(78 days)
The device is a plasma based functional IVD assay for the decemination of resistance to activated protein C caused by the factor V Leiden mulation (EV-QEAC) vated protein C castin bascu for the december (FV: CS00) on automation of resistance to activated protein C caused by the factor V Leiden mulation (FV: (SOO) on automated a the super of of C backed by the factor v Leiden mulation (FV:Q506) on automated and
Pefakit® APC-R Factor V Leiden is an in vitro diagnostic test kit containing 3 vials each of the following 4 lyophilized reagents: R1: APC / RVV-V (+APC) Reagent (APC, RVV-V, Polybrene, Hepes, BSA) R2: APC / RVV-V (-APC) Reagent (RVV-V, Polybrene, Hepes, BSA) R3: PTA Reagent (Prothrombin Activator, EDTA, Hepes, BSA) R4: Dilution Plasma (Human Plasma, processed) For Quality Assurance/Quality Control the corresponding control kit 'Pefakit® APC-R Factor V Leiden Controls' has to be used. It contains 3 vials each of the following 2 lyophilized control plasmas: C1: pooled human plasma from donors confirmed to be normal wild-type by FV Leiden PCR testing C2: pooled human plasma from donors confirmed to be heterozygous by FV Leiden PCR testing
This 510(k) summary describes the Pefakit® APC-R Factor V Leiden, an in vitro diagnostic test kit used to detect resistance to activated protein C caused by the Factor V Leiden mutation. The summary details the device's technological characteristics, non-clinical and clinical study results, and its substantial equivalence to a predicate device.
1. Table of Acceptance Criteria and Reported Device Performance
The acceptance criteria are implied by the direct comparison to the predicate device and the claims of "superior" performance in certain aspects. The submission doesn't explicitly state quantitative acceptance criteria targets but rather compares performance to the predicate device and internal standards.
| Performance Metric | Acceptance Criteria (Implied) | Reported Device Performance |
|---|---|---|
| Precision | Comparable to predicate device; CV < 6% | Within-series and Day-to-day precision: Overall CV < 6% (in-house testing). Side-by-side comparison with predicate on STA® R analyzer showed equivalent precision. |
| Diagnostic Sensitivity | High; comparable or superior to predicate device | In-house testing: 100% diagnostic sensitivity. Clinical studies: Superior diagnostic sensitivity compared to the predicate device. |
| Diagnostic Specificity | High; comparable or superior to predicate device | In-house testing: 100% diagnostic specificity. Clinical studies: Superior diagnostic specificity compared to the predicate device. |
| Resolution Power | Discrimination between carriers and non-carriers, heterozygous, and homozygous mutant carriers | High power of resolution not only between carriers and non-carriers of the FV Leiden mutation but also between heterozygous and homozygous carriers. |
| Interference (Lupus Anticoagulants - LA) | Insensitivity to LA (superior to predicate device) | In-house testing: No influence of LA on the discrimination power. CIMCLD/AKH study: LA clearly visible with predicate, but no influence on Pefakit® assay. DUMC study: LA had no influence on the outcome of the Pefakit® assay. Clearly superior to the predicate device in this respect. |
| Interference (High Factor V Deficiency (< 50%) & Aprotinin, Protamine, DTI) | Acknowledged interference, similar to predicate device | Interferes with the test, similar to the predicate device. |
| Interference (Oral Coagulant Treatment) | No influence, similar to predicate device | Clinical studies: Both tests (new device and predicate) were not influenced by oral coagulant treatment of the patients. |
| Stability (On-board reconstituted reagents) | At least 24 hours; equivalent or superior to predicate | At least 24h. |
| Stability (Kit and reagents, unopened) | At least 2 years when stored at 2-8°C | Real time long-term stability studies ongoing; currently proved stable for 2 years when stored unopened at 2-8°C. |
| Batch-to-batch Variability | Very low | Demonstrated to be very low across three pilot batches (100, 250, and 1000 device boxes) for both the basic device and the control device. |
2. Sample Size Used for the Test Set and Data Provenance
The exact sample sizes for the test sets in the clinical studies are not explicitly stated in this 510(k) summary. It mentions "clinical studies at two haematology laboratories of big central Hospitals in Europe (CIMCLD/AKH, Vienna) and the USA (Duke University Medical Center/DUMC, Durham/Raleigh NC)."
Data Provenance:
- Country of Origin: Europe (Vienna, Austria) and USA (Durham/Raleigh NC, Duke University Medical Center).
