DuraGraft Vascular Conduit Solution is a solution indicated for adult patients undergoing Coronary Artery Bypass Grafting Surgeries and is intended for flushing and storage of the saphenous vein grafts from harvesting through grafting for up to 4 hours.

Device Description

DuraGraft Vascular Conduit Solution is a clear, colorless to slightly yellow, aseptically processed, non-pyrogenic solution for room temperature flushing and storage of vascular conduits used during the harvesting and grafting interval in Coronary Artery Bypass Grafting (CABG) surgeries. DuraGraft Vascular Conduit Solution is supplied in two separate containers composed of a Solution A (237.5mL) and a Solution B (12.5-13.5mL). Solution A is mixed with 12.5mL of Solution B prior to use. DURAGRAFT Vascular Conduit Solution has an osmolality of about 305 mOsmol/kg, viscosity of 1.06 cST, a sodium concentration of 155-160 mEq/L, a potassium concentration of 5.8 mEq/L, and a pH of about 7.4 at room temperature.

AI/ML Overview

The provided document describes the DuraGraft Vascular Conduit Solution, a medical device used for flushing and short-term storage of saphenous vein grafts during Coronary Artery Bypass Grafting (CABG) surgeries.

The acceptance criteria for the device are implicitly defined by the "Risks to Health" and "Special Controls" sections, which outline the potential risks associated with such devices and the measures necessary to mitigate them, along with specific performance characteristics that must be demonstrated.

Here's an analysis of the acceptance criteria and the studies proving the device meets them:

1. Table of Acceptance Criteria and Reported Device Performance

Acceptance Criteria (Derived from Risks to Health & Special Controls)	Reported Device Performance
1. Adverse Tissue Reaction	Biocompatibility Evaluation:- Device evaluated per ISO 10993-1. Testing on final mixed solution and heparin mixture included Cytotoxicity, Irritation, Guinea Pig Maximization Test (GPMT) sensitization, Acute systemic toxicity, Hemolysis, Material mediated pyrogen, and Chemical leachable testing. - Results "supported the biocompatibility of the DuraGraft device."
2. Damage to Vascular Grafts (leading to MACE or Vascular Injury)	a) Clinical Performance Data (DuraGraft Prospective Randomized Study): - Safety Endpoints: Vein graft occlusions: 7.2% for DuraGraft vs. 8.8% for saline. Fitzgibbon class B/O stenosis: 1.6% for DuraGraft vs. 2.4% for saline. MACE: 0 for DuraGraft vs. 1 (0.8%) for saline. Composite event rate: 8.8% for DuraGraft vs. 11.2% for saline. - Anatomic Parameters: At 12 months, DuraGraft treated SVGs had smaller mean wall thickness (0.12±0.06 mm vs. 0.20±0.31 mm for saline) and change in maximal focal narrowing (0.2 ± 3.8 mm vs. 4.7 ± 12.7 mm for saline).b) Non-clinical Performance Testing: - Maintenance of Cell Viability & Structural Integrity: - Pachuk et al., 2019: Maintained graft cell viability in human saphenous vein segments for up to 5 hours. Showed normal morphology and strong immunostaining of endothelial surface markers (CD31 and vWF) at both 45 minutes and 24 hours (NSS showed loss of viability at 15 minutes, multifocal aggregation/missing patches of endothelium at 24 hours, weaker CD31/vWF staining). - Aschacher et al., 2021: Showed normal endothelial and sub-endothelial structure in DuraGraft-treated grafts (RL-treated showed damaged endothelial surface and beginning incongruence of intimal structure). Associated with lower reactive oxygen species and significant increase in oxidation-reduction potential. - Korkmaz-Icoz et al., 2021: Alleviated vasoactive physiologic arterial dysfunction in rat aortic rings compared to saline. c) Shelf life testing: - Testing supported a 3-year shelf life.
3. Particulate Matter Contamination	a) Non-clinical Performance Testing (Bench Testing):- Evaluation of visible and non-visible particulates in the final mixed solution (per USP <788>).b) Shelf life testing:- Conducted after aging and simulated shipping, including container closure integrity (CCI) testing.
4. Infection	Sterilization Validation:- Aseptically processed. Sterilization testing validated sterility of containers with SAL of 10-6. Endotoxin testing used 3-log reduction as acceptable level. Aseptic filling in accordance with EN ISO 13408-2:2011 and FDA guidance. Testing included aseptic filling validation and filter validation. Sterility and endotoxin testing provided following aging.
5. Stability of Device's Chemical Components	Shelf Life Testing:- Testing conducted to evaluate the stability of Solution B (arginine, glucose, ascorbic acid, and glutathione) at time points from 0 to 36 months to support device stability and a 3-year shelf-life. Evaluation of pH (USP <791>) and osmolality (USP <785>).
6. Labeling Requirements	Labeling Provided:- Instructions for use and package labels provided. Includes intended patient population, maximum storage duration (up to 4 hours), L-arginine component warning, not for direct injection/IV infusion, pre-use inspection of containers, re-use hazard warning, summary of non-clinical and clinical performance testing.

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

DuraGraft Prospective Randomized Study:

Sample Size: 125 patients were randomized.
- 125 grafts treated with DuraGraft.
- 125 grafts treated with Saline (control).
Data Provenance:
- Country of Origin: Canada, Ireland, and Denmark.
- Retrospective or Prospective: Prospective, multicenter, randomized controlled trial.

DuraGraft EU Registry:

Sample Size: 2,964 patients enrolled.
- 4,454 venous grafts and 586 arterial conduits treated with DuraGraft.
Data Provenance:
- Country of Origin: Austria, Germany, Ireland, Italy, Spain, Switzerland, Turkey, and United Kingdom.
- Retrospective or Prospective: Ongoing European post-market study (Observational Registry) designed to support an international CABG registry database.

