SurVeil Drug-Coated Balloon

P210025 · Surmodics,Inc. · ONU · Jun 16, 2023 · Cardiovascular

Device Facts

Record IDP210025
Device NameSurVeil Drug-Coated Balloon
ApplicantSurmodics,Inc.
Product CodeONU · Cardiovascular
Decision DateJun 16, 2023
DecisionAPPR
Device ClassClass 3
AttributesTherapeutic

Indications for Use

The SurVeil™ DCB is indicated for use for percutaneous transluminal angioplasty, after appropriate vessel preparation, of de novo or restenotic lesions (≤ 180 mm in length) in femoral and popliteal arteries having reference vessel diameters of 4 mm to 7 mm.

Device Story

SurVeil DCB is a sterile, single-use, over-the-wire drug-coated balloon (DCB) catheter. It combines a standard PTA balloon catheter with a paclitaxel/polyethyleneimine (PEI) coating. Used in clinical settings by physicians to treat peripheral arterial disease (PAD) in femoral and popliteal arteries. The device is inserted via a sheath; the balloon is inflated to mechanically dilate the lesion while simultaneously transferring paclitaxel to the arterial wall. Paclitaxel stabilizes microtubules to inhibit neointimal growth, reducing restenosis. The PEI excipient facilitates drug transfer. The physician monitors the procedure via fluoroscopy. Successful treatment restores vessel patency, reduces the need for repeat revascularization, and improves patient symptoms (e.g., claudication).

Clinical Evidence

Prospective, multi-center, randomized controlled trial (TRANSCEND, N=446). Primary safety endpoint (composite of freedom from device/procedure-related death at 30 days and freedom from major target limb amputation/clinically-driven TVR at 12 months) was 91.7% for SurVeil vs 89.6% for IN.PACT (p<0.0001 for non-inferiority). Primary effectiveness endpoint (primary patency at 12 months) was 81.7% for SurVeil vs 85.9% for IN.PACT (p=0.0035 for non-inferiority). No unanticipated adverse device effects reported.

Technological Characteristics

Over-the-wire PTA catheter (135 cm length) with semi-compliant balloon. Materials: Surmodics™ PhotoLink™ lubricious coating on shaft. Drug coating: Paclitaxel (2.0 µg/mm²) with PEI excipient (70 kDa). Compatible with 5-7 Fr sheaths. Nominal inflation 6 atm; RBP 10-14 atm. Sterilization: E-beam. Connectivity: None (standalone).

Indications for Use

Indicated for percutaneous transluminal angioplasty of de novo or restenotic lesions (≤ 180 mm length) in femoral and popliteal arteries (RVD 4-7 mm) in adults. Contraindicated in patients with paclitaxel hypersensitivity, those unable to receive antiplatelet/anticoagulant therapy, lesions preventing balloon inflation, pregnant/breastfeeding women, men intending to father children, and coronary, renal, or supra-aortic/cerebrovascular arteries.

Regulatory Classification

Identification

A drug-eluting peripheral transluminal angioplasty catheter is a combination product intended for balloon dilatation of peripheral vasculature to establish or maintain patency. A drug-eluting PTA catheter delivers a drug to the vessel as part of the angioplasty procedure and is intended to inhibit restenosis. Intended to provide percutaneous transluminal angioplasty of lesions in peripheral arteries including iliac, popliteal, femoral, and iliofemoral.

Reference Devices

Related Devices

Submission Summary (Full Text)