- Retrospective or Prospective: The summary does not explicitly state if the studies were retrospective or prospective, but the phrasing "In these studies both tests showed to have comparable precision..." and "For all other possible interference factors included in these studies no correlation could be found between patient parameters and test outcome" suggests a prospective collection or at least a controlled comparison of samples within the designated studies.
3. Number of Experts Used to Establish the Ground Truth for the Test Set and Qualifications of Those Experts
The summary does not specify the number of experts or their qualifications used to establish the ground truth for the clinical study test sets. It refers to "donors confirmed to be normal wild-type by FV Leiden PCR testing" and "donors confirmed to be heterozygous by FV Leiden PCR testing" for the control plasmas C1 and C2, respectively. This implies that PCR testing was the method of establishing the true genotype, but not who performed or confirmed these results.
4. Adjudication Method for the Test Set
The summary does not describe any adjudication method for the test set. The ground truth for the control plasmas was established by PCR. For the clinical studies, it is implied that the assessment of diagnostic sensitivity and specificity was based on the underlying Factor V Leiden status of the patients, likely confirmed by a gold standard method.
5. 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
This device is an in vitro diagnostic (IVD) test kit for functional assay, not an AI-powered diagnostic imaging or interpretation tool. Therefore, a multi-reader multi-case (MRMC) comparative effectiveness study of human readers with vs. without AI assistance is not applicable to this type of device. The study compared the performance of the new IVD device against a predicate IVD device.
6. If a Standalone (i.e. algorithm only without human-in-the loop performance) was Done
The device is an IVD test kit, designed to be run on automated or semi-automated blood coagulation analyzers. Its performance is inherent to the chemical reactions and detection methods of the reagents. Therefore, the "standalone performance" is its intended use, without human interpretation of the raw chemical reaction, but rather the interpretation of the results provided by the machine. The summary reports its standalone performance in terms of precision, sensitivity, specificity, and resistance to interferences.
7. The Type of Ground Truth Used
The primary ground truth mentioned for the control plasmas is molecular pathology, specifically "FV Leiden PCR testing." For the broader clinical studies, it is strongly implied that the ground truth for the Factor V Leiden mutation status of the patient samples was also established through molecular diagnostics (e.g., PCR or similar genotyping methods), given that the device aims to detect resistance caused by the Factor V Leiden mutation.
8. The Sample Size for the Training Set
The summary does not explicitly mention a "training set" as this is not an AI/ML device in the modern sense. The development of the assay would have involved internal testing and optimization (potentially using various sample sizes for method development), but the submission focuses on the validation studies, not the development phase. The "in-house testing" for precision and diagnostic performance can be seen as part of the internal validation and optimization, but a distinct "training set" is not delineated.
9. How the Ground Truth for the Training Set Was Established
As there is no explicitly defined "training set" in the context of an AI/ML device, this question is not directly applicable. However, for the development and in-house validation of the assay, the ground truth for establishing performance metrics (like sensitivity and specificity) would have been established through a reference method, most likely molecular genotyping (e.g., PCR) for the Factor V Leiden mutation. The control plasmas (C1 and C2) are described as confirmed by FV Leiden PCR testing, indicating this was the gold standard used.
{0}------------------------------------------------
DEC 22 2004
510(k) SUMMARY
Pefakit® APC-R Factor V Leiden
In accordance with the requirements of Safe Medical Devices Act (SMDA) of 1990, a 510(k) summary is provided as outlined in 21 CFR 807.92.
Part A
-
- Submitter's name, address, telephone number, contact person, and the date the summary was prepared
| Submitter's Name: | Pentapharm Ltd. |
|---|---|
| Submitter's Address: | Engelgasse 109 |
| CH-4002 Basel/Switzerland | |
| Submitter's Telephone Number: | ++41 61 706 48 48 |
| Submitter's Contact: | Reto Schöni, PhDRegulatory Affairs Specialist Diagnostics,R&D Hemostasis and Test Kit Development |
| Date of 510(k) Preparation: | September 30, 2004 |
-
- Name of the device, including the trade or proprietary name, the common or usual name and the classification name
| Trade or Proprietary Name: | Pefakit® APC-R Factor V Leiden |
|---|---|
| Common or Usual Name: | APC Resistance Test |
| Classification Name: | Hematology, Factor Deficiency Test |
3. Identification of the legally marketed device to which the submitter claims substantial equivalence
| Predicate Device Name: | COATEST® APC™ RESISTANCE V /COATEST® APC™ RESISTANCE VS |
|---|---|
| 510(k) Number: | K963111 |
| Regulation Number: | 864.7925 |
| Regulatory Class: | II |
{1}------------------------------------------------
4. Description of the device
Pefakit® APC-R Factor V Leiden is an in vitro diagnostic test kit containing 3 vials each of the following 4 lyophilized reagents:
R1: APC / RVV-V (+APC) Reagent (APC, RVV-V, Polybrene, Hepes, BSA)
R2: APC / RVV-V (-APC) Reagent (RVV-V, Polybrene, Hepes, BSA)
R3: PTA Reagent (Prothrombin Activator, EDTA, Hepes, BSA)
R4: Dilution Plasma (Human Plasma, processed)
For Quality Assurance/Quality Control the corresponding control kit 'Pefakit® APC-R Factor V Leiden Controls' has to be used. It contains 3 vials each of the following 2 lyophilized control plasmas:
C1: pooled human plasma from donors confirmed to be normal wild-type by FV Leiden PCR testing
C2: pooled human plasma from donors confirmed to be heterozygous by FV Leiden PCR testing
5. Statement on the intended use of the device
Pefakit® APC-R Factor V Leiden is a plasma based functional assay for the determination of resistance to activated protein C caused by the factor V Leiden mutation (FV:Q506).
