostics ACCUCLOT™ Thrombin Time Reagent (A8713/A4589) is a device intended to measure fibrinogen concentration and to detect fibrin or fibrinogen split products for the evaluation of bleeding disorders.
(PLEASE DO NOT WRITE BELOW THIS LINE-CONTINUE ON ANOTHER PAGE IF NEEDED)
Concurrence of CDRH, Office of Device Evaluation (ODE)
Teter E. Marlini
(Division Sign-Off)
Division of Clinical Laboratory Devices / 4982209
510(k) Number
Prescription Use √
(Per 21 CFR 801.109)
)
Over-The-Counter Use _________________________________________________________________________________________________________________________________________________________
§ 864.7875 Thrombin time test.
(a)
Identification. A thrombin time test is a device used to measure fibrinogen concentration and detect fibrin or fibrinogen split products for the evaluation of bleeding disorders.(b)
Classification. Class II (performance standards).