{0} SUMMARY OF SAFETY AND EFFECTIVENESS DATA (SSED) # I. GENERAL INFORMATION Device Generic Name: Drug-Coated Balloon (DCB) Percutaneous Transluminal Angioplasty Catheter Device Trade Name: SurVeil™ Drug Coated Balloon Device Procode: ONU Applicant's Name and Address: Surmodics, Inc. 9924 West 74th Street Eden Prairie, MN 55344 USA Date(s) of Panel Recommendation: None Premarket Approval Application (PMA) Number: P210025 Date of FDA Notice of Approval: 6/16/2023 # II. INDICATIONS FOR USE The SurVeil™ DCB is indicated for use for percutaneous transluminal angioplasty, after appropriate vessel preparation, of de novo or restenotic lesions (≤ 180 mm in length) in femoral and popliteal arteries having reference vessel diameters of 4 mm to 7 mm. # III. CONTRAINDICATIONS The SurVeil DCB is contraindicated for use in: - Patients with known hypersensitivity to paclitaxel or structurally related compounds. - Patients who cannot receive recommended antiplatelet and/or anticoagulant therapy - Patients judged to have a lesion that prevents complete inflation of an angioplasty balloon or proper placement of the delivery system. - Women who are breastfeeding, pregnant or are intending to become pregnant or men intending to father children. - Coronary, renal and supra-aortic/cerebrovascular arteries. # IV. WARNINGS AND PRECAUTIONS A signal for increased risk of late mortality has been identified following the use of paclitaxel-coated balloons and paclitaxel-eluting stents for femoropopliteal arterial PMA P210025: FDA Summary of Safety and Effectiveness Data {1} disease beginning approximately 2-3 years post-treatment compared with the use of non-drug coated devices. There is uncertainty regarding the magnitude and mechanism for the increased late mortality risk, including the impact of repeat paclitaxel-coated device exposure. Physicians should discuss this late mortality signal and the benefits and risks of available treatment options with their patients. Adhere to the following use parameters for the index procedure: $\bigcirc$ Do not use more balloons than necessary. No more than $200 \mathrm{~mm}$ of total balloon length should be used, for a total maximum treatable length of $180 \mathrm{~mm}$ . $\bigcirc$ This product should not be used bilaterally or in multiple lesions that cannot be treated with up to $200 \mathrm{~mm}$ total balloon length. The safety of exposure to higher doses of the paclitaxel/polyethyleneimine (PEI) drug coating has not been established. Additional warnings and precautions can be found in the SurVeil™ Drug Coated Balloon Catheter labeling. # V. DEVICE DESCRIPTION The SurVeil™ Drug Coated Balloon Catheter (SurVeil DCB) (Figure 1) is a sterile, single-use, over-the-wire (OTW) device/drug combination product comprised of two regulated components: - Base percutaneous transluminal angioplasty (PTA) Balloon Catheter: PTA balloon catheter uses mechanical force of balloon expansion across a lesion to establish patency - Balloon Drug Coating: A formulation of the active pharmaceutical ingredient paclitaxel with an excipient, to serve as an adjunct to the mechanical action of balloon angioplasty by reducing restenosis and repeat revascularization rates at the treatment site ![img-0.jpeg](img-0.jpeg) Figure 1: SurVeil™ DCB Catheter The SurVeil DCB is available in multiple balloon sizes as listed in Table 1. Table 1: SurVeil™ DCB Product Matrix | Balloon diameter (mm) | Balloon length (mm) | | | | | | | --- | --- | --- | --- | --- | --- | --- | | | 40 | 60 | 80 | 100 | 120 | 150 | | 4 | X | X | X | X | X | X | PMA P210025: FDA Summary of Safety and Effectiveness Data {2} PMA P210025: FDA Summary of Safety and Effectiveness Data Page 3 of 54 | 5 | X | X | X | X | X | X | | --- | --- | --- | --- | --- | --- | --- | | 6 | X | X | X | X | X | X | | 7 | X | X | X | X | -- | -- | ## Device Component The SurVeil DCB uses a standard 0.035” over-the-wire (OTW) PTA catheter, with a 135 cm usable catheter length and a semi-compliant balloon at the distal tip. A portion of the distal catheter shaft is coated with Surmodics™ PhotoLink™ lubricious coating. The SurVeil DCB is compatible with 5-7 Fr sheaths (depending on balloon size). The nominal inflation pressure is 6 atm and the rated burst pressure is 10-14 atm (depending on balloon size). ## Drug Component The drug coating of the SurVeil DCB comprises the active pharmaceutical ingredient paclitaxel and a polyethyleneimine polymer excipient. The drug coating is uniformly distributed across the balloon surface at a nominal paclitaxel dose density of 2.0 µg/mm². The key functional characteristic of the excipient in the drug coating is to facilitate efficient transfer of paclitaxel to the arterial wall. Based on the nominal drug dose density of 2.0 µg/mm², the total amount of paclitaxel for each balloon size is provided in Table 2. Table 2: Nominal Paclitaxel Dose per Balloon size | Balloon diameter (mm) | Balloon length (mm) | | | | | | | --- | --- | --- | --- | --- | --- | --- | | | 40 | 60 | 80 | 100 | 120 | 150 | | 4.0 | 1005 µg | 1508 µg | 2011 µg | 2513 µg | 3016 µg | 3770 µg | | 5.0 | 1257 µg | 1885 µg | 2513 µg | 3142 µg | 3770 µg | 4712 µg | | 6.0 | 1508 µg | 2262 µg | 3016 µg | 3770 µg | 4524 µg | 5655 µg | | 7.0 | 1759 µg | 2639 µg | 3519 µg | 4398 µg | -- | -- | ## Active Pharmaceutical Ingredient (API) – Paclitaxel The API of the SurVeil DCB is paclitaxel. The principal mechanism by which paclitaxel inhibits neointimal growth is through the stabilization of microtubules by preventing their depolymerization during the final G2/M phase of cell division. The CAS Registry number of paclitaxel is 33069-62-4 and the chemical formula is C₄₇H₅₁NO₁₄. The chemical structure of paclitaxel is illustrated in Figure 2. {3} ![img-1.jpeg](img-1.jpeg) Figure 2: Paclitaxel Chemical Structure # Excipient - Polyethyleneimine The polycationic polymer polyethyleneimine is used as an excipient to facilitate delivery and efficient transfer of the active pharmaceutical ingredient (paclitaxel) from the balloon to the vessel wall upon balloon expansion. The CAS Registry number of polyethyleneimine is 9002-98-6 and the chemical formula is $(\mathrm{C}_2\mathrm{H}_5\mathrm{N})_{\mathrm{n}}$ . The number average molecular weight is labeled as $70\mathrm{kDa}$ . The chemical structure of PEI is shown in Figure 3. ![img-2.jpeg](img-2.jpeg) Figure 3: Representative structure of branched PEI # Mechanism of Action The primary mode of action for SurVeil DCB is mechanical dilatation of de novo or restenotic lesions by means of percutaneous transluminal angioplasty, with a secondary action of reducing neointimal proliferation from vessel injury due to PTA, and thereby reducing the rate of restenosis, through the application of paclitaxel to the vessel wall. # VI. ALTERNATIVE PRACTICES AND PROCEDURES There are several other alternatives for the treatment of femoral and popliteal artery atherosclerotic disease, including: Non-invasive treatment (risk factor modification, exercise, and/or drug therapy) - Minimally invasive treatment (balloon angioplasty, bare metal or drug-eluting stent, or plaque debulking by atherectomy), and - Surgical treatment (surgical bypass) PMA P210025: FDA Summary of Safety and Effectiveness Data {4} Each alternative has its own advantages and disadvantages. A patient should fully discuss these alternatives with his/her physician to select the method that best meets expectations and lifestyle. ## VII. MARKETING HISTORY The SurVeil DCB has not been marketed in the United States or any foreign country. ## VIII. POTENTIAL ADVERSE EFFECTS OF THE DEVICE ON HEALTH Below is a list of the potential adverse effects (e.g., complications) associated with the use of the device. - Acute re-occlusion necessitating surgical intervention - Allergic reaction to contrast solution, anti-platelet therapy, or catheter system components - Amputation - Aneurysm - Arrhythmias - Arterio-venous fistula - Bleeding - Death - Endocarditis - Femoral nerve compression with associated neuropathy - Groin area bruising and discomfort - Ischemia or infarction of tissue/organ - Renal insufficiency or