6. Summary of the technological characteristics of the new device in comparison to those of the predicate device
The predicate device COATEST® APC™ RESISTANCE V / COATEST® APC™ RESISTANCE VS is an aPTT-based test which contains purified phospholipids and colloidal silica as contact activator. It makes use of excess FV deficient plasma to enhance the sensitivity of the test. It also contains polybrene to antagonize heparin eventually present in the patient's blood.
The new device Pefakit® APC-R Factor V Leiden also uses FV deficient plasma and polybrene with the same goal. It was shown that not only heparin is antagonized, but also the more and more frequently used heparinoids like low molecular weight heparins (LMWH) or pentasaccharide (PES). In contrast to the predicate device it is prothrombin based. It means that it is not aPTT based and contains no phosphorlipids. This feature makes it insensitive to even high titres of lupus anticoagulants present in the blood of LAC patients. The formation/activation of thrombin from prothrombin present in the patients blood is induced by a specific FVa-dependent and Ca2+ -independent prothrombin activator (Noscarin) purified from the venom of the tiger snake Notechis scutatus. Thus the test is also independent from all other factors influencing the thrombin formation based on the prothrombinase complex.
Discrimination of different patients with different factor V Leiden genotypes is based on a ratio. As for the predicate device this ratio is calculated from the clotting times measured using a reagent containing activated protein C (+APC reagent) and a reagent containing no activated Protein C (-APC reagent). Both reagents are added to
2 ·
{2}------------------------------------------------
the patient's plasma sample previously diluted with FV deficient plasma. In contrast to the predicate device in the proposed device a specific FV activator (RVV-V) purified from the venom of Russel's Viper (Daboia russelli) activates the FV present in the patients blood, which makes the test also independent from all other factors present in the patients blood influencing FV activation by other means.
Part B
1. Brief discussion of the non-clinical tests submitted, referenced , or relied on in the premarket notification submission for a determination of substantial equivalence
Non-clinical tests were done in-house to determine precision, diagnostic sensitivity and specificity, interferences, stability, and batch-to-batch variability.
The device was shown to have a high precision within the series (20 tests) and from day to day (10 days) on all instruments tested so far, with an overall coefficient of variation (CV) < 6%. This is comparable to what has been claimed for the predicate device. A side-by-side comparison of the precision within the series and from day to day with two devices on the same analyzer (STA® R) within the frame of a clinical study at the Clinical Institute for Medical and Chemical Laboratory Diagnostics (CIMCLD), Allgemeines Krankenhaus (AKH) in Vienna/Austria showed that the precision of both tests is equivalent.
In-house testing showed that the submitted device has a diagnostic sensitivity and specificity of 100%, with a high power of resolution not only between carriers and non-carriers of the FV Leiden mutation, but also between heterozygous and homozygous carriers of this mutation.
The submitted device proved to be insensitive to most interference factors. Those interfering with the test like high factor V (FV) deficiency (< 50%) and Aprotinin, Protamine and/or direct thrombin inhibitor (DTI) treatment are also interfering with the predicate device. On the other hand, Lupus Anticoagulants (LA) which can lead to test failure or misleading results with the predicate device and other comparable devices for FV Leiden APC Resistance screening has no influence on the discrimination power of the device. This has well been demonstrated in the CIMCLD/AKH study. Thus in this respect, the submitted device is clearly superior to the predicate device.
