The VerifyNow-P2Y12 Assay is a whole blood assay used in the laboratory or point of care setting to measure the level of platelet P2Y12 receptor blockade.

Device Description

The VerifyNow System is a turbidimetric based optical detection system, which measures platelet induced aggregation as an increase in light transmittance. The system consists of a stand-alone instrument and disposable assay device with reagents based on microbead agglutination technology. The quality control system includes an electronic control, an assay device internal control, and two levels of liquid control. The instrument controls assay sequencing, establishes the assay temperature, controls the reagent-sample mixing for the required duration, determines the degree of platelet function, displays the results and status information to the user, and performs self-diagnostics.

The assay device contains a lyophilized preparation of human fibrinogen coated beads. adenosine-5-diphosphate (ADP), a peptide, a fatty acid, buffer, and preservative. The patient sample is citrated whole blood, which is automatically dispensed from the blood collection tube into the assay device by the instrument, with no blood handling required by the user.

Fibrinogen-coated microparticles are used in the VerifyNow-P2Y12 assay device to bind activated platelet GP IIb/Illa receptors. ADP is incorporated into the assay to activate platelets, and the reagent is formulated to specifically measure P2Y12 - mediated platelet aggregation.

When the activated platelets are exposed to the fibrinogen-coated microparticles, aggregation occurs in proportion to the number of activated platelet receptors. The VerifyNow-P2Y12 Assay reports results in P2Y12 Reaction Units (PRU).

AI/ML Overview

Here's a breakdown of the acceptance criteria and study information for the Accumetrics VerifyNow P2Y12 Assay, based on the provided text:

1. Table of Acceptance Criteria and Reported Device Performance

The submission does not explicitly state pre-defined acceptance criteria for the VerifyNow P2Y12 Assay. Instead, it presents performance characteristics and demonstrates its ability to measure changes in P2Y12 receptor blockade in response to clopidogrel and its specificity compared to Light Transmittance Aggregometry (LTA).

Performance Metric	Reported Device Performance
Measurement Range (PRU)	Measured changes in PRU ranging from a minimum of 18 PRU to a maximum of 435 PRU with a mean change of 185 PRU (demonstrated in patients before and after clopidogrel administration).
Reference Range (Baseline PRU)	Calculated at 95% confidence level for baseline (pre-clopidogrel) dataset: Mean = 306.7, SD = 58.5, Reference Range = 194 - 418 (n=147).
Specificity for P2Y12 Receptor	Comparison to LTA with ADP only: 73% average inhibition with ADP only. Comparison to LTA with ADP and additive: 95% average inhibition. Agreement with VerifyNow-P2Y12: VerifyNow-P2Y12 showed 93% average inhibition, demonstrating very good agreement (93% vs 95%) with LTA using the additive. This demonstrates the benefit of the additive for achieving P2Y12 specificity, which is a key design aspect of the VerifyNow assay to overcome the non-specificity of LTA with ADP only (due to P2Y1 mediated aggregation).
Clear Separation of Baseline vs. Post-Clopidogrel PRU	Demonstrated visually by a vertical histogram showing distinct distributions of PRU values before and after clopidogrel administration, indicating the device's ability to detect the effect of the drug.

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

Sample Size for Main Performance Study: 147 subjects.
Sample Size for Specificity Study: 10 individuals/blood donors.
Data Provenance: The studies were performed in "clinical studies at 4 centers". The country of origin is not explicitly stated, but given the FDA 510(k) submission, it is highly likely to be within the United States. The studies appear to be prospective, as they involve "patients treated with clopidogrel" and include "before and after clopidogrel administration" measurements. The specificity study also involved drawing blood and adding inhibitors, indicating a prospective experimental design.

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

The submission does not rely on expert opinion to establish ground truth in the traditional sense for diagnostic image analysis or clinical endpoint assessment. Instead, the "ground truth" is established by:

Pharmacological Intervention: The known effect of clopidogrel (a drug specifically designed to block the P2Y12 ADP receptor) is used as a reference for assessing the device's ability to measure P2Y12 receptor blockade.
Predicate Device Comparison: The CHRONO-LOG Optical Aggregometer (Light Transmittance Aggregometry - LTA) with 5 uM ADP as the agonist serves as the comparative method. LTA is a well-established method for measuring platelet aggregation.
Known Inhibitors: In the specificity study, a known specific P2Y12 inhibitor, 2-methylthio-AMP (2MeSAMP), was added to blood samples to establish the "ground truth" for maximal P2Y12 inhibition.

Therefore, no external "experts" were explicitly used to interpret data for ground truth establishment; rather, established biochemical and pharmacological principles and comparative methods were employed.