failure - Local hematoma - Local hemorrhage - Local infections - Local or distal thromboembolic episodes - Low blood pressure - Pain and tenderness - Pseudoaneurysm - Pyrogenic reaction - Respiratory failure - Restenosis of the dilated artery - Sepsis/infection - Short-term hemodynamic deterioration - Stroke - Systemic embolization - Total occlusion or thrombosis - Vessel damage, dissection, perforation, rupture, or spasm Potential adverse events that may be unique to the paclitaxel drug coating may include, but are not limited to: - Allergic/immunologic reaction - Alopecia - Anemia - Gastrointestinal symptoms - Hematologic dyscrasia (including leukopenia, neutropenia, thrombocytopenia) - Hepatic enzyme changes - Histologic changes in vessel wall, including inflammation, cellular damage, or necrosis - Myalgia/arthralgia - Myelosuppression - Peripheral neuropathy For the specific adverse events that occurred in the clinical study, please see Section X.D below. PMA P210025: FDA Summary of Safety and Effectiveness Data {5} IX. SUMMARY OF NONCLINICAL STUDIES A series of non-clinical laboratory studies were performed on the SurVeil DCB. These studies included biocompatibility, preclinical animal studies, in vitro bench testing, packaging, shelf life, and sterilization. A summary for each is provided below. A. Biocompatibility Biocompatibility testing was completed on the SurVeil DCB in accordance with ISO 10993-1. Biocompatibility testing was conducted separately on 1) the balloon with drug coating, 2) the balloon with excipient only, 3) the balloon catheter with excipient only, and 4) balloon catheter with no drug coating. Thrombogenicity was evaluated in the large animal safety study of the entire drug coated balloon catheter. In addition, chemical characterization and toxicological risk assessment was conducted to support various biocompatibility endpoints for the SurVeil DCB. The balloon with the drug coating was categorized as an implant device with permanent blood contact (&gt; 30 days), and the base balloon catheter was categorized as an externally communicating device with limited contact duration (≤ 24 hours) with circulating blood. A summary of the biocompatibility testing and results can be found in Table 3. PMA P210025: FDA Summary of Safety and Effectiveness Data Page 6 of 54 {6} Table 3: Summary of Biocompatibility Testing | Test Name | Test Description | Balloon with drug coating | Balloon with excipient, no drug | Balloon catheter with excipient, no drug | Balloon catheter, no excipient, no drug | Results | | --- | --- | --- | --- | --- | --- | --- | | Cytotoxicity | Minimum Essential Medium (MEM) Extraction Cytotoxicity Assay Using L-929 Cells | X | -- | X | X | Non-toxic response for catheter body; acceptable response for the coated balloon and balloon catheter with excipient only after extract dilutions* | | Sensitization | ISO Guinea Pig Maximization | X | -- | X | X | Non-sensitizing | | Irritation | ISO Intracutaneous Reactivity | X | -- | X | X | Non-irritating for catheter body with excipient only and without excipient/drug; extract dilution of coated balloon non-irritating. | | Acute Systemic Toxicity | ISO Systemic Toxicity | X | -- | X | X | Non-toxic response for catheter body; acceptable response for coated balloon through determination of no observed adverse effect level (NOAEL) and tolerable intake | | Pyrogenicity | Material Mediated Pyrogenicity | X | -- | X | X | Non-pyrogenic response for catheter body; Acceptable response for the coated balloon and balloon catheter with excipient only after extract dilutions ** | | Hemocompatibility | American Society of Testing and Materials (ASTM) Hemolysis | X | X | X | X | Non-hemolytic for catheter body without drug/excipient coating (direct and indirect); non-hemolytic for the coated balloon (indirect) and acceptable hemolytic response for excipient and drug coated balloon (direct)***. | PMA P210025: FDA Summary of Safety and Effectiveness Data {7} | | Clinically-relevant in vitro hemolysis (direct contact) | X | -- | -- | -- | Non-hemolytic *** | | --- | --- | --- | --- | --- | --- | --- | | | Complement Activation Assay (SC5b-9) | X | -- | X | X | Not a complement activator | | | Partial Thromboplastin Time (PTT) | X | -- | X | X | Non-activator of intrinsic coagulation pathway | | | Platelet and leukocyte count | X | -- | -- | X | Acceptable response for coated balloon*** | | | In vivo thrombogenicity | Finished device (catheter and coated balloon) | | | | The test article showed similar thrombogenic potential in comparison to a currently marketed device. | | Genotoxicity | Ames Bacterial Reverse Mutation Assay | X | -- | X | -- | Non-mutagenic and non-clastogenic | | | Mouse Lymphoma Assay | -- | X | X | -- | | | | In Vivo Mouse Micronucleus Assay | -- | -- | X | -- | | | Chemical Characterization | Gas Chromatography - Mass Spectroscopy (GC/MS) for volatile and semi-volatile, organic compounds | X | X | -- | X*** | Compounds consistent with manufacturing materials and amounts do not raise toxicity concerns for the endpoints of carcinogenicity, genotoxicity, and sub-chronic/chronic systemic toxicity | | | Inductively Coupled Plasma (ICP) Spectroscopy for metallic compounds | X | X | -- | X*** | Compounds consistent with manufacturing materials and amounts do not raise toxicity concerns for the endpoints of carcinogenicity, genotoxicity, and sub-chronic/chronic systemic toxicity | | | Liquid Chromatography - Mass Spectroscopy (LC/MS) for semi-volatile and non-volatile organic compounds | X | X | -- | X*** | Compounds consistent with manufacturing materials and amounts do not raise toxicity concerns for the endpoints of carcinogenicity, genotoxicity, and sub-chronic/chronic systemic toxicity | PMA P210025: FDA Summary of Safety and Effectiveness Data {8} *Although a cytotoxic response was noted for the neat extract of the balloon, the results are considered acceptable following extract dilutions and based on acceptable implantation response from in vivo safety study **Animal deaths were noted for neat extracts. Acceptable results were observed using more clinically relevant dosages ***Direct contact hemolysis testing demonstrated elevated hemolytic indices for the coated balloon. This may be due to background interference of the drug coated balloon. Clinically relevant hemolysis testing was conducted and the results were comparable to negative control. Thus, the hemolysis testing was considered acceptable ***Although the platelet counts showed significant change, the results were considered acceptable based on more clinically relevant hemocompatibility testing and in vivo testing ***Balloon-only portion extracted The endpoints of implantation, subchronic toxicity, and chronic toxicity were evaluated as part of other in vivo studies conducted to evaluate the safety of the SurVeil DCB in a porcine iliofemoral model, as described in the summary of Animals Studies in Section IX.H below. These studies demonstrated acceptable local tissue response and no indication of toxicity when the device was used in a clinically relevant vascular location. Chemical characterization and toxicological risk assessments were also conducted to support sub-acute (sub-chronic) toxicity, chronic toxicity, genotoxicity, and carcinogenicity endpoints. The information provided demonstrates that the SurVeil DCB is biocompatible for its intended use. # B. In Vitro Bench Testing Table 4 provides an overview of the functional engineering testing performed with the SurVeil DCB. The table includes the tests performed, the objective of the tests, the acceptance criteria, and the result of the test. Table 4: Summary of Bench Testing Performed | Test | Test Description and/or Objective | Acceptance Criteria | | Pass/Fail | | --- | --- | --- | --- | --- | | Delivery system dimensions (balloon diameter and length) | Confirm balloon meets labeled dimensions | Diameter: ± 5% of nominal Length: ± 5% of nominal | | Pass | | Delivery system dimensions (inner marker band distance, tip length, shaft OD, usable catheter length, proximal bond OD) | Confirm dimensions and to confirm