The Chrono-log™ Model 490 4+4 Aggregometer measures platelet function on patient samples using LTA which measures a change in optical density of platelet rich plasma. The Model 490 4+4 is also used to run the Ristocetin Cofactor Assay to aid in diagnosis of patients with von Willebrand disease. The instrument comes with a starter kit of reagents and supplies. The output of the Model 490 4+4 can be connected to either a strip chart recorder or to a Computer. Software is provided with the computer interface option. The computer interface option is used to collect data only. The computer is not used for diagnosis or treatment and does not have any control over or input into the Model 490 4+4 Aggregometer.

LTA or Born method of platelet aggregation measures the change in optical density of a Platelet Rich Plasma (PRP) sample in comparison to optical density of a Platelet Poor Plasma (PPP) sample. The PRP sample, platelets in a suspension of plasma, is isolated from an anticoagulated blood sample by a relatively low centrifugation. The PPP sample is prepared by centrifuging the blood sample at a relatively high force. The Chrono-log sample chambers are designed so that a beam of infra red light shines through two cuvettes. one containing PRP (the sample) and one containing PPP (the reference). Silicon photodiodes detect the light able to pass through the samples: PRP is arbitrarily considered to be 0% light transmission or 0% aggregation: PPP is considered to be 100% light transmission or 100% aggregation. When a stimulus is added to the cuvette containing PRP and the platelets respond forming aggregates, more light is allowed to pass through the PRP sample. The change in light transmission, recorded over time, shows a trend towards the platelet poor plasma, or 100% light transmission. A graphical tracing of the change in optical density during the course of platelet aggregation is produced either on a strip chart recorder or on a computer using Chrono-log provided software. This device is designed to be used in the clinical laboratory as an in vitro diagnostic tool. The 490 4+4 varies from the predicate devices only in the number of channels.

AI/ML Overview

The document describes the acceptance criteria and the study proving the device, Chrono-log™ Platelet Aggregometer, Model 490 4+4, meets these criteria, primarily through demonstrating substantial equivalence to a predicate device (Chrono-log™ Whole Blood Lumi-Aggregometer Model 700).

Here's the breakdown of the requested information:

1. Table of Acceptance Criteria and Reported Device Performance

The acceptance criteria are implicitly defined by demonstrating "strong correlation" and "good agreement" with the predicate device, as well as maintaining performance specifications (though specific numerical targets for metrics like R-squared or bias are not explicitly stated as pre-defined acceptance criteria, they function as such in the reported performance metrics). The device's performance is gauged by the Coefficient of Variation (which seems to be used interchangeably with R-squared in this context, given the R2 mentions in the conclusion) between the new device and the predicate.

Acceptance Criteria (Implied)	Reported Device Performance (Coefficient of Variation / R$^2$)
Strong correlation/equivalence to predicate for all samples	0.9771 (for all 114 comparison tests)
Strong correlation for normal samples (500 µL)	0.9648
Strong correlation for aspirin samples (500 µL)	0.9943
Strong correlation for normal samples (250 µL)	0.9758
Strong correlation for aspirin samples (250 µL)	0.9871
Strong correlation for Arachidonic Acid reagent	0.9945
Strong correlation for Epinephrine reagent	0.9509
Strong correlation for Collagen reagent	0.9786
Strong correlation for ADP reagent	0.9421
Strong correlation for Ristocetin reagent	0.9863
Clinically insignificant bias (Bland Altman Plot)	Bias of -4.56, 2SD cut-off not beyond historical levels

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

Test Set Sample Size:
- Optical Aggregation: 114 comparison tests in total.
- Volume Comparison: A "small subset" of tests was used to compare 500uL and 250uL samples (8 normal samples in 500 µL, 8 aspirin samples in 500 µL, 8 normal samples in 250 µL, 8 aspirin samples in 250 µL).
Data Provenance:
- The study involved "patient samples" from "four normal, healthy, drug-free subjects" and "a subject taking aspirin." Additionally, samples treated with ticagrelor and GPIIb/IIIa antagonist, and deficient vW plasma with lyophilized platelets were used to demonstrate abnormal results.
- The document does not explicitly state the country of origin for the data/samples but implies it was conducted by the manufacturer, Chrono-log Corp., based in Havertown, PA, USA.
- Retrospective or Prospective: The testing appears to be prospective or specially collected for this comparison study, as it describes the collection and testing of specific subject samples (normal, aspirin, treated with inhibitors) on both the new and predicate devices.