4. Adjudication Method for the Test Set

Not applicable. As described above, the ground truth is established through pharmacological means and comparison to a predicate device, not through expert consensus on interpretations that would require adjudication.

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

No. This is an in-vitro diagnostic (IVD) device for measuring a biological marker (platelet P2Y12 receptor blockade). MRMC studies are typically applicable to medical imaging devices where human readers interpret images, and the AI's role is to assist or replace that interpretation. This submission describes standalone device performance.

6. Standalone (i.e., algorithm only without human-in-the-loop performance) Study

Yes, the studies described are standalone performance evaluations of the VerifyNow P2Y12 Assay. The device measures in vitro platelet function automatically and provides a quantitative result (PRU). There is no human interpretation of an algorithm's output or human-in-the-loop component described in the performance evaluation.

7. Type of Ground Truth Used

The ground truth used is a combination of:

Pharmacological Effect: The known and expected biological response to a specific drug (clopidogrel) that targets the P2Y12 receptor.
Comparative Reference Method: Light Transmittance Aggregometry (LTA) using 5 uM ADP as an agonist, which is a recognized method for assessing platelet aggregation.
Known Biochemical Inhibition: The use of a specific chemical inhibitor (2MeSAMP) to induce a known level of P2Y12 inhibition.

8. Sample Size for the Training Set

The document does not explicitly mention a separate "training set" or "validation set" in the context of machine learning model development. This is a traditional IVD device, not an AI/ML-driven device that typically requires distinct training and test sets for model development and evaluation. The described studies are performance evaluations of a pre-defined assay.

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

Not applicable, as a distinct training set for an AI/ML model is not described or implied in this 510(k) summary. The device's underlying principles (turbidimetric optical detection, fibrinogen-coated beads, ADP, specific additives) are based on established biochemical and biophysical mechanisms, not data-driven machine learning.

Summary

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K 05/23/

AUG 5 - 2005

510(k) Summary

Accumetrics VerifyNow P2Y12

Accumetrics 3985 Sorrento Valley Blvd. San Diego, CA 92121

July 29, 2005

For information regarding this 510(k) Summary, please contact Accumetrics, Barbara Stevens (858) 404-8281.

Device Names:

Trade Name: VerifyNow-P2Y12 Assay

Common Name: VerifyNow-P2Y12 Assay Devices VerifyNow Assay Wet Controls. Levels 1 and 2 VerifyNow Instrument VerifyNow Electronic Control
Classification Name:

System, Automated Platelet Aggregation 21 CFR 864.5700 81 JOZ Hematology Panel

Accumetrics is claiming substantial equivalence of the VerifyNow-P2Y12 Assay to other currently marketed, automated aggregation devices, specifically the CHRONO-LOG Whole Blood Aggregometer with CHRONO-PAR® ADP Reagent, as the predicate device. The CHRONO-LOG Whole Blood Aggregometer was cleared under K830749.

Device Description:

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Intended Use:

The VerifyNow-P2Y12 Assay is a whole blood assay used in the laboratory or point of care setting to measure the level of platelet P2Y12 receptor blockade.

Technological Characteristics:

The VerifyNow-P2Y12 Assay is similar to the CHRONO-LOG Optical Aggregometer in that it employs an optical measurement method. Whereas the CHRONO-LOG Whole Blood Aggregometer measures impedance, it has been found to be substantially equivalent to the optical detection version of the aggregometer. The VerifyNow-P2Y12 Assay is similar to the CHRONO-LOG Whole Blood Aggregometer in that it uses citrated, whole blood samples and measures platelet aggregation. The VerifyNow-P2Y12 Assay adds the use of fibringgen-coated microparticles, which are not used in the CHRONO-LOG aggregometry methods.

Performance Characteristics:

The VerifyNow P2Y12 Assay was evaluated in patients treated with clopidogrel, a drug known to specifically block the platelet P2Y12 ADP receptor. The VerifyNow Assay was compared to platelet aggregometry using a CHRONO-LOG Optical Aggregometer (Light Transmittance Aggregometry - LTA) with 5 uM ADP as the agonist. Testing was performed in clinical studies at 4 centers on 147 subjects with a history of vascular disease or risk factors

The following vertical histogram shows the distribution of PRU values in patients before and after clopidogrel administration. The figure demonstrates a clear separation in the subjects' baseline and their post-clopidogrel P2Y12 assay values. The VerifyNow-P2Y12 Assay measured changes in PRU ranging from a minimum of 18 PRU to a maximum of 435 PRU with a mean change of 185 PRU.

Image /page/1/Figure/8 description: The image shows a graph comparing PRUMEAN values at baseline and post-dose. The y-axis, labeled "PRUMEAN", ranges from -10 to 500, with marked values at 160 and 330. The x-axis, labeled "Dose", has two categories: "Baseline" and "Post", with data points scattered vertically above each category, showing the distribution of PRUMEAN values for each dose condition.