compatibility with accessory devices | Tip length: 5.0 ± 0.5 mm Shaft OD: 1.70 +0.06/-0.03 mm Usable catheter length: 1350 ± 20 mm | | Pass | | | | Marker band distance: | | Pass | | | | Balloon | Distance | | PMA P210025: FDA Summary of Safety and Effectiveness Data {9} | Test | Test Description and/or Objective | Acceptance Criteria | Pass/Fail | | --- | --- | --- | --- | | | | Length | | | | | 40 mm | 36 +0 / -2 mm | | 60 mm | 55 +1 / -3 mm | | 80 mm | 75 +1 / -3 mm | | 100 mm | 94 +1 / -3 mm | | 120 mm | 113 +1 / -3 mm | | 150 mm | 141 +1 / -3 mm | | Proximal bond OD:4 mm diameter: ≤ 1.90 mm (5.7 Fr)5 mm diameter: ≤ 2.00 mm (6 Fr)6 mm diameter: ≤ 2.08 mm (6.24 Fr)7 mm diameter: ≤ 2.15 mm (6.45 Fr) | Pass | | Trackability | Catheter is tracked through a simulated use track model over guidewire | Able to track through model on 0.035”guidewire | Pass | | Burst pressure (balloon, catheter shaft) | Balloon catheter is steadily inflated until burst and balloon rated burst pressure is calculated | Balloon burst pressure ≥ RBP RBP for 4-5 mm diameter: 14 atm/bar RBP for 6 mm diameter: 12 atm/bar RBP for 7 mm diameter: 10 atm/bar Shaft burst pressure ≥ 24 bar | Pass | | Balloon Fatigue (Repeat Balloon Inflations) | Balloon is inflated to RBP and deflated a minimum of 20 times | Balloons withstand 20x inflations up to RBP with no failure | Pass | | Balloon compliance | Balloon is incrementally inflated and diameter measured to determine compliance curve | Diameter within 5% | Pass | | Catheter Bond Tensile Strength:a) Stem-to-balloonb) Balloon-to-shaftc) Shaft-to-stemd) Hub-to-shaft | Confirm the tensile strength of the catheter | a) ≥ 10 Nb) ≥ 20 Nc) ≥ 10 Nd) ≥ 20 N | Pass | | Balloon crossing profile | Determine the maximum diameter between the proximal end of the balloon and the distal tip of the catheter | 4 mm diameter: ≤ 1.80 mm (5.4 Fr)5 mm diameter: ≤ 2.08 mm (6.24 Fr)6-7 mm diameter: ≤ 2.15 mm (6.45 Fr) | Pass | | Balloon deflation time | Time to deflate the balloon from RBP using contrast media | ≤ 87 seconds | Pass | | Sheath passage, Insertion, and Retraction | Measure the axial force required to move the device through the recommended introducer sheath in the IFU pre-inflation (insertion) and post-inflation (retraction) | Insertion: ≤ 3 NRetraction: ≤ 20 N | Pass | | Kink evaluation | Catheter is tracked through a fixture of decreasing radius until 0.5” radius is reached | Traverse 0.5” radius without kinking | Pass | PMA P210025: FDA Summary of Safety and Effectiveness Data {10} | Test | Test Description and/or Objective | Acceptance Criteria | Pass/Fail | | --- | --- | --- | --- | | Torque Strength | Demonstrate catheter is able to withstand torque forces without damage | Minimum of 10 rotations without failure | Pass | | Hub Durability | Demonstrate ability to meet performance standard | ISO 80369-7 | Pass | | Radiopacity | Confirm the marker bands are acceptably visible under fluoroscopic imaging | Visible under fluoroscopy | Pass | # C. Coating Characterization Testing was conducted to characterize the drug coating on the SurVeil DCB following ASTM F3320-18. See summary in Table 5 below. Table 5: Coating Characterization Summary | Test | Test Description and/or Objective | Results | | --- | --- | --- | | Coating Integrity and Appearance | Characterization of the drug coating morphology on the balloon surface using optical and SEM techniques | N/A (characterization only) | | Drug Coating Thickness | Characterization of the drug coating thickness on the balloon surface | N/A (characterization only) | | Drug Coating Uniformity – Circumferential | Measure the relative uniformity of the drug content around the balloon circumference with a specification of ±15% of nominal | Pass | | Drug Coating Uniformity – Longitudinal | Measure the relative uniformity of the drug content along the balloon length with a specification of ±15% of nominal | Pass | | Particulates (Simulated use) | Particulate sizes and counts measured | Pass | | Particulate Identification | Chemical identification of the particulate generated | N/A (characterization only) | | Crystallinity Characterization | Characterize degree of crystallinity of the coating | N/A (characterization only) | PMA P210025: FDA Summary of Safety and Effectiveness Data {11} # D. Chemistry, Manufacturing and Controls (CMC) Testing Analytical testing was conducted to determine the identity, safety, purity, and quality of the SurVeil DCB, including coating containing drug substance (paclitaxel) and excipient (PEI). See summary in Table 6 below. Table 6: Summary of Analytical Testing | Test | Description | Acceptance Criteria | | --- | --- | --- | | Finished Goods Appearance | Visual inspection was conducted to verify the SurVeil DCB drug coating meets the appearance criteria | Must meet visual standards | | Paclitaxel Content (Assay) | Quantitative assay to determine the total amount of paclitaxel on the SurVeil DCB | Drug content must be within 90-110% of nominal values for each balloon size | | Paclitaxel Content Uniformity | Verification of the content uniformity of the paclitaxel coating from balloon to balloon | Units shall meet uniformity of dosage requirements in USP <905> | | Paclitaxel Impurities | Quantitative determination of the type and amount of impurities and degradation products on the SurVeil DCB | ICH Q3B | | Paclitaxel Identification | Test for identity and ensure conformity to specifications (matches reference spectrum) | Identity must be confirmed by two different tests | | PEI Identity | Test for identity and ensure conformity to specifications | Identity confirmed by UV-vis | | PEI Molecular Weight (MW) | Test PEI MW by gel permeation chromatography (GPC). | For information only | | Dissolution | Dissolution tests are performed to verify the drug release profile of the SurVeil DCB | USP <711> | | Particulates | Particulate sizes and counts are measured for the SurVeil DCB following simulated use | Particulate sizes and counts must be within specified limits | | Residual Solvent | Quantitative assay to determine the amount of residual solvents on the SurVeil DCB | ICH Q3C | | Endotoxin | Conduct LAL test to confirm lack of endotoxin. | ≤20 EU/device | | Sterility | Confirm product sterility | Pass dosimetric release per ISO 11137 | PMA P210025: FDA Summary of Safety and Effectiveness Data {12} # E. Packaging Packaging verification tests were performed on SurVeil DCB packaging subjected to the worst-case shipping simulation and then aged to ensure that the packaging would remain acceptable and maintain sterile barrier throughout the shelf life of the SurVeil DCB. Package integrity testing included a visual assessment, bubble leak testing, and seal strength testing. Testing was conducted on both packaging at the baseline condition and packaging aged to the product shelf life. Testing indicated that packaging will ensure product sterility throughout its shelf life. # F. Shelf Life Finished product shelf life for the SurVeil DCB was established based on drug coating stability, functional/mechanical performance, and packaging testing. Appropriate mechanical tests were performed on aged product and compared to baseline to ensure that the SurVeil DCB performed acceptably. A stability study was conducted according to International Conference on Harmonization (ICH) guidelines on SurVeil DCB finished product to establish shelf life. The data generated from the stability and shelf life studies supports the 24-month labeled shelf life. # G. Sterilization The SurVeil DCB is sterilized using E-beam sterilization. The sterilization process is validated per ISO 11137-1 Sterilization of health care products - Radiation - Part 1: Requirements for development, validation and routine control of a sterilization process for medical devices, ISO 11137-2 Sterilization of health care products - Radiation - Part 2: Establishing the sterilization dose, and ANSI/AAMI/ISO TIR13004 Sterilization of health care products — Radiation — Substantiation of a selected sterilization dose: Method $VD_{max}^{SD}$ . Results show that the product satisfies a minimum Sterility