3. Number of Experts Used to Establish Ground Truth and Qualifications

The document does not describe the use of experts to establish a "ground truth" for the performance study. The study focuses on demonstrating equivalence to a predicate device using measured values of platelet aggregation, not on expert interpretation of results. The "ground truth" for the device's function is the direct measurement of optical density changes in plasma samples, interpreted as percentage aggregation.

4. Adjudication Method for the Test Set

Not applicable. The study compares objective quantitative measurements from two devices, not subjective interpretations requiring adjudication.

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

No, a multi-reader multi-case (MRMC) comparative effectiveness study was not conducted. This device is a measurement instrument (platelet aggregometer) and its performance is evaluated based on quantitative agreement with a predicate device, not on human reader performance or improvement with AI assistance.

6. Standalone (Algorithm Only) Performance

Yes, the study primarily demonstrates standalone performance of the device (Chrono-log Model 490 4+4) by comparing its measurements directly to those of the predicate device (Chrono-log Model 700). There is no AI algorithm involved; it's a direct hardware and measurement comparison. The software provided with the computer interface option is explicitly stated to "collect data only" and "is not used for diagnosis or treatment and does not have any control over or input into the Model 490 4+4 Aggregometer."

7. Type of Ground Truth Used

The "ground truth" is established by the measurements from the predicate device (Chrono-log Model 700). The study aims to show that the new device's measurements are substantially equivalent to those of the already legally marketed and established predicate device. It relies on the predicate device's accepted performance as the de facto standard for comparison.

8. Sample Size for the Training Set

Not applicable. This device is a medical measurement instrument, not an AI/ML model that requires a "training set" in the conventional sense. The "training" for the device would be its engineering design, calibration, and manufacturing processes.

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

Not applicable, as there is no training set for an AI/ML model. The predicate device's established performance serves as the reference point for the new device's engineering design and verification.

Summary

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Food and Drug Administration 10903 New Hampshire Avenue Document Control Center - WO66-G609 Silver Spring, MD 20993-0002

December 2, 2016

Chrono-log Corporation Nicholas J. Veriabo Executive Director 2 West Park Road Havertown, PA 19083-4691

Re: K161329

Trade/Device Name: Chrono-log Platelet Aggregometer, Model 490 4+4 Regulation Number: 21 CFR 864.5700 Regulation Name: Platelet aggregometer Regulatory Class: Class II Product Code: JOZ Dated: November 2, 2016 Received: November 4, 2016

Dear Mr. Veriabo:

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. Please note: CDRH does not evaluate information related to contract liability warranties. We remind you, however, that device labeling must be truthful and not misleading.

If your device is classified (see above) into either class II (Special Controls) or class III (PMA), it may be subject to additional controls. Existing major regulations affecting your device can be found in the Code of Federal Regulations, Title 21, Parts 800 to 898. 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

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medical device-related adverse events) (21 CFR 803); good manufacturing practice requirements as set forth in the quality systems (QS) regulation (21 CFR Part 820); and if applicable, the electronic product radiation control provisions (Sections 531-542 of the Act); 21 CFR 1000-1050.

If you desire specific advice for your device on our labeling regulation (21 CFR Part 801), please contact the Division of Industry and Consumer Education at its toll-free number (800) 638-2041 or (301) 796-7100 or at its Internet address

http://www.fda.gov/MedicalDevices/ResourcesforYou/Industry/default.htm. Also, please note the regulation entitled, "Misbranding by reference to premarket notification" (21CFR 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/ReportaProblem/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 Industry and Consumer Education at its toll-free number (800) 638-2041 or (301) 796-7100 or at its Internet address

http://www.fda.gov/MedicalDevices/ResourcesforYou/Industry/default.htm.