Propensity Matched Comparison of DuraGraft EU Registry to STS Registry:

Sample Size: 2,400 patients were matched from the DuraGraft cohort to 2,400 patients in the STS Database.
Data Provenance:
- Country of Origin: DuraGraft (Europe) vs. STS (US and US territories for mortality data linkage).
- Retrospective or Prospective: Retrospective comparison analysis using existing registry data.

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

The document does not explicitly state the number of experts or their specific qualifications used to establish ground truth for the clinical test sets in the DuraGraft Prospective Randomized Study or the DuraGraft EU Registry.

However, the "DuraGraft Prospective Randomized Study" mentions "adjudicated safety outcomes" and "MDCT analysis." In clinical trials, adjudication typically involves a committee of independent clinical experts, but their number and specific qualifications (e.g., "radiologist with 10 years of experience") are not detailed here. Similarly, MDCT analysis would be interpreted by trained radiologists or cardiologists, but their specific experience levels are not provided.

For the "Propensity Matched Comparison," the ground truth for mortality was established via linkage to the US National Death Index (NDI), which is a governmental database of all death records. This does not involve individual expert review for each case.

4. Adjudication Method for the Test Set

DuraGraft Prospective Randomized Study: The document states "Adjudicated safety outcomes" in the table. This implies an adjudication process was used, likely by an independent committee, but the specific method (e.g., 2+1, 3+1) is not detailed.
DuraGraft EU Registry: No specific mention of an adjudication method is provided for the registry data. Outcomes like MACE and individual components are reported, which are typically derived from clinical records and may or may not undergo independent adjudication in a registry setting unless it's a specific endpoint.
Propensity Matched Comparison: This was a retrospective statistical comparison of mortality data, not an adjudication process of individual cases.

5. If a Multi Reader Multi Case (MRMC) Comparative Effectiveness Study Was Done, and the Effect Size of How Much Human Readers Improve with AI vs. Without AI Assistance

No, an MRMC comparative effectiveness study involving AI assistance for human readers was not done. The DuraGraft device is a flushing and storage solution, not an AI-powered diagnostic or assistive tool. The studies described evaluate the biological and clinical effectiveness of the solution itself, not the performance of human readers with or without AI.

6. If a Standalone (i.e., algorithm only without human-in-the-loop performance) Was Done

No, a standalone algorithm-only performance study was not done. As mentioned above, the DuraGraft device is a biological solution, not an algorithm. Its performance is evaluated through biological assays, bench testing, and clinical outcomes in patients.

7. The Type of Ground Truth Used

DuraGraft Prospective Randomized Study:
- Clinical Outcomes: Vein graft occlusion, MACE events (death, MI, repeat revascularization, angina, arrhythmia, shortness of breath), Fitzgibbon classification of stenosis, and anatomic parameters (wall thickness, focal narrowing) via MDCT. These are established through clinical events and objective imaging measurements.
- Adjudication: Implied for safety outcomes, suggesting expert review.
DuraGraft EU Registry:
- Clinical Outcomes: MACE (death, MI, repeat revascularization), stroke, all-cause death. These are derived from patient records in a post-market registry.
Propensity Matched Comparison (STS Registry):
- Mortality: Established by linkage to the US National Death Index (NDI), which is a definitive source for death records.
Nonclinical/Bench Studies (Pachuk et al., Korkmaz-Icoz et al., Aschacher et al.):
- Biological Ground Truth: Graft cell viability, morphology (H&E staining, Immunohistochemistry for CD31 and vWF), vasoactive physiologic arterial dysfunction, endothelial and sub-endothelial structure, reactive oxygen species, oxidation-reduction potential. These are experimentally determined biological endpoints.

8. The Sample Size for the Training Set

The concept of a "training set" is not applicable here as the DuraGraft device is a therapeutic solution, not a machine learning algorithm. The studies described are for validation and efficacy of the biological product.

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

As there is no training set for an algorithm, this question is not applicable. The device's development would have involved extensive pre-clinical research and formulation, guided by biological principles and experimental observations, rather than an ML-model training paradigm.

Summary

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DE NOVO CLASSIFICATION REQUEST FOR DURAGRAFT VASCULAR CONDUIT SOLUTION

REGULATORY INFORMATION

FDA identifies this generic type of device as:

Flushing and storage solution for vascular autografts at room temperature. A flushing and storage solution for vascular autografts at room temperature is a device that is used for flushing or short-term storage of vascular grafts. This generic type of device is intended to maintain cell viability and structural integrity of vascular grafts during shortterm storage at room temperature during the surgical procedure.

NEW REGULATION NUMBER: 21 CFR 876.4100

CLASSIFICATION: Class II

PRODUCT CODE: QEJ

BACKGROUND

DEVICE NAME: DuraGraft Vascular Conduit Solution

SUBMISSION NUMBER: DEN230002

DATE DE NOVO RECEIVED: January 3, 2023

SPONSOR INFORMATION:

Marizyme, Inc. 555 Heritage Drive Suite 205 Jupiter, FL 33458-5290

INDICATIONS FOR USE

The DuraGraft is indicated as follows:

LIMITATIONS

The sale, distribution, and use of the DuraGraft Vascular Conduit Solution are restricted to prescription use in accordance with 21 CFR 801.109.

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DuraGraft Vascular Conduit Solution is not intended for direct injection or intravenous infusion.

DuraGraft Vascular Conduit Solution includes a component, L-arginine. L-arginine may cause an allergic reaction in certain patients.

PLEASE REFER TO THE LABELING FOR A COMPLETE LIST OF WARNINGS, PRECAUTIONS AND CONTRAINDICATIONS.

DEVICE DESCRIPTION

DuraGraft Vascular Conduit Solution is supplied in two separate containers composed of a Solution A (237.5mL) and a Solution B (12.5-13.5mL). Solution A is mixed with 12.5mL of Solution B prior to use.