Assurance Level (SAL) of $10^{-6}$ . In addition, the amounts of bacterial endotoxin are verified on every lot to be within the specification limit. # H. Animal studies Surmodics conducted four (4) studies compliant with 21 CRF 58 (Good Laboratory Practices) to evaluate the safety and biological effect of the SurVeil DCB (Table 7). Table 7: Summary of GLP Preclinical Animal Studies Demonstrating Safety and Biological Effect of the SurVeil DCB | Study ID (Primary Focus) | Animal Count and Type | Study Arms (local exposure) | Balloon Sizes | Major Endpoints & Study Term | Endpoint Met | | --- | --- | --- | --- | --- | --- | | UTE018 (Local Safety) | n=38 | DCB 1X | 4x40 mm | Artery Histopathology: 28, 90, 180, 365 days | Yes | | | (n=20 | DCB 3X | 5x40 mm | | | | | Domestic | Excipient-only | 6x40 mm | | | PMA P210025: FDA Summary of Safety and Effectiveness Data {13} | | Yorkshire; n=18 Yucatan | Uncoated SurVeil DCB Only | | | | | --- | --- | --- | --- | --- | --- | | UTE019 (Downstream and Systemic Safety) | n=25 (n=16 Domestic Yorkshire; n=9 Yucatan) | DCB 1X DCB 3X SurVeil DCB Only | 5x80 mm | Downstream histopathology and PK: 28, 90, 180 days Plasma PK: 0, 5, 15, 60 minutes, 1 day, term Artery Histopathology (secondary): 28, 90, 180 days | Yes | | UTE107 (Downstream and Systemic Safety) | n=7 (All Domestic Yorkshire) | DCB 4X SurVeil DCB & IN.PACT Admiral DCB | 5x80 mm | Downstream histopathology and PK: 30 days Plasma PK: 0, 15, 60 minutes, 1 day, term | Yes | | UTE020 (Pharmacokinetics) | n=25 (n=20 Domestic Yorkshire; n=5 Yucatan) | DCB 1X SurVeil DCB Only | 4x40 mm 5x40 mm 6x40 mm | PK of local artery, downstream muscles, & non-target organs: 1, 6, 12, 24 hours, 3, 7, 14, 21, 28, 90, 180, 365 days Plasma PK: 0, 5, 15, 60 minutes, 1 day, term | Yes | Collectively, the results of these preclinical studies confirm the safety and biological effect of the SurVeil DCB as demonstrated by the following: - Successful deployment of the SurVeil DCB with no sign of device-related adverse effects. - Animals were generally healthy through the duration of their terms following treatment. - Local analyses showed the desired biological effects of paclitaxel with substantial resolution within one year and no evidence of unacceptable vessel toxicity or aneurysmal dilatation at up to 3X dosing. - Downstream embolic evaluations with up to 4X local treatment demonstrated acceptable outcomes. PMA P210025: FDA Summary of Safety and Effectiveness Data {14} - Evidence of the expected pharmacokinetic profile with clearance from all tissues within one year. - Paclitaxel plasma concentrations peaked immediately after treatment and were below limits of quantification beyond 24 hours in all studies. - The treated artery showed the highest tissue paclitaxel concentration, which peaked at 1-hour and was undetectable at 365 days with an estimated half-life of 19 days. - Downstream muscle and non-target organ concentrations peaked within 72 hours and paclitaxel was not detected in any tissue beyond 180 days. The half-life values ranged from 8.0 to 73 days. - The observed concentrations of paclitaxel in non-target organs was not associated with adverse effects. ## X. SUMMARY OF PRIMARY CLINICAL STUDY ### TRANSCEND TRIAL The applicant performed a clinical study to establish a reasonable assurance of safety and effectiveness of percutaneous transluminal angioplasty with the SurVeil™ Drug-Coated Balloon, after appropriate vessel preparation, for treatment of de novo or restenotic lesions in femoral and popliteal arteries having reference vessel diameters (RVD) of 4 mm to 7 mm at US and OUS sites under IDE # G150121. Data from this clinical study were the basis for the PMA approval decision. A summary of the clinical study is presented below. ### A. Study Design Patients were treated between October 20, 2017 and August 17, 2019. The database for this PMA reflected data collected through November 13, 2020 and included 446 patients. There were 65 investigational sites, located in the United States, Australia, New Zealand, and Europe. The TRANSCEND Study is a global, prospective, multi-center, single-blind, randomized, controlled trial (RCT) to evaluate the noninferiority of the SurVeil DCB compared to the Medtronic IN.PACT Admiral DCB. Subjects with a stenosed femoral and/or popliteal artery were randomized in a 1:1 ratio to either the SurVeil or the IN.PACT Admiral DCB. ### 1. Clinical Inclusion and Exclusion Criteria Enrollment in the TRANSCEND study was limited to patients who met the following inclusion criteria: - Subject was ≥18 years of age. - Subject had target limb Rutherford classification 2, 3, or 4. PMA P210025: FDA Summary of Safety and Effectiveness Data Page 15 of 54 {15} - Subject provided written informed consent and was willing to comply with the study follow-up requirements. - De novo lesion(s) or non-stented restenotic lesion(s) occurring &gt;90 days after prior POBA or &gt;180 days after prior DCB treatment. - Target lesion started ≥10 mm below the common femoral bifurcation and terminated distally at or above the end of the P1 segment of the popliteal artery. - Target vessel diameter ≥4 mm and ≤7 mm. - Target lesion with angiographic evidence of ≥70% stenosis by operator visual estimate. - Chronic total occlusions were allowed only after successful, uncomplicated wire crossing of the target lesion via an anterograde approach. Successful crossing of the target lesion occurred when the tip of the guide wire was distal to the target lesion without the occurrence of flow-limiting dissection or perforation and was judged by visual inspection to be within the true lumen. Subintimal dissection techniques were allowed if re-entry occurred above the knee and without the use of re-entry devices. - Target lesion was ≤180 mm in length (one long lesion or multiple serial lesions) by operator visual estimate. - Target lesion was located at least 30 mm from any stent if target vessel was previously stented. - Successful, uncomplicated (without use of a crossing device) wire crossing of target lesion. Successful crossing of the target lesion occurred when the tip of the guide wire was distal to the target lesion without the occurrence of flow-limiting dissection or perforation and was judged by visual inspection to be within the true lumen. - After pre-dilatation, the target lesion had ≤70% residual stenosis, absence of a flow limiting dissection and treatable with available device matrix. - A patent inflow artery free from significant stenosis (≥50% stenosis) as confirmed by angiography. - At least one patent native outflow artery to the ankle or foot, free from significant stenosis (≥50% stenosis) as confirmed by angiography. Patients were not permitted to enroll in the TRANSCEND study if they met any of the following exclusion criteria: - Subject had acute limb ischemia. - Subject underwent intervention involving the target vessel within 90 days of enrollment. - Subject underwent any lower extremity percutaneous treatment in the ipsilateral limb using a paclitaxel-eluting stent or a DCB within 90 days of enrollment. - Subject underwent PTA of the target lesion using a DCB within 180 days of enrollment. - Subject had prior vascular intervention in the contralateral limb within 14 days before the planned index procedure or subject had planned vascular intervention in the contralateral limb within 30 days after the index PMA P210025: FDA Summary of Safety and Effectiveness Data Page 16 of 54 {16} procedure. - Women who were pregnant, breast-feeding or intended to become pregnant or men who intended to father children during the time of the study. - Subject had life expectancy of less than 2 years. - Subject had a known allergy to contrast medium that could not be adequately premedicated. - Subject was allergic to ALL antiplatelet treatments. - Subject had impaired renal function (i.e., serum creatinine level ≥2.5 mg/dL). - Subject was dialysis dependent. - Subject was receiving immunosuppressant therapy. - Subject had known or suspected active infection at the time of the index procedure. - Subject had platelet count &lt;100,000/mm³ or &gt;700,000/mm³. - Subject had history of gastrointestinal hemorrhage requiring a transfusion within 90 days prior to the index procedure. - Subject was diagnosed with coagulopathy that precluded treatment with systemic anticoagulation and/or DAPT. - Subject had history of stroke within 90 days of enrollment. - Subject had history of MI within 30 days of enrollment. - Subject was unable to tolerate blood transfusions because of religious beliefs or other reasons. - Subject was incarcerated, mentally incompetent, or abusing drugs or alcohol. - Subject was participating in another investigational drug or medical device study that had not completed primary endpoint(s) evaluation or that clinically interfered with the endpoints from this study, or subject was planning to participate in such studies prior to the completion of this study. - Subject had any major (e.g., cardiac, peripheral, abdominal) surgical procedure or intervention unrelated to this study within 30 days prior to the index procedure or had planned major surgical procedure or intervention within 30 days after the index procedure. - Subject had previous bypass surgery of the target lesion. - Subject had previous treatment of the target vessel with thrombolysis or surgery. - Subject was unwilling or unable to comply with procedures specified in the protocol or had difficulty or inability to return for follow-up visits as specified by the protocol. - Target lesion had severe calcification (as defined by the Peripheral Academic Research Consortium [PARC] classification of calcification). - Target lesion involved an aneurysm or was adjacent to an aneurysm (within 5 mm). - Target lesion required treatment with alternative therapy such as stenting, laser, atherectomy, cryoplasty, brachytherapy, or re-entry devices. - Significant target vessel tortuosity or other parameters prohibiting access to the target lesion. PMA P210025: FDA Summary of Safety and Effectiveness Data Page 17 of 54 {17} - Presence of thrombus in the target vessel. - Iliac inflow disease requiring treatment unless the iliac artery disease was successfully treated first during the index procedure. Success was defined as ≤30% residual diameter stenosis without death or major complications. - Presence of an aortic, iliac or femoral artificial graft. 2. Follow-up Schedule All patients were scheduled for follow-up examinations at 1 month, 6 months, 12 months, 2 years, 3 years, 4 years and 5 years postoperatively. Preoperatively, screening and baseline procedures and assessments were completed within 14 days of the index procedure. Table 8 below presents the study procedures and assessments performed at the respective time intervals in the study. PMA P210025: FDA Summary of Safety and Effectiveness Data Page 18 of 54 {18} Table 8: Schedule of Treatments and Assessments | Study Requirement (Visit Window) | Screening/Baseline (Within 14 Days Prior to Procedure) | Index Procedure to Discharge (Day 1) | 1 Month (30 -2 to +15 Days) | 6 Months (30 -2 to +15 Days) | 12 Months (365 ±30 Days) | 24 Months (730 ±60 Days) | 36 Months^{1} (1095 ±60 Days) | 48 Months^{1} (1460 ±60 Days) | 60 Months^{1} (1825 ±60 Days) | Unscheduled Visit(s)^{6} | | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | | Contact Type | Office Visit | | Office Visit | Office Visit | Office or Telephone Visit | Office or Telephone Visit | Telephone or Office Visit | Telephone or Office Visit | Telephone or Office Visit | Office Visit | | Informed Consent | X | | | | | | | | | | | Inclusion/Exclusion Criteria | X | X | | | | | | | | | | Medical History | X | | | | | | | | | | | Physical Exam^{2} | X | | X | X | X | X | | | | X | | Medications | X | X | X | X | X^{10} | X | X | X | X | X | | Target Limb Resting ABI (TBI if ABI can’t be assessed) | X^{3} | | | X | X | X | | | | X | | Rutherford Classification | X | | X | X | X^{10, 12} | 10, 12 | | | | X | | PARC Classification | X | | X | X | X^{10} | 10 | | | | X | | Pregnancy Test^{4} | X | | | | | | | | | | | CBC | X | | X | | | | | | | | | Comprehensive Metabolic Panel^{5} | X | | X | | | | | | | | | PAQ | X | | X | | X^{10} | 10 | | | | X | | WIQ | X | | X | | X^{10} | 10 | | | | X | | 6-MWT | X | | | | X | X | | | | X | | Angiogram | | X | | | | | | | | X^{7} | | Randomization | | X | | | | | | | | | PMA P210025: FDA Summary of Safety and Effectiveness Data {19} | Study Requirement (Visit Window) | Screening/Baseline (Within 14 Days Prior to Procedure) | Index Procedure to Discharge (Day 1) | 1 Month (30 -2 to +15 Days) | 6 Months (365 ±30 Days) | 12 Months (365 ±30 Days) | 24 Months (730 ±60 Days) | 36 Months1 (1095 ±60 Days) | 48 Months1 (1460 ±60 Days) | 60 Months1 (1825 ±60 Days) | Unscheduled Visit(s)6 | | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | | DUS | | | X8 | X | X9 | 9 | | | | X | | AE/SAE Collection11 | X | X | X | X | X10 | 10 | X | X | X | X | Abbreviations: 6-MWT, 6-minute walk test; ABI, ankle brachial index; AE, adverse event; CBC, complete blood count; DUS, duplex ultrasound; PAQ: peripheral artery questionnaire; PARC, Peripheral Academic Research Consortium; SAE, serious adverse event; TBI, toe brachial index; WIQ, walking impairment questionnaire. 1 The 36-, 48-, and 60-month visits may be conducted via a telephone call or at the clinic. 2 Physical exam (PE) included weight, height, blood pressure, target limb examination at Baseline/Screening. PE included exam of access site and target limb at the 1-month visit. PE includes clinical assessment of target limb at the 6-, 12-, and 24-month and unscheduled visits. 3 Target limb resting ABI or TBI could have been collected up to 90 days prior to the index procedure, provided that the subject had signed the informed consent form and that there was no change in the subject's clinical symptoms between the ABI/TBI assessment and the baseline visit. If there was a change in the subject's clinical symptoms, the target limb ABI/TBI should have been reassessed. 4 For women of childbearing potential only, per standard of care. 5 Comprehensive metabolic panel included kidney and liver function tests. 6 An unscheduled visit is defined as any visit for an ischemic event of the target limb. 7 Angiogram to be performed only if re-intervention is deemed necessary from clinical symptoms. 8 30-Day DUS was intended to establish a post-treatment baseline and help to inform the primary endpoint assessment. 9 A mobile DUS may be performed. 10 When conducting a telephone visit, these assessments will be performed. 11 All AEs (serious and non-serious) will be recorded for the entire study period to the extent required by national and/or local requirements. For US sites only: After the 12-month visit, ongoing AEs will be followed through to resolution or until the event becomes stable, and only SAEs, including Historical MAEs, and clinical study endpoints, will be recorded. 12 When conducting a telephone visit, target limb Rutherford classification without the use of treadmill may only be performed. If a treadmill had been previously used in the assessment, it must consistently be used throughout the study and therefore would require an office visit. PMA P210025: FDA Summary of Safety and Effectiveness Data {20} PMA P210025: FDA Summary of Safety and Effectiveness Data Page 21 of 54 ## 3. Clinical Endpoints ### Primary Safety Endpoint: The primary safety endpoint was a composite of freedom from device- and procedure-related death through 30 days post-index procedure and freedom from major target limb amputation (above the ankle) and clinically-driven target vessel revascularization (TVR) through 12 months post-index procedure. This effectiveness endpoint was designed to demonstrate that the 12 month safety for the SurVeil™ Drug-Coated Balloon is non-inferior to the Medtronic IN.PACT® Admiral® Drug-Coated Balloon. ### Primary Effectiveness Endpoint: The primary effectiveness endpoint was primary patency, defined as a composite of freedom from clinically-driven TLR and binary restenosis (restenosis defined as DUS peak systolic velocity ratio [PSVR] ≥2.4 or ≥50% stenosis as assessed by independent angiographic and