Sincerely,

Leonthena R. Carrington -S

Leonthena R. Carrington, MS. MBA. MT(ASCP) Director

Division of Immunology and Hematology Devices Office of In Vitro Diagnostics and Radiological Health Center for Devices and Radiological Health

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Indications for Use

510(k) Number (if known) K161329

Device Name

Chrono-log Platelet Aggregometer, Model 490 4+4

Indications for Use (Describe)

The Chrono-log Model 490 4+4 Aggregometer is intended for use for in-vitro diagnostic use for measuring Platelet Aggregation in Platelet Rich Plasma.

This device is intended to be used in a clinical laboratory environment by laboratory technicians.

For use only with light transmission aggregometry assays cleared for use with the Chrono-log Platelet Aggregometry systems.

Type of Use (Select one or both, as applicable)

Depreciating Use (Part 21 CFR 606 Subpart D)
One-Time Use (Part 21 CFR 606 Subpart C)

Prescription Use (Part 21 CFR 801 Subpart D)

| | Over-The-Counter Use (21 CFR 801 Subpart C)

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11. 510(k) Summary

Device: Chrono-log™ Platelet Aggregometer, Model 490 4+4

Date: March 17, 2016

Submitted by: Chrono-log Corp., 2 West Park Rd., Havertown, PA 19083

Contact: Nicholas J. Veriabo (610) 853-1130

Name of Device:

Trade/Proprietary Name - Chrono-log™ Platelet Aggregometer Model 490 4+4

Common/Usual Name - Platelet Aggregometer

Classification Name - System, Automatic Platelet Aggregation 21CFR 864.5700

Regulatory Class – Class II

Product Code – JOZ

510(k) Review Panel - Hematology

Predicate Device:

Trade/Proprietary Name - Chrono-log™ Whole Blood Lumi-Aggregometer Model 700

Common/Usual Name - Platelet Aggregometer, Whole Blood Aggregometer, Lumi-Aggregometer

Classification Name - System, Automatic Platelet Aggregation 21CFR 864.5700

Regulatory Class – Class II

Product Code – JOZ

510(k) Review Panel - Hematology

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11.1 Device Description:

11.2 Intended Use:

The Chrono-log Model 490 4+4 Aggregometer is intended for use for in-vitro diagnostic use for measuring platelet aggregation in platelet rich plasma. This device is intended to be used in a clinical laboratory environment by laboratory technicians. For use only with light transmission aggregometry assays cleared for use with the Chrono-log™ Platelet Aggregometry systems.

11.3 Technical Description:

The Chrono-log™ Model 490 4+4 Aggregometer is an instrument used in the Laboratory for the determination of Platelet Aggregation in samples of PRP. The 490 4+4 is a modified Model 700. Substantial equivalency between the Model 490 4+4 and the Model 700 (K050265) currently in commercial distribution by Chrono-log Corp is claimed.

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The fundamental scientific technology of the modified device was unchanged. The energy type is the same. Environmental specifications are the same. Performance specifications are the same as the optical method of the predicate device. The ergonomics of the user interface is the same and the firmware is the same.

The critical components of the Model 490 4+4 are exactly the same as the predicate device. The circuits that drive these components are the same as the circuits used in the Model 700. Due to various parts in the predicate device becoming obsolete, some circuit parts were upgraded in the Model 490 4+4. The chart on the following page gives a detailed description of the component differences between the Model 490 4+4 and the Model 700.

The chassis has also been redesigned to accommodate four channels. The front panel for both use a Liquid Crystal Display (LCD) for displaying Temperature and Stirring Speed. Both instruments have front panel controls which are tactile membrane switches.

The output of the Model 490 4+4 can be connected to either a strip chart recorder or to a Computer. Chrono-log provides software for the computer interface option as an accessory. The computer interface option is used to collect data and is not used for diagnosis or treatment and does not have any control over or input into the Model 490 4+4 Aggregometer.