DURAGRAFT Vascular Conduit Solution has an osmolality of about 305 mOsmol/kg, viscosity of 1.06 cST, a sodium concentration of 155-160 mEq/L, a potassium concentration of 5.8 mEq/L, and a pH of about 7.4 at room temperature. Composition and molar concentrations of DuraGraft (mixed solution) is given in Table 1 below.

SOLUTIONS A + B (19:1 ratio)
Ingredients	Concentration in mM
Calcium chloride	0.95
Potassium chloride	5.37
Potassium phosphate monobasic	0.44
Magnesium sulfate	0.41
Magnesium chloride	0.49
Sodium chloride	136.89
Sodium bicarbonate	4.29
Sodium phosphate dibasic	0.19
L-Glutathione	1.01
D-Glucose	5.55
L-Arginine	0.86
L-Ascorbic acid	0.51
pH	7.4
Water For Injection

Table 1: Composition of DuraGraft (Mixed Solution)

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Please refer to the labeling for additional device description details.

SUMMARY OF NONCLINICAL/BENCH STUDIES

BIOCOMPATIBILITY/MATERIALS

DuraGraft is considered to have limited indirect contact with the blood (<24 hours) based on the nature of use and duration of exposure. The device was evaluated with respect to its intended use per FDA guidance. "Use of International Standard ISO 10993-1. 'Biological evaluation of medical devices -- Part 1: Evaluation and testing within a risk management process." Testing was performed on the final mixed solution and heparin mixture as used clinically. The following tests were performed:

1. Cytotoxicity
1. Irritation
1. Guinea Pig Maximization Test (GPMT) sensitization
1. Acute systemic toxicity
1. Hemolysis
1. Material mediated pyrogen
1. Chemical leachable testing of container on aged solutions

The results supported the biocompatibility of the DuraGraft device.

SHELF LIFE/STERILITY

DuraGraft Vascular Conduit Solution is provided aseptically processed in two bottles using aseptic filling procedures. Sterilization testing was performed to validate the sterility of the solution containers with a sterility assurance level (SAL) of 10 6 prior to aseptic filling. The containers also underwent endotoxin testing using a 3-log reduction of endotoxin as an acceptable level of endotoxin reduction for the container. Aseptic filling is conducted in accordance with EN ISO 13408-2: 2011. Aseptic Processing of Health Care Products-Part: Filtration, and in compliance with the FDA guidance, "Sterile Drug Products Produced by Aseptic Processing - Current Good Manufacturing Practice", September 2004. Testing to support aseptic filling for both solutions included aseptic filling validation and filter validation testing. Testing was provided to support a 3 year shelf life using devices accelerated-aged at 40° C and simulated shipping testing after devices were real-time aged for 3 years per ASTM D4169 DC13 and Assurance level II. Container closure integrity (CCI) testing was provided for kits that were real-time aged 3 years and then simulated shipped. Sterility and endotoxin testing was provided following aging.

PERFORMANCE TESTING - BENCH

Solution A and Solution B of DuraGraft were evaluated for pH per USP <791>, osmolality per USP <785>, and particle count per USP <788>. Testing was also conducted to evaluate the stability of Solution B (arginine, glucose, ascorbic acid, and glutathione) at time points from 0 to 36 months to support the device stability and 3-year shelf-life.

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The following preclinical studies support DuraGraft for use as a short-term flushing and storage solution for vascular conduits.

Publication	Experimental Conditions	Summary and Conclusions
Pachuk et al.,20191	Human saphenous vein (HSV)segments collected from 9 patientsundergoing CABG surgery stored forup to 5 hours in DuraGraft or normalsaline solution (NSS)Pig mammary vein segments wereflushed and stored with DuraGraft orNSS for 45 minutes and 24 hours.	Graft cell viability was maintained in human saphenous veinsegments when the segments were flushed and stored in DuraGraftup to 5 hours.Loss of graft cell viability was observed within 15 minutesfollowing flushing and storage in NSS.H&E staining and Immunohistochemistry staining for CD31 andvon Willibrand factor (vWF) showed normal morphology by H&Estaining and strong immunostaining of endothelial surface markersCD31 and vWF that was continuous across the endothelium at bothtimepoints for veins stored in DuraGraft.NSS stored veins had normal morphology by H&E staining at 45minutes but displayed multifocal aggregation of and missingpatches of endothelium at 24 hours. CD31 and vWF staining wasweaker for NSS stored grafts.
Korkmaz-Icozet al., 20212	Rat thoracic aortic rings undergoingcold ischemic storage in eitherDuraGraft or NSS at 4 °C for 24 hourswere incubated in an organ bathculture containing 200µM sodiumhypochlorite for 30 minutes to inducefree radical formation as seen inreperfusion.	Vasoactive physiologic arterial dysfunction was observed whenaortic rings were stored in saline.
Aschacher etal., 20213	Radial Artery and HSV segments from23 patients undergoing CABG surgerywere flushed and stored in eitherDuraGraft or Ringers lactate solution(RL) at room temperature for 60minutes or times up to 3 hours at roomtemperature.	DuraGraft treated grafts showed normal endothelial and sub-endothelial structure whereas RL-treated grafts showed damagedendothelial surface and beginning incongruence of intimalstructure.DuraGraft treated grafts were associated with a lower level ofreactive oxygen species that correlated with a reduction of hypoxicdamage and significant increase in oxidation-reduction potential.