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A reference range for the VerifyNow-P2Y12 Assay was calculated at the 95% confidence level for the baseline (pre-clopidogrel) dataset, using NCCLS Guideline C28-A2. This is summarized in the following table.

n	147
Mean	306.7
SD	58.5
Reference Range	194 - 418

The VerifyNow-P2Y12 Assay is formulated to be specific to aggregation mediated by only the P2Y12 receptor, whereas in LTA, using ADP as the agonist, aggregation results are affected by both platelet ADP receptors - P2Y1 and P2Y12. Since clopidogrel acts only on the P2Y12 receptor site. LTA has a non-specific aggregation artifact due to P2Y1 mediated aggregation that is not seen in the VerifyNow-P2Y12 Assay. In order to compare the clinical PRU and LTA results, post-clopidogrel data are expressed as percent inhibition, or percent reduction from baseline.

To accomplish the goal of having an assay with reduced non-specific aggregation, the VerifyNow P2Y12 assay uses an additive (a fatty acid) in addition to ADP to make the assay more sensitive and specific for the effects of ADP mediated by the P2Y12 receptor.

The following data illustrate the effect of the additive on LTA assay specificity to the P2Y12 receptor. Blood was drawn from 10 individuals, and a known specific P2Y12 inhibitor, 2methylthio-AMP (2MeSAMP), was added to each blood sample at a concentration to achieve near maximal inhibition. LTA was performed using 10 uM ADP, with and without addition of the additive. The VerifyNow-P2Y12 Assay was also run on these samples. The figure below shows that for all ten blood donors, the percent inhibition (% decrease in aggregation) is less for aggregometry with ADP only (73% avg inhibition) than for aggregometry with ADP and the additive (95% ava inhibition). In addition, agreement between VerifyNow-P2Y12 and LTA using the additive was very good (93% vs 95% avg inhibition). This study demonstrates the benefit of using the additive to achieve P2Y12 specificity.

Image /page/2/Figure/5 description: The image is a bar graph titled "% Inhibition with P2Y12 Specific Inhibitor VerifyNow P2Y12 Assay vs Light Transmittance Aggregometry". The x-axis is labeled "Donor ID" and lists the IDs FF142, FF220, FF125, O59, 132, FF109, FF197, FF218, FF122, and 131. The y-axis is labeled "% Inhibition" and ranges from 0% to 100%. There are three sets of bars for each donor ID, representing LTA ADP, LTA ADP/FA, and VN P2Y12.

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DEPARTMENT OF HEALTH & HUMAN SERVICES

Image /page/3/Picture/1 description: The image shows the seal of the Department of Health & Human Services (HHS). The seal features a stylized eagle with three lines representing its wings. The words "DEPARTMENT OF HEALTH & HUMAN SERVICES - USA" are arranged in a circular pattern around the eagle. The seal is black and white.

AUG 5 - 2005

Food and Drug Administration 2098 Gaither Road Rockville MD 20850

Ms. Barbara E. Stevens Regulatory and Clinical Affairs Accumetrics 3985 Sorrento Valley Boulevard San Diego, California 92121

Re: K051231

Trade/Device Name: VerifyNow™-P2Y12 Assay Regulation Number: 21 CFR § 864.5700 Regulation Name: Automated platelet aggregation system Regulatory Class: II Product Code: JOZ Dated: May 12, 2005 Received: May 13, 2005

Dear Ms. Stevens:

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.

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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 (240) 276-0484. 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/industry/support/index.html

Sincerely yours,

lobatz Beckerh

Robert L. Becker, Jr., MD, P/ 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

510(k) Number (if known): K051231

VerifyNow™-P2Y12 Assay Device Name:

Indications For Use:

The VerifyNow-P2Y12 Assay is a whole blood assay used in the laboratory or point of care setting to measure the level of platelet P2Y12 receptor blockade.

X Prescription Use AND/OR Over-The-Counter Use (Part 21 CFR 801 Subpart D) (21 CFR 801 Subpart C)

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

Concurrence of CDRH, Office of Device Evaluation (ODE)

Af Reeves for S. Bautista
Division Sign-Off

1 Page 1 of

Office of In Vitro Diagnostic Device Evaluation and Safety

10051231 510(k)_

Regulation Number and Section

§ 864.5700 Automated platelet aggregation system.

(a)
Identification. An automated platelet aggregation system is a device used to determine changes in platelet shape and platelet aggregation following the addition of an aggregating reagent to a platelet-rich plasma.(b)
Classification. Class II (performance standards).