DUS core labs) through 12 months post-index procedure. This effectiveness endpoint was designed to demonstrate that the 12 month primary patency for the SurVeil™ Drug-Coated Balloon is non-inferior to the Medtronic IN.PACT® Admiral® Drug-Coated Balloon. ### Secondary Endpoints: - Device Success: defined as successful delivery, balloon inflation, deflation and retrieval of the intact study device without burst below rated burst pressure, and achievement of &lt;50% residual stenosis of the target lesion (by core lab-assessed quantitative angiography [QA]) without flow-limiting arterial dissection using only the study device - Technical Success: defined as achievement of a final residual diameter stenosis of &lt;50% (by core lab-assessed QA) without flow-limiting arterial dissection at the end of the procedure - Procedure Success: defined as evidence of both acute technical success and absence of Peripheral Academic Research Consortium major adverse events (PARC MAEs; e.g., death, stroke, myocardial infarction, acute onset of limb ischemia, index bypass graft or treated segment thrombosis, and or need for urgent/emergent vascular surgery) within 72 hours of the index procedure - Freedom from all-cause death, major target limb amputation and TVR through 30 days - Primary patency through 24 months - Target vessel patency, defined as freedom from clinically-driven TVR and binary restenosis (restenosis defined as DUS PSVR ≥2.4 or ≥50% stenosis as assessed by independent angiographic and DUS core labs), within 12 and 24 months - Sustained clinical improvement, defined as freedom from major target limb amputation, TVR and worsening target limb Rutherford class, within 6, 12, and 24 months {21} $\bigcirc$ Clinically-driven TLR within 6, 12, 24, 36, 48, and 60 months $\bigcirc$ Historical major adverse events (Historical MAEs), defined as composite of all-cause death, clinically-driven TLR, major target limb amputation, or thrombosis at the target lesion within 6, 12, 24, 36, 48, and 60 months Major target-limb amputation within 6, 12, 24, 36, 48, and 60 months $\bigcirc$ Thrombosis at the target lesion within 6, 12, 24, 36, 48, and 60 months Change in target limb Rutherford class from baseline to 1, 6, 12, and 24 months Change in target limb PARC clinical symptom classification from baseline to 1, 6, 12, and 24 months Decrease in target limb resting ankle brachial index (ABI) or toe brachial index (TBI) $\geq 0.15$ from baseline to 6, 12, and 24 months Change in Walking Impairment Questionnaire (WIQ) score from baseline to 1, 12, and 24 months Change in 6-minute walk test (6-MWT) from baseline to 12 and 24 months Change in Peripheral Artery Questionnaire (PAQ) score from baseline to 1, 12, and 24 months With regard to success/failure criteria, the study was considered successful if both primary safety and effectiveness endpoints were met. # B. Accountability of PMA Cohort At the time of database snapshot on November 13, 2020, of 446 patients randomized in the PMA study, $89\%$ $(n = 398)$ patients were available for the primary endpoint analysis, the 12-month postoperative visit. Figure 4 displays the subject disposition at each follow-up visit for the RCT. ![img-3.jpeg](img-3.jpeg) PMA P210025: FDA Summary of Safety and Effectiveness Data {22} Figure 4: Subject Flow Chart through 12 Months ![img-4.jpeg](img-4.jpeg) 1 Includes one subject who died on day 366 post-procedure before completing the 12-month follow-up visit. 2 Difference between Subjects Active at Visit and Subjects Completed Visit is Follow-up Visit Not Done (see Table 9) ![img-5.jpeg](img-5.jpeg) Follow-up compliance through the 12-month follow-up visit is presented in Table 9 below. At the 12 month primary endpoint assessment visit, $87.9\%$ (174/198) of subjects in the SurVeil DCB group and $88.8\%$ (190/214) in the IN.PACT Admiral DCB group completed their visit within window. In the SurVeil DCB group, $7.6\%$ (15/198 of subjects completed their visits outside the visit window on average 24 days outside of the window (3 subjects completed the visit before the window opened and 12 completed the visit after the window closed). In the IN.PACT Admiral group, $8.9\%$ (19/214) of subjects completed their visit on average 50 days outside of the window (5 came in before the window opened and 14 completed their visit after the window had closed). A total of 398 of 412 eligible subjects $(96.6\%)$ completed their 12-month follow-up visit. Of them, 182 $(45.7\%)$ had their 12-month follow-up visit occur between 1 March 2020 and 30 August 2020; concurrent with the COVID-19 pandemic, which created challenges for completing timely in-person follow-up with study subjects. Of the 182 subjects that completed their 12-month follow-up visit during that 6-month time frame, 169 were within window and 13 were out of window (12 months $\pm 30$ days). Overall, visit compliance was complicated by a global pandemic; however, visit completion for the 12-month primary endpoint visit (both in- and out-of-window visits) was satisfactory for both groups. Table 9: Subject Follow-up Compliance at 12-Months PMA P210025: FDA Summary of Safety and Effectiveness Data {23} | | SurVeil DCB (N=222 Subjects) | IN.PACT Admiral DCB (N=224 Subjects) | | --- | --- | --- | | 1 Month | | | | Eligible Subjects^{1} | 215 | 224 | | Death^{2} | 1 | 0 | | Withdrawal^{2} | 6 | 0 | | Lost to follow-up^{2} | 0 | 0 | | Physician decision^{2} | 0 | 0 | | Follow-up Visit Within Window^{3} | 187 | 204 | | Follow-up Visit Out of Window^{3} | 23 | 17 | | Follow-up visit Not Done | 5 | 3 | | Follow-up Compliance (%)^{4} | 87.0% | 91.1% | | 6 Months | | | | Eligible Subjects^{1} | 209 | 223 | | Death^{2} | 4 | 1 | | Withdrawal^{2} | 9 | 0 | | Lost to follow-up^{2} | 0 | 0 | | Physician decision^{2} | 0 | 0 | | Follow-up Visit Within Window^{3} | 186 | 195 | | Follow-up Visit Out of Window^{3} | 10 | 19 | | Follow-up Visit Not Done | 13 | 9 | | Follow-up Compliance (%)^{4} | 89.0% | 87.4% | | 12 Months | | | | Eligible Subjects^{1} | 198 | 214 | | Death^{2} | 8 | 7 | | Withdrawal^{2} | 14 | 3 | | Lost to follow-up^{2} | 1 | 0 | | Physician decision^{2} | 1 | 0 | | Follow-up Visit Within Window^{3} | 174 | 190 | | Follow-up Visit Out of Window^{3} | 15 | 19 | | Follow-up Visit Not Done | 9 | 5 | | Follow-up Compliance (%)^{4} | 87.9% | 88.8% | 1 Eligible subjects are all subjects who either have a follow-up visit form or are past due for their follow-up (beyond the upper limit of window and did not exit the study before the upper limit of the window). 2 Death, withdrawal, lost to follow-up and physician decision are cumulative through the follow-up period. 3 Within window visits are defined as visits within Day 30 (-2 days/+15 days) for the 1-month visit, Day 180 (±30 days) for the 6-month visit and Day 365(±30 days) for the 12-month visit and include those subjects with a protocol deviation for a delayed in-office visit due to COVID-19. 