Table 2. Preclinical Studies Supporting DuraGraft

SUMMARY OF CLINICAL INFORMATION

DuraGraft Prospective Randomized Study

The sponsor conducted a prospective, multicenter, randomized controlled trial outside of the U.S. to evaluate the effects of DuraGraft on graft level anatomic parameters (Perrault 2019)4. The study employed a "within-patient control" design, in which patients received both a control saline-treated saphenous vein graft (SVG) and a DuraGraft-treated SVG, randomly assigned per graft. The initial trial included multidetector computed tomography (MDCT) evaluation at 1 and 3 months. Follow-up was extended to 1-year with an additional MDCT evaluation in the second protocol requiring re-consenting the patients. Safety was assessed in both protocols through the incidences of vein graft thrombosis/occlusion, composite safety events, adverse events and SAEs. The primary safety endpoint for both protocols was the incidence of graft thrombosis/occlusion. Secondary safety endpoints included a composite safety endpoint consisting of Major Adverse Cardiac Events (MACE) (deaths, myocardial infarction (MI) and repeat revascularization), increased angina, arrhythmia, shortness of breath, decreased lumen change, graft occlusion, significant stenosis based on Fitzgibbon's scale B and O, if determined to be related to a specific graft, and incidence of adverse events (AE) and serious adverse events (SAE).

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A total of 125 patients were randomized and enrolled from September 2014 to December 2016 at seven investigational sites in Canada, Ireland, and Denmark. 125 grafts were treated with DuraGraft, and 125 grafts treated with saline. Mean Society of Thoracic Surgeons score for mortality was 0.9 ± 0.6 and mean European System for Cardiac Operative Risk Evaluation II score was 1.1 ± 0.6. Grafts were assessed using serial MDCT at 1 month (n=116), 3 months (n=118), and 12 months (n=97), respectively.

Inclusion & Exclusion Criteria:

Inclusion Criteria:

1. Subject to undergo primary, multi-vessel CABG with at least two SVGs
1. Subject >18 years and <80 years of age
1. Subject with no contraindications to cardiopulmonary bypass
1. Subject who were willing and able to provide consent and shows commitment to participate in a follow-up evaluation, including a clinical visit between 4-6 weeks and 3 months (+1 Week) post CABG
1. If female, subject surgically sterile or postmenopausal
1. Subject has had no previous CABG surgery
1. Subject who was hemodynamically stable

Exclusion Criteria:

1. Subject with in-situ internal mammary artery (IMA) graft(s) only (no SVG or free arterial grafts)
1. Subject with prior CABG or planned concomitant valve surgery or aortic aneurysm repair
1. Subject that was pregnant or lactating woman
1. Subject had left ventricular ejection fraction (LVEF) <40%
1. Subject was known to be HIV positive, is receiving anti-retroviral drugs, or is immunosuppressed
1. Subject had an acute infection at screening
1. Subject had active chronic bacterial, parasitic or viral infection within 3 months prior to CABG surgerv
1. Subject had a malignancy diagnosed within the previous 5 years (except successfully resected basal cell cancer)
1. Subject unable to provide consent or undergoing emergency cardiac surgery for an immediately life-threatening condition
1. Subject is participating in a device study or received active drug product in an investigational drug study within1 month prior to screening
1. Subject has a history of transient ischemic attack or stroke within the 12 weeks prior to the CABG procedure
1. Subject who had significant renal impairment (Glomerular Filtration Rate <50 mL/min)
1. Subject who had liver impairment as demonstrated by hepatic transaminases (AST and/or ALT) >2.5x upper limit of normal (ULN) or conjugated bilirubin >1.5x ULN
1. Subject had any condition or disease detected prior to study start that would render the subject unsuitable for the study, place the subject at undue risk or interfere with the ability of the subject to complete the study in the opinion of the investigator (e.g., drug dependence, mental illness)

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1. Subject had uncontrolled diabetes mellitus (HbA1C >10%)
1. Subject had any confirmed significant allergic reactions against any drug or multiple allergies (non-active hav fever is accepted)
1. Subject who required uninterrupted use of systemic steroids or immunosuppressive agents
1. Subject had platelet count <100,000/mm3, hematocrit >62% (Hb >18 g/dL) or <30% (Hb<10 g/L)
1. Subject had varicose veins or veins <2 mm in diameter
1. Subject had target coronary artery <1.5 mm in internal diameter
1. Subject had diffuse coronary disease
1. Subject had severe uncontrolled systemic hypertension (i.e., systolic pressure >160 mmHg)
1. Subject with prior severe reaction to contrast dye

Results:

The results of the safety endpoint analysis is exhibited below (Table 3). Vein graft occlusions were observed in 7.2% of the DuraGraft treated grafts and 8.8% of the saline treated grafts. According to the Fitzgibbon classification, a stenosis type B (flow limited) or type O (occlusion) was observed in 1.6% of the grafts in the DuraGraft group and 2.4% of the saline group. No MACE events were observed in the DuraGraft group compared to 1 in the saline group and in particular no deaths were observed in either group. The composite event rate was 8.8% for DuraGraft treated grafts and 11.2% for saline treated grafts.

Table 3. Adjudicated safety outcomes after graft treatment by either DuraGraft or saline after a follow-up duration of 110.3 patient-years (1 year follow-up timepoint)

Outcome	DuraGraft(n = 125)	Saline(n = 125)
Major adversecardiac events†	0	1 (0.8) [0.009]
Composite end point	11 (8.8) [0.100]	14 (11.2) [0.127]
Death	0	0
Myocardial infarction	0	1 (0.8) [0.009]
Repeat revascularization	0	0
Increased angina	0	1 (0.8) [0.009]
Increased arrhythmia	0	0
Increased shortnessof breath	0	0
Vein graft thrombosis/occlusion	9 (7.2) [0.082]	11 (8.8) [0.100]
Fitzgibbonclass B and O	2 (1.6) [0.018]	3 (2.4) [0.027]

Values are n (%) [number of events per patient-year]

Death, myocardial infarction, or repeat revascularization.

1Composite of all adverse events

*Perrault et al., JTCVS 2019

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MDCT analysis revealed that there was no significant difference between the DuraGraft group and the saline group in terms of change in mean wall thickness between 1 and 3 months in the analysis of whole grafts. However, at 12 months, DuraGraft treated SVGs had smaller mean wall thickness versus their saline-treated counterparts 0.12±0.06 mm vs 0.20±0.31 mm (Figure 1) and the change in maximal focal narrowing 0.2 ± 3.8 mm versus 4.7 ± 12.7 mm (Figure 2).