490 4+4 Component change
Component	Functionality	Description of change	MaterialChange	Impact of change	Mitigation
HeaterBlock	Holds sampleHeats sample	Heater Block was madesmaller. Remove holes forluminescence measurements	None	Minimal - LED andphotodiodes arecloser to sample	Verification testingwas performed bymeasuring opticaldensity samples andrecording voltagereadings. All samplesmeasured tospecifications.
PhotodiodeAmplifier	Measures theamount of lightshining throughthe samples	Resistors R1, R2, R3 & R4were changed from 20MΩ to10MΩ to reduce the gain onthe amplifier. A lower gainwas needed because theheater blocks are closer.	None	No known impact.The output voltageis the same forvarious opticaldensity	Verification testingwas performed bymeasuring opticaldensity samples andrecording voltagereadings. All samplesmeasured tospecifications.
HeaterControlBoard	Heats theheater blocksand has theDoor switch forLuminescence	The following parts areremoved: U5, C8, C11, D1, D2,D3, D4, D5, D6, D7. Thesecomponents are used forluminescence in the Model700. In the Model 490 4+4there isn't a luminescence	None	Luminescencefeature removed.Cannot measureATP release, whichis within the designspecifications.	Verification notneeded for theremoval of theLuminescencefeature.
		feature. These componentsare removed to reduced costs.
AnalogControlBoard	Processes theoutput fromthe detectiondevices.	The following parts wereremoved U10, U11, C10, C11,R17, R18, R19, R20, R21, R26,P1 & P2. These componentsare for the luminescence andthe selection between opticaland Impedance methods inthe Model 700. In the Model490 4+4, the luminescenceand impedance features arenot used, so thesecomponents were removed toreduce costs.	None	Luminescence andImpedance featuresremoved. Cannotmeasure ATPrelease orImpedanceaggregation, whichis within the designspecifications.	Verification notneeded for theremoval of theLuminescence andImpedance features.
SwitchCircuit onHeaterBlock Board	Turns power onto PMT whenheater blockdoor is closed,shuts off powerwhen door isopened. ThePMT is used forluminescencemeasurementof ATP release.	The following parts areremoved U1, C1, C2, R2, R4,R5, R6, RL1, Con 2, Con 3, andCon 4,. All components aboveare for the door switch circuitused for luminescence in theModel 700. In the Model 4904+4 there isn't a luminescencefeature, so this circuit is notneeded. These componentsare removed to reduce cost.	None	Luminescencefeature removed.Cannot measureATP release, whichis within the designspecifications.	Verification notneeded for theremoval of theLuminescencefeature.
Heaterblockcircuit	Heats theheater blocksto thetemperatureset on the frontpanel.	R2 was removed and R1resistance was increased. Thecircuits for heating the blockare the same except theModel 700 uses two resistorsto heat the block where as theModel 490 4+4 needs only 1resistor to heat the smallerblock. This is why R2 wasremoved. The value of R1 wasincreased because lesscurrent is needed to heatsmaller block size in theModel 490 4+4.	None	Minimal - Theheater blocktemperature ismaintained at thetemperature set onthe front panel,usually 37°C.	Verification testingwas performed bymeasuring thetemperature of theblocks for everypossible setting. Alltemperature settingstested tospecifications.
Four MotorDriverBoard	Drives thestirring motors.Controls thestirring motorsspeed.Monitors themotor speed.	The combination of U2, R1,R2, R3, R4, C8 and C9 onDrawing 6811 replacescomponents U2, T1, T2, T3,T4, D1, D2, D3, D4, D5, C1, C2,C3, C4, C5, C6, C7, R1, R2, R3,R4, R5, R6, R7, R8, R9, R10,R11, R12, R13, R14 and R15on Drawing 6597 and alsoreplaces U3, Q 1, R1, R2, R3,C10 and C11 on Drawing6718. The rest of the circuit isthe same.	None	Minimal- Stirrerdriver operates as aPhase-locked circuitkeeping the stirrerspeed locked to thereferencefrequency providedby aMicrocontroller.Both circuits(original andrevised) accomplishthis and arefunctionally equal.	Verification testingwas performed bymeasuring thefrequency of thesignals andrevolution rate of themotors. Faultconditions wereinduced to test theerror checkingfeature. Allconditions tested tospecifications.