4 Percentage is based on the number of subjects who had a follow-up visit within window divided by the total number of eligible subjects. C. Study Population Demographics and Baseline Parameters PMA P210025: FDA Summary of Safety and Effectiveness Data {24} The demographics of the study population are typical for a PAD study performed in the US. Table 10 provides a review of baseline demographics and medical history of the 446 subjects enrolled into the TRANSCEND study. Table 10: Baseline Demographics and Medical History – TRANSCEND RCT (N=446) | Patient Characteristics | SurVeil DCB (N=222 Subjects) | IN.PACT Admiral DCB (N=224 Subjects) | | --- | --- | --- | | Demographics | | | | Age (years) | | | | Mean ± SD (N) | 68.7±9.4 (222) | 67.4±9.3 (224) | | Median (Q1,Q3) | 69.0 (62.0,76.0) | 67.0 (60.0,74.0) | | Range (Min,Max) | (44.0,93.0) | (38.0,99.0) | | Male | 62.6% (139/222) | 63.4% (142/224) | | Race | | | | White | 86.0% 191/222 | 88.8% 199/224 | | Black or African American | 10.4% (23/222) | 9.4% (21/224) | | Asian | 0.5% (1/222) | 0.4% (1/224) | | Native Hawaiian or Other Pacific Islander | 0.0% (0/222) | 0.0% (0/224) | | American Indian or Alaska Native | 0.5% (1/222) | 0.0% (0/224) | | Other | 0.5% (1/222) | 0.9% (2/224) | | Not Answered | 2.3% (5/222) | 0.4% (1/224) | | Ethnicity | | | | Hispanic or Latino | 2.7% (6/222) | 3.1% (7/224) | | Not Hispanic or Latino | 95.5% (212/222) | 96.4% (216/224) | | Not Answered | 1.8% 4/222) | 0.4% (1/224) | | Medical History | | | | Smoking Status | | | | Current Smoker | 41.9% (93/222) | 37.9% 85/224 | | Former Smoker | 42.8% 95/222 | 46.0% (103/224) | | Never Smoked | 15.3% (34/222) | 16.1% (36/224) | | Diabetes Mellitus | 41.4% (92/222) | 40.2% (90/224) | | Diabetes Control Method | | | | No Treatment | 1.1% (1/92) | 1.1% (1/90) | | Diet and/or Exercise Only | 7.6% (7/92) | 2.2% (2/90) | | Oral or Other Non-Insulin Therapies | 51.1% (47/92) | 58.9% 53/90) | | Requiring Insulin | 40.2% (37/92) | 37.8% 34/90) | | Rutherford Classification at Baseline | | | | 2 - Moderate claudication | 21.6% 48/222 | 34.4% (77/224) | | 3 - Severe claudication | 75.7% 168/222 | 61.2% (137/224) | | 4 - Ischemic rest pain | 2.7% (6/222) | 4.5% (10/224) | | Hypertension | 91.4% (203/222) | 87.9% 197/224 | | Hypercholesterolemia | 86.5% 192/222 | 86.6% 194/224 | | Chronic Angina | 6.8% 15/221) | 7.2% (16/223) | PMA P210025: FDA Summary of Safety and Effectiveness Data {25} Table 11 presents the baseline lesion characteristics, procedural characteristics, and post procedure measurements for the TRANSCEND study. Table 11: Angiographic Core Lab Baseline, Procedural, Post-procedure Reported Lesion Characteristics | Characteristics | SurVeil DCB (N=222 Subjects L=222 Lesions) | IN.PACT Admiral DCB (N=224 Subjects L=224 Lesions) | | --- | --- | --- | | Pre-Procedure Morphology | | | | Vessel Location | | | | SFA | | | | Proximal | 11.8% 26/221 | 9.9% (22/223) | | Mid | 40.3% 89/221 | 40.4% (90/223) | | Distal | 42.5% (94/221) | 41.3% (92/223) | | Ostial | 0.0% (0/221) | 1.8% 4/223) | | Popliteal | | | | Proximal | 3.6% 8/221) | 5.4% (12/223) | | Mid | 1.8% 4/221) | 0.9% (2/223) | | Distal | 0.0% (0/221) | 0.0% (0/223) | | Ostial | 0.0% (0/221) | 0.0% (0/223) | PMA P210025: FDA Summary of Safety and Effectiveness Data {26} | Characteristics | SurVeil DCB (N=222 Subjects L=222 Lesions) | IN.PACT Admiral DCB (N=224 Subjects L=224 Lesions) | | --- | --- | --- | | Distal | 0.0% (0/221) | 0.4% (1/223) | | Lesion Length (mm) | | | | Mean ± SD (N) | 72.5±48.4 (221) | 70.0±50.5 (223) | | Median (Q1,Q3) | 60.6 (33.1,99.0) | 55.7 (28.2,99.0) | | Range (Min,Max) | (10.5,215.0) | (9.8,232.8) | | Eccentric | 21.7% 48/221 | 25.1% (56/223) | | Bend | | | | <45 degrees | 100.0% (221/221) | 100.0% (223/223) | | ≥45 degrees to <90 degrees | 0.0% (0/221) | 0.0% (0/223) | | ≥90 degrees | 0.0% (0/221) | 0.0% (0/223) | | Thrombus | 0.0% (0/221) | 0.4% (1/223)1 | | Calcification | | | | None/Mild | 50.7% (112/221) | 48.0% (107/223) | | Moderate | 36.2% 80/221 | 41.3% (92/223) | | Severe | 13.1% (29/221) | 10.8% 24/223 | | Ulcerated | 7.7% (17/221) | 5.4% (12/223) | | Aneurysm | 0.0% (0/221) | 0.0% (0/223) | | Ectasia | 5.0% (11/221) | 4.5% (10/223) | | Blood Flow | | | | Normal | 73.8% 163/221 | 72.2% (161/223) | | Decreased | 3.6% 8/221) | 2.7% (6/223) | | No Flow | 22.6% (50/221) | 25.1% (56/223) | | Collaterals | 24.0% (53/221) | 27.8% 62/223 | | Collateral Grade | | | | 1-Minimal | 1.9% (1/53) | 1.6% (1/62) | | 2-Moderate | 22.6% (12/53) | 33.9% (21/62) | | 3-Good | 75.5% (40/53) | 64.5% (40/62) | | Occluded2 | 22.2% (49/221) | 26.5% (59/223) | | Pre-Procedure Quantitative Vascular Angiography | | | | Reference Vessel Diameter (RVD) (mm)3 | | | | Mean ± SD (N) | 5.3±0.9 (221) | 5.3±0.7 (223) | | Median (Q1,Q3) | 5.2 (4.6,5.8) | 5.2 (4.7,5.8) | | Range (Min,Max) | 3.2,8.4 | (3.7,8.4) | | Minimum Lumen Diameter (MLD) (mm)4 | | | | Mean ± SD (N) | 1.4±1.1 (221) | 1.3±1.0 (223) | | Median (Q1,Q3) | 1.5 (0.5,2.2) | 1.3 (0.0,2.0) | | Range (Min,Max) | (0.0,4.4) | (0.0,4.3) | | Diameter Stenosis (%)5 | | | | Mean ± SD (N) | 72.9±18.8 (221) | 75.8±18.1 (223) | | Median (Q1,Q3) | 71.1 (58.0,87.5) | 74.4 (60.5,100.0) | | Range (Min,Max) | (22.0,100.0) | (31.2,100.0) | PMA P210025: FDA Summary of Safety and Effectiveness Data {27} PMA P210025: FDA Summary of Safety and Effectiveness Data Page 28 of 54 | Characteristics | SurVeil DCB (N=222 Subjects L=222 Lesions) | IN.PACT Admiral DCB (N=224 Subjects L=224 Lesions) | | --- | --- | --- | | **Post-Procedure** | | | | Thrombus | 0.0% (0/217) | 0.0% (0/223) | | Spasm | 0.0% (0/217) | 0.0% (0/223) | | Abrupt Closure | 0.0% (0/217) | 0.0% (0/223) | | No Reflow | 0.0% (0/217) | 0.0% (0/223) | | Distal Embolization | 0.0% (0/217) | 0.0% (0/222) | | Perforation | | | | 0 | 100.0% (217/217) | 100.0% (223/223) | | I | 0.0% (0/217) | 0.0% (0/223) | | II | 0.0% (0/217) | 0.0% (0/223) | | III | 0.0% (0/217) | 0.0% (0/223) | | Blood Flow | | | | Normal | 100.0% (217/217) | 100.0% (223/223) | | Decreased | 0.0% (0/217) | 0.0% (0/223) | | No Flow | 0.0% (0/217) | 0.0% (0/223) | | Dissection | | | | None | 41.9% (91/217) | 48.0% 107/223 | | A | 11.5% (25/217) | 11.2% (25/223) | | B | 24.9% (54/217) | 25.1% (56/223) | | C | 17.1% (37/217) | 11.2% (25/223) | | D | 4.6% (10/217) | 4.5% (10/223) | | E | 0.0% (0/217) | 0.0% (0/223) | | F | 0.0% (0/217) | 0.0% (0/223) | | Staining | 0.0% (0/215) | 0.0% (0/222) | | **Post-Procedure Quantitative Vascular Angiography** | | | | RVD (mm)^{1} | | | | Mean ± SD (N) | 5.3±0.9 (217) | 5.3±0.8 (223) | | Median (Q1,Q3) | 5.3 (4.7,5.9) | 5.3 (4.8,5.8) | | Range (Min,Max) | 3.4,8.4 | (3.7,8.4 | | MLD (mm)^{2} | | | | Mean ± SD (N) | 4.3±0.8 (217) | 4.3±0.7 (223) | | Median (Q1,Q3) | 4.3 (3.9,4.8) | 4.2 (3.8,4.8) | | Range (Min,Max) | (2.5,6.6) | (2.6,6.9) | | Diameter Stenosis (%)^{3} | | | | Mean ± SD (N) | 18.7±9.6 (217) | 18.9±9.3 (223) | | Median (Q1,Q3) | 17.9 (11.4,25.6) | 18.8 (13.1,24.7 | | Range (Min,Max) | (-1.6,45.0) | (-3.5,47.1) | | **Procedural Characteristics** | | | | Pre-dilatation Performed | 100.0% (222/222) | 100.0% (224/224) | | Post-dilatation Performed | 18.0% 40/222^{6} | 17.4% (39/224) | | Bailout Stenting Performed | 8.1% 18/222) | 6.7% (15/224) | {28} | Characteristics | SurVeil DCB (N=222 Subjects L=222 Lesions) | IN.PACT Admiral DCB (N=224 Subjects L=224 Lesions) | | --- | --- | --- | | Device Success7 | 92.1% (199/216) | 93.7% 208/222 | | Technical Success8 | 100.0% (217/217) | 100.0% (223/223) | | Procedure Success9 | 99.5% 217/218 | 99.6% (222/223) | 1 Per the angiographic core laboratory, subject 115-009 had thrombus in the target vessel. 2 Occluded was defined as 100% diameter stenosis. $^{3}$ RVD was calculated as the average of the distal and proximal user-defined target lesion normal references from 2 projections. 4 MLD is based on the average of 2 projections. 5 Percent diameter stenosis was calculated as follows: (1-minimum lumen diameter/RVD ×100. $^{6}$ SurVeil DCB subject 117-019 had post-dilatation performed using 2 post dilatation balloons. 7 Device Success: defined as successful delivery, balloon inflation, deflation and retrieval of the intact study device without burst below rated burst pressure, and achievement of &lt;50% residual stenosis of the target lesion (by core lab-assessed QA) without flow-limiting arterial dissection, using only the study device. 8 Technical Success: defined as achievement of a final residual diameter stenosis of &lt;50% without flow-limiting arterial dissection at the end of the procedure. 9 Procedure Success: defined as evidence of both acute technical success and absence of PARC MAEs (e.g., death, stroke, myocardial infarction, acute onset of limb ischemia, index bypass graft or treated segment thrombosis, and or need for urgent/ emergent vascular surgery) within 72 hours of the index procedure. # D. Safety and Effectiveness Results # 1. Safety Results The analysis of safety was based on the ITT full study cohort of 222 SurVeil DCB subjects and 224 IN.PACT Admiral DCB subjects available for the 12- month evaluation. Table 12 presents the primary safety results for the full study cohort. The SurVeil™ Drug-Coated Balloon was concluded to be non-inferior to the IN.PACT® Admiral® Drug-Coated Balloon for the primary safety endpoint if the one-sided lower