Image /page/6/Figure/1 description: This image is a graph titled "Wall Thickness Whole Graft" that compares the wall thickness of DuraGraft and Saline over a period of 12 months. The x-axis represents the months, ranging from 1 to 12, while the y-axis represents the wall thickness in millimeters, ranging from 0 to 0.25. The graph shows that the wall thickness of Saline is initially lower than DuraGraft, but it increases rapidly and then decreases slowly, while the wall thickness of DuraGraft remains relatively constant over the 12 months.

Figure 1: Wall thickness analysis by MDCT for whole graft

Image /page/6/Figure/3 description: The image is a title for a figure. The title reads, "Figure 2: Maximum Focal Narrowing analysis by MDCT for whole graft". The title is written in a clear, legible font. The title is centered and easy to read.

Image /page/6/Figure/4 description: This image is a graph titled "Maximal Focal Narrowing Whole Graft". The graph compares DuraGraft and Saline over a period of months. The x-axis represents the months, ranging from 1 to 12, and the y-axis represents the value in mm, ranging from 0 to 0.2. The graph shows that Saline has a higher value than DuraGraft.

DuraGraft EU Registry

The DuraGraft EU Registry5 is an ongoing European post-market study designed to support an international CABG registry database used to assess patients receiving DuraGraft during CABG surgery and whose free vascular grafts (4,454 venous grafts and 586 arterial conduits) have been treated with DuraGraft. A total of 2,964 patients were enrolled in the Registry, which enrolled patients between December 2016 and August 2019. There were 45 enrolling centers in eight countries: Austria, Germany, Ireland, Italy, Spain, Switzerland, Turkey and United Kingdom. Follow-up data has been completed out to one (1) year and will continue for up to five (5) years.

The subjects have an average age of 67.8 ±9.2 years (range 33 - 90 years). The majority of subjects were males (82.3%, 2438/2964) and were Caucasian (88.3%, n=2610/2956). The majority of subjects had a history of hypertension 84.4% (2486/2946), dyslipidemia 76.9% (2251/2929), and diabetes was present in 43.7% (1294/2962). The overall mean EuroSCORE II (ESII) for all patients is 2.6 ± 3.7 (n=2964). For CABG only patients (n=2532), the mean score is 2.3 ± 3.4 and for CABG +valve patients (n=432) is 4.3 ± 5.0.

Results:

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In the total study population, 120 (4.1%) patients experienced a MACE at 30 days and 7.4% at 1 year. The 30-day incidence of death, myocardial infarction and repeat revascularization was 2.7%, 1.6% and 1.1%, respectively for all patients, isolated CABG and CABG + valve cohorts and at 1 year was 5.2%, 2.2% and 2.1%, respectively. In the total population, 2.3% of the patients experienced a stroke at 1 year. The 1-year all-cause death rate was 5.2% (148/2964). 30day and 1-year Kaplan Meir rates for MACE are given in Table 4.

In the isolated CABG group, the 30-day MACE rate was 3.5% with all-cause death (2.3%), myocardial infarction (1.3%), and repeat revascularization (1.0%). The I-year MACE rate was 6.6% with all-cause death (4.4%), myocardial infarction (2.0%), and repeat revascularization (2.2%).

The 30-day MACE rate for the combined CABG + valve groups was 7.5% with rates of death 5.4%, myocardial infarction 3.1% and repeat revascularization 0.7%. The 1-year MACE rate was 12.0% with rates of death 9.9%, myocardial infarction 3.3% and repeat revascularization 1.3% Cumulative incidence of primary endpoints and incidents are shown in Figure 3.

	All patients(n=2964)% (No. of events)		Isolated CABG(n=2532)% (No. of events)		CABG and valve(n=432)% (No. of events)
	30 days	1 year	30 days	1 year	30 days	1 year
MACE	4.1% (120)	7.4% (210)	3.5% (88)	6.6% (160)	7.5% (32)	12.0% (50)
MACCE	5.2% (153)	8.6% (247)	4.6% (115)	7.8% (190)	8.9% (38)	13.6% (57)
All-Cause Death	2.7% (80)	5.2% (148)	2.3% (57)	4.4% (107)	5.4% (23)	9.9% (41)
Cardiovascular Death	2.7% (80)	4.5% (130)	2.3% (57)	3.8% (92)	5.4% (23)	9.1% (38)
Myocardial Infarction	1.6% (46)	2.2% (63)	1.3% (33)	2.0% (49)	3.1% (13)	3.3% (14)
All RepeatRevascularization	1.1% (31)	2.1% (58)	1.1% (28)	2.2% (53)	0.7% (3)	1.3% (5)
PCI	0.8% (22)	1.8% (48)	0.8% (21)	1.9% (45)	0.2% (1)	0.8% (3)
Re-CABG	0.3% (9)	0.3% (10)	0.3% (7)	0.3% (8)	0.5% (2)	0.5% (2)
Stroke	1.7% (50)	2.3% (65)	1.5% (37)	1.9% (46)	3.1% (13)	4.6% (19)

Table 4. 30-Day and 1-Year Kaplan Meier rates for MACE

Percentages indicate cumulative event rates by Kaplan Meier estimates.

** MACE: major adverse cardiac events: MACCE: major adverse cardine and cerebrovascular events, PCI percutaneous coronary intervention, CABG, coronary artery bypass graffing,

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Image /page/8/Figure/0 description: The image contains four cumulative incidence plots comparing different surgical procedures. The plots show the cumulative incidence of MACCE (major adverse cardiac and cerebrovascular events), mortality, myocardial infarction (MI), and revascularization over a 12-month period. Each plot compares "Isolated CABG", "CABG + Valve", and "All Subjects", with the number of patients at risk at different time points listed below each plot. The cumulative incidence at 12 months varies across the different outcomes and surgical groups.