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11.4 Performance:

Design control activities conforming to 21.CFR 820.30 were implemented in the device modification process. As demonstrated by risk analysis and by verification and validation activities, no questions of safety and effectiveness were raised. Verification and validation activities were performed and the results show conformance with predetermined acceptance criteria. These nonclinical tests suggest that the modified device is substantially equivalent to the predicate device.

A Comparison study was run to compare the performance of the Model 490 4+4 to the Model 700. Platelet Rich Plasma samples from four normal, healthy, drug free subjects and a subject taking aspirin, a known inhibitor of platelet aggregation by acetylation of the platelet cyclooxygenase pathway. These samples were tested with both instruments.

To demonstrate abnormal results with ADP and Collagen, samples were treated with ticagrelor and GPIIb/IIIa antagonist (Hart Biologicals, Hartlepool, UK), as per manufacturer's instructions. The ticagrelor blocks the P2Y12 ADP-receptor, which reduces the aggregation with ADP. GPIIb/IIIa antagonist blocks the GPIIb/IIIa receptor which reduces aggregation by collagen.

To demonstrate abnormal Ristocetin results, samples were run using deficient vw plasma and lyophilized platelets.

The samples were tested using CHRONO-PAR™ Arachidonic Acid, Epinephrine, Collagen, ADP and Ristocetin. The following concentrations of reagents were run: Arachidonic Acid 0.5 mM, Epinephrine 5uM, Collagen 1ug/mL, Collagen 5ug/mL, ADP 5uM, ADP 10uM, Ristocetin 0.25mg/mL and Ristocetin 1.25 mg/mL. Tests were run using Platelet Rich Plasma samples of both 500uL and 250uL volume.

In total, there were 114 comparison tests using optical aggregation. To demonstrate sample size equivalence, a small subset of tests was used to compare the results for 500uL and 250uL volume samples from a normal donor and a donor taking aspirin. These two sample volumes were run because these are the two recommended sample

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sizes in the instructions. For both donors, one test with each reagent for both sample sizes was run using the recommended concentrations in the IFU.

The Tables below show the correlation between the Model 490 4+4 and the Model 700.

ALL SAMPLES

No. of Samples	Coefficient of Variation
114	0.9771

NORMAL SAMPLES IN 500 µL

No. of Samples	Coefficient of Variation
8	0.9648

ASPIRIN SAMPLES IN 500 µL

No. of Samples	Coefficient of Variation
8	0.9943

NORMAL SAMPLES IN 250 µL

No. of Samples	Coefficient of Variation
8	0.9758

ASPIRIN SAMPLES IN 250 µL

No. of Samples	Coefficient of Variation
8	0.9871

When comparing the results of the 490 4+4 to the predicate device with each individual reagent, there is a strong correlation with each reagent.

Reagent	Coefficient of Variation
Arachidonic Acid	0.9945
Epinephrine	0.9509
Collagen	0.9786
ADP	0.9421
Ristocetin	0.9863

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11.5 Conclusion:

The results of the study show strong correlation between the Model 490 4+4 and the predicate device. The R2 Value of all samples run is 0.9771. There is also a strong correlation when comparing each reagent. In a subset of samples, values for the two recommended sample sizes were compared and strong correlation was found with the normal donors and donors on aspirin. Normal donors gave an R2 result of 0.9648 for the 500 uL samples and 0.9758 for the 250 uL samples. Aspirin donors gave an R2 result of 0.9943 for the 500 µL samples and 0.9871 for the 250 µL samples.

An agreement analysis using a Bland Altman Plot showed good agreement between the 490 4+4 and the predicate device. There is a small bias of -4.56 which is not clinically significant for this assay. The Bland Altman Plot shows agreement and the 2SD cut-off is not beyond what is historically seen with platelet aggregation.12

Since the assay is the same for the 490 4+4 and the predicate device, the aim is to show equivalence results for the two devices. The enclosed data supports the claim of substantial equivalence.

Riess et al: Clinical Evaluation of Platelet Aggregation in Whole Human Blood 1. American Journal of Clinical Pathology (1986) 85 (1): 50-56
1. Alshameeri et al (1995): Comparisons of Platelet Aggregation in Platelet Rich Plasma and Whole Blood. Disorders of Thrombosis & Hemostasis, Abstract.

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).