The kit and its reagents have shown to be very stable under different conditions relevant for their use and storage. On-board stability of the reconstituted reagents is at least 24h which is equivalent or even superior to what has been claimed for the predicate device. Real time long-term stability studies for the kit and its reagents are still ongoing, but so far the kit proved to be stable for 2 years when stored unopened at 2-8°C.
Batch-to-batch variability has been demonstrated to be very low on three pilot batches of increasing size (100, 250, and 1000 device boxes) of both the basic device and the control device.
ప
{3}------------------------------------------------
2. Brief discussion of the clinical tests submitted, referenced or relied on in the premarket notification submission for a determination of substantial equivalence
The Pefakit® APC-R Factor V Leiden was compared side-by-side with the predicate device COATEST® APC™ RESISTANCE V in clinical studies at two haematology laboratories of big central Hospitals in Europe (CIMCLD/AKH, Vienna) and the USA (Duke University Medical Center/DUMC, Durham/Raleigh NC). In these studies both tests showed to have comparable precision within the series and from day to day. Both tests were not influenced by oral coagulant treatment of the patients. In both studies the Pefakit® showed superior diagnostic sensitivity and specificity compared to the predicate device. In the CIMCLD/AKH study the influence of lupus anticoagulants on the COATEST® was clearly visible, but less so in the DUMC study. In both studies LA had no influence on the outcome of the Pefakit® assay. For all other possible interference factors included in these studies no correlation could be found between patient parameters and test outcome.
-
- Conclusions drawn from the non-clinical and clinical tests that demonstrate that the device is as safe, as effective, and as well or better than the legally marketed device identified in part A (3)
Pefakit® APC-R Factor V Leiden and the predicate device COATEST® APC™ RESISTANCE V have the same intended use and can be used with the same patient groups. Both tests can be used on and adapted to a wide range of semi-automated and automated blood coagulation analyzers with mechanical and/or optical detection principle. They are thus considered to be substantially equivalent in terms of intended use, method, safety of use and overall performance characteristics.
- Conclusions drawn from the non-clinical and clinical tests that demonstrate that the device is as safe, as effective, and as well or better than the legally marketed device identified in part A (3)
In direct comparison with the predicate device in clinical trials the Pefakit® APC-R Factor V Leiden showed to have a higher diagnostic sensitivity and a better discrimination of the different genotypes. Even in patients with high titres of lupus anticoagulants a good test performance and genotype discrimination could be obtained.
G. Mitron
Reto Schöni, Ph. D.
September 30, 2004
{4}------------------------------------------------
Image /page/4/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 department's mission to promote health, well-being, and human services. The text "DEPARTMENT OF HEALTH & HUMAN SERVICES • USA" is arranged in a circular pattern around the eagle.
Food and Drug Administration 2098 Gaither Road Rockville MD 20850
Pentapharm Ltd. c/o Ms. M. Elisabeth Bierman Morgan, Lewis & Bockius LLP. 1111 Pennsylvania Avenue., NW Washington DC 20004
DEC 2 2 2004
K042762 Re: Trade/Device Name: Pefakit® APC-R Factor V Leiden Regulation Number: 21 CFR 864.7925 Regulation Name: Partial thromboplastin time tests Regulatory Class: Class II Product Code: GGW Dated: December 7, 2004 Received: December 9, 2004
Dear Ms. Bierman:
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 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.
{5}------------------------------------------------
Page 2
If you desire specific information about the application of labeling requirements to your device, or questions on the promotion and advertising of your device, please contact the Office of In Vitro Diagnostic Device Evaluation and Safety at (301) 594-3084. Also, please note the regulation entitled, "Misbranding by reference to premarket notification" (21CFR Part 807.97). 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) 443-6597 or at its Internet address http://www.fda.gov/cdrh/dsma/dsmamain.html.
Sincerely yours,
Robert L. Becker Jr.
Robert L. Becker, Jr., M.D., 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
{6}------------------------------------------------
Indications for Use
510(k) Number (if known):
Device Name: Pefakit® APC-R Factor V Leiden
Indications for Use:
The device is a plasma based functional IVD assay for the decemination of resistance to activated protein C caused by the factor V Leiden mulation (EV-QEAC) vated protein C castin bascu for the december (FV: CS00) on automation of resistance to activated protein C caused by the factor V Leiden mulation (FV: (SOO) on automated a the super of of C backed by the factor v Leiden mulation (FV:Q506) on automated and
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
EEDED) NEEDED)
Concurrence of CDRH, Office of In Vitro Diagnostic Devices (OIVD)
Josephine Bautista
Division/Sign-Off
Page 1 of _
Office of In Vitro Diagnostic Device
Evaluation and Safety
§ 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).