IBJ All Dealt

Figure 3: Cumulative incidence of Primary endpoints and components (A.) MACE

Figure 3: Cumulative incidence of (A) the primary outcome; Major Adverse Cardiac Events (MACE); and the individual components of the primary outcome (B) all-cause death; (C) myocardial infarction; (D) repeat revascularization, at 1 year.

Propensity Matched Comparison of DuraGraft EU Registry to STS Registry

To compare mortality of patients in the single arm DuraGraft Registry, the Society of Thoracic Surgery (STS) Database was identified and determined suitable for use as a contemporaneous control. 2532 patients underwent isolated CABG surgery in the DuraGraft Registry between December 2016 and August 2019. 294.725 isolated CABG patients were identified in the STS Registry who were operated on between 2016 and had at least 1 year mortality data available from linkage to the US National Death Index (NDI), a database maintained by the National Center for Health Statistics (NCHS), which captures all death records for the US and US territories. An analysis was conducted comparing Isolated CABG patients from the DuraGraft Registry to a propensity matched control group from the STS Registry Adult Cardiac Surgery Database. 2400/2532 patients were matched from the DuraGraft cohort to 2400 patients in the STS Database, matching on the following 35 prespecified variables, selected to be predictive of mortality risk in the operative, peri-operative, and follow-up periods.

Demographics

1. Age
1. Male sex
1. Black race

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Cardiac Risk Factors

1. BMI < 20 kg/m2
1. Previous or current smoker
1. Diabetes on insulin
1. Diabetes not on insulin
1. CRF (Cr > 2.0 mg/dl)
1. Renal dialysis
1. Peripheral vascular disease
1. Pulmonary hypertension
1. History of pulmonary disease
1. History of CVA

Pre-Operative Cardiac Status

1. MI < 24h
1. MI > 24h
1. Unstable angina
1. Congestive heart failure
1. Cardiogenic shock
1. Pre-operative atrial fibrillation
1. Re-operation
1. Left ventricular function (EF<30%)
1. Status urgent
1. Status emergent

Coronary Anatomy

1. Left main stem coronary artery stenosis > 50%
1. Three (3) vessel disease
1. Previous CABG
1. Previous PCI

Surgical Technique

1. Number of distal anastomoses
1. On pump status
1. Presence of LIMA graft
1. Number of arterial grafts
1. Number of venous grafts
1. All arterial grafts
1. All venous grafts
1. Harvesting technique endoscopic

Results:

The cumulative incidence of mortality through 36 months of follow up in the 2,400 propensity matched DuraGraft and STS registry subjects is presented as Kaplan Meier estimates in Figure 4 And Table 5. At 30 days and 12 months the mortality estimate in DuraGraft was 2.38% [95% CI, 1.84% - 3.07%] and 4.32% [CI, 3.58% - 5.22%] compared to the STS Registry patients 1.96% [95% CI 1.47% - 2.60%] and 4.79% [95% CI 4.01% - 5.72%], respectively. At 36 months the

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mortality estimate in DuraGraft patients was reduced compared to the STS Registry patients (7.37% [95% C1, 6.36% - 8.53%] vs. 9.65% [95% C1 8.37% - 11.10%]).

Figure 4. Kaplan Meier estimates of all-cause mortality through 36 months in 2400 DuraGraft patients and Kaplan Meier estimates of all-cause mortality through 36 months in 2400 Propensity Matched STS patients

Image /page/10/Figure/2 description: The image is a graph comparing the cumulative mortality rate between DuraGraft and a control group (STS). The x-axis represents time, ranging from 0 to 36, while the y-axis represents the cumulative mortality rate, ranging from 0% to 12%. The DuraGraft group, represented by a solid black line, shows a lower cumulative mortality rate compared to the control group, which is represented by a dashed red line. At the end of the observed period, the DuraGraft group has a mortality rate of approximately 7%, while the control group has a mortality rate of approximately 9.5%.

Time (Months)

Table 5. Kaplan Meier estimates of all-cause mortality through 36 months in 2400 DuraGraft patients that were Propensity Matched to STS patients. Product Limit (PL) Estimates.

TimePoints(days)	DuraGraft				STS Registry
	Numberat Risk	NumberFailed	SurvivalEstimate	StandardError	Numberat Risk	NumberFailed	SurvivalEstimate	StandardError
0	2400	1	99.96%	0.04%	2400	1	99.96%	0.04%
30	2341	57	97.62%	0.31%	2353	47	98.04%	0.28%
180	2264	90	96.23%	0.39%	2316	84	96.50%	0.38%
365	2209	103	95.68%	0.42%	2285	115	95.21%	0.44%
725	2024	126	94.63%	0.47%	1552	160	93.04%	0.53%
1085	1729	166	92.63%	0.55%	798	194	90.35%	0.69%

Clinical Outcomes for DuraGraft Registry vs Published Literature

The sponsor conducted a literature review of published registries to gain further perspective on the observed outcomes in the single-arm DuraGraft Registry. Outcomes evaluated at 30 days and 1 year included all-cause mortality and the components of MACE versus the published literature using EuroSCORE II values for comparison. Values are presented in the table when reported in each study.

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Mortality data for the DuraGraft Registry is comparable to contemporary registry studies, which reported 30-day and/or in-hospital mortality for patients undergoing isolated CABG surgery as seen in Table 6. The 30-day death rate was 2.3% in the DuraGraft Registry and ranged from 1.1% in Bangalore et alb to 3.2% in Adelborg et al7. It is notable that the comparative registries mostly reported in-hospital mortality. One-vear mortality in real world registry studies ranged from 4.8% in the MAIN COMPARE® registry to 10.5% in Biancari et al9, compared to 4.5% in the DuraGraft Registry.

Surgery - Registry Studies
	European Registries				Non-European Registries
Study	DuraGraftRegistry	Paparella(2014)10	Biancari(2012)9	Kieser(2016)11	Adelborg(2017)7	Beckman(2019)11	Bangalore(2015)6	MAIN-COMPARE(2008)8	Puskas(2012)12
Number of CABGpatients	2,544	2,605	1,027	1,125	47,415	34,224	9,223	542	20,014
EuroSCORE (II)	2.3% ± 3.4	4.5% ± 6.7	1.5%
Syntax score
30 days or In-Hospital	30 days	In-hospital	30 days	In-hospital	30 days	In hospital	30 days +in-hospital		30 days
Death	2.3%	3%	3.7%	3.2%	3.2%	2.7%(3% OPCAB)	1.1%		2.1%
Cardiac death	2.3%				1.4%
Non cardiovascular	0.0%

2.4%

1 year

10.5%

0 4%

1 2%

I vear

4.8%

1 5%

I year

5.49

	Table 6. 30-Day and 1-Year Comparative MACE Event Rates in Patients Receiving Isolated CABG
Surgery - Registry Studies

Pediatric Extrapolation

1.3%

1.596

1 year

4.506

2196

2546

2156

In this De Novo request, existing clinical data were not leveraged to support the use of the device in a pediatric patient population.

I year

6.03

References

I vear

Death

Stroke

Revascularization

Bevascularization

1 Pachuk CJ. Rushton-Smith SK. Emmert MY. Intraoperative storage of saphenous yein grafts in coronary bypass grafting. Expert Review of Medical Devices, 2019

2 Korkmaz-Icoz S, Ballikaya B, Soethoff J, et al, Graft Preservation Solution DuraGraft Alleviates Vascular Dysfunction Following In Vitro Ishemia/Reperfusion Injury in Rats. Pharmaceuticals 2021 doi: 10.3390/ph14101028

3 Aschacher T., Baranyl U., Aschacher O. et al. A Novel Endothelial Damage Inhibitor Reducers Oxidative Stress and Improves Cellular Integrity in Radial Artery Grafts for Coronary Artery Bypass. Frontiers in CV Med. 2021; 8:1-12.

4 Perrault LP, Carrier M, Voisine P, Olsen PS, Noiseux N, Jeanmart H, Cardemartiri F, Veerasingam D, Brown C, Guertin MC, Satishchandran V, Goeken T, Emmert MY. Sequential multidetector computed tomography assessments after venous graft treatment solution in coronary artery bypass grafting. J Thorac Cardiovasc Surg. 2019 Nov 9:S0022-5223(19)32503-6. doi: 10.1016/j.jtcvs.2019.10.115.

5 Caliskan E. Sandner S. Misfeld M. Aramendi J. Salzberg SP. Choi YH. Satishchandran V. Iyer G. Perrault LP, Böning A. Emmert MY. A novel endothelial damage inhibitor for the treatment of vascular conduits in coronary artery bypass grafting; protocol and rationale for the European,

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multicentre, prospective, observational DuraGraft registry. J Cardiothorac Surg. 2019 Oct 15:14(1):174.

6 Bangalore, Sripal, et al. "Everolimus-eluting stents or bypass surgery for multivessel coronary disease." New England Journal of Medicine 372.13 (2015): 1213-1222.

7 Adelborg, Kasper, et al. "Thirtv-year mortality after coronary artery bypass graft surgery: a Danish nationwide population-based cohort study." Circulation: Cardiovascular Quality and Outcomes 10.5 (2017): e002708.

8 Seung, Ki Bae, et al. "Stents versus coronary-artery bypass grafting for left main coronary artery disease." New England Journal of Medicine 358.17 (2008): 1781-1792.

9 Biancari, Fausto, et al. "Validation of EuroSCORE II in patients undergoing coronary artery bypass surgery." The Annals of thoracic surgery 93.6 (2012): 1930-1935.

10 Paparella, Domenico, et al. "Risk stratification for in-hospital mortality after cardiac surgery: external validation of EuroSCORE II in a prospective regional registry." European journal of cardio-thoracic surgery 46.5 (2014): 840-848.

11 Kieser, Teresa M., M. Sarah Rose, and Stuart J. Head. "Comparison of logistic EuroSCORE and EuroSCORE II in predicting operative mortality of 1125 total arterial operations." European Journal of Cardio-Thoracic Surgery 50.3 (2016): 509-518.

12 Beckmann, Andreas, et al. "German heart surgery report 2018: the annual updated registry of the German Society for Thoracic and Cardiovascular Surgery." The Thoracic and cardiovascular surgeon 67.05 (2019): 331-344.

13 Puskas, John D., et al. "The society of thoracic surgeons 30-day predicted risk of mortality score also predicts long-term survival." The Annals of thoracic surgery 93.1 (2012): 26-35.

LABELING

The sponsor provided labeling that included the instructions for use and package labels. The labeling includes instructions intended to minimize the risk of improper use of the DuraGraft device. The labeling also includes a summary of the non-clinical performance testing that supports use of the device as a flushing and storage solution for vascular autografts.

Important components of the labeling include:

A description of the intended patient population, age, and condition. DuraGraft is indicated for adult patients undergoing Coronary Artery Bypass Grafting Surgeries and is intended for flushing and storage of the saphenous vein grafts.

Saphenous vein grafts may be stored in DuraGraft for up to 4 hours.

DuraGraft Vascular Conduit Solution includes a component. L-arginine. L-arginine may cause an allergic reaction in certain patients.

DuraGraft is not intended for direct injection or intravenous infusion.

Prior to use, each container should be checked for leaks and particulate matter. If a leak, particulate matter, precipitates, or contamination are evident in the solution, the product should be discarded.

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The re-use of this product is hazardous to patient safety and may cause serious infections from contamination of opened product, leading to serious injury or death.

RISKS TO HEALTH

The table below identifies the risks to health that may be associated with use of the flushing and storage solution for vascular autografts at room temperature and the measures necessary to mitigate these risks.

Risks to Health	Mitigation Measures
Adverse tissue reaction	Biocompatibility evaluation
Damage to vascular grafts leading tomajor adverse cardiac events orvascular injury	Clinical performance dataNon-clinical performance testingShelf life testingLabeling
Particulate matter contaminationleading to vascular occlusion,coronary artery embolization andocclusion, phlebitis, infarction, anddeath	Clinical performance dataNon-clinical performance testingShelf life testingLabeling
Infection	Sterilization validation

SPECIAL CONTROLS

In combination with the general controls of the FD&C Act, the flushing and storage solution for vascular autografts at room temperature is subject to the following special controls:

(1) Clinical data must evaluate adverse events associated with clinical use of the device. Devices indicated for vascular grafts for coronary artery bypass graft surgeries must include an evaluation of the incidence of major adverse cardiac events, vein graft occlusion, and mortality.
Non-clinical performance testing must demonstrate that the device performs as (2) intended under anticipated conditions of use. The following performance characteristics must be tested:
- Maintenance of cell viability and structural integrity of vascular conduits during (i) storage at the labeled temperature and storage duration: and
- (ii) Evaluation of visible and non-visible particulates in the final mixed solution.
(3) Shelf life testing must demonstrate the stability of the device's chemical components over the identified shelf life.
The device must be demonstrated to be biocompatible. (4)
(ર) Performance data must demonstrate the sterility of the device.
(6) Labeling must include:
- The maximum storage duration for vascular autografts in the solution; (i)
- A description of all additives or supplements that are added at the point of care; (ii)
- (iii) The need for visual inspection of the solution for particulate matter prior to use;

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(iv) A statement regarding the duration of stability of the final solution after preparation:
A summary of the non-clinical performance testing that supports use of the (v) device as a flushing and storage solution for vascular autografts; and
(vi) A summary of the clinical data that supports use of the device as a flushing and storage solution for vascular autografts.

BENEFIT-RISK DETERMINATION

The risks to health of a flushing and storage solution for vascular autografts can generally include adverse tissue reaction, damage to the vascular graft leading to major adverse cardiac events or vascular injury, and clinical risk of particulate matter contamination including vascular occlusion, coronary artery embolization and occlusion, phlebitis, infarction, and death. However, there is no evidence from the preclinical and clinical studies of any adverse events related to the DuraGraft Vascular Conduit Solution. The preclinical testing for the DuraGraft Vascular Conduit Solution demonstrated that these risks are adequately mitigated by biocompatibility testing, non-clinical performance testing, and clinical performance testing. The device safety is supported by data collected in the clinical studies described above. The sponsor provided short-term and follow-up data up to 1 year from an ongoing all-comers European prospective registry of patients who received DuraGraft-treated vascular grafts as a postapproval study for CE Mark in Europe. A total of 2,964 patients were enrolled in the Registry, between December 2016 and August 2019, at 45 centers in eight countries. Following a comprehensive review of the literature, the sponsor compared Major Adverse Cardiac Events (MACE) and the individual components that make up MACE (e.g., death, myocardial infarction and repeat MI) from the registry to contemporary literature derived from trials of CABG surgery. The 30-day death rate was 2.3% in the DuraGraft Registry and ranged from 1.1% to 3.2% in the cited references. The observed mortality of 4.5% at one year is comparable to rates reported in multiple clinical trials, which range from 2.7% to 7.5%. In the isolated CABG registry, the 30 day and 1-year all-cause mortality are within the range of what has been reported in the literature for comparable patient populations. The incidence for myocardial infarction and revascularization were also within the same range. The DuraGraft Registry includes 2,522 patients who underwent Isolated CABG surgery. An additional comparison was made to select propensity matched cohorts of patients from the STS database and evaluate all-cause mortality between the matched cohorts at 30 days, 1 year, and 3 years of follow-up.

The review of these clinical studies is supportive of the device safety; however, there is no clear clinical evidence that the device is more effective compared to the standard of care. In a prospective randomized self-control study, the sponsor demonstrated favorable effects related to the use of DuraGraft on saphenous vein wall thickness compared to standard of care. A radiographic assessment of the saphenous vein grafts at 12 months by multidetector computed tomography (MDCT) evaluation showed reduced wall thickness in DuraGraft-treated saphenous vein grafts compared to standard of care treated saphenous vein grafts. However, there is no evidence that this biomarker can serve as a surrogate for long term vein graft patency.

The probable benefits of the device are based on nonclinical laboratory studies described above to support the device use as a flushing and storage solution for saphenous vein grafts at room

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temperature for up to 4 hours. Non-clinical performance testing demonstrated that human saphenous vein segments and pig mammary vein segments that were flushed and stored in DuraGraft for time points ranging from 15 minutes to 24 hours exhibited increased graft cell viability and improved maintenance of graft endothelial morphology compared to vein segments that were stored in normal saline solution.

Additionally, as there is no alternative legally marketed solution for the short-term flushing and storage of saphenous vein grafts during CABG surgery, the device addresses an unmet need.

Patient Perspectives

This submission did not include specific information on patient perspectives for this device.

Benefit/Risk Conclusion

In conclusion, given the available information above, for the following indication statement:

The probable benefits outweigh the probable risks for the DuraGraft Vascular Conduit Solution device. The device provides benefits and the risks can be mitigated by the use of general controls and the identified special controls.

CONCLUSION

The De Novo request for DuraGraft Vascular Conduit Solution is granted and the device is classified as follows:

Product Code: OEJ Device Type: Flushing and storage solution for vascular autografts at room temperature Regulation Number: 21 CFR 876.4100 Class: II

Regulation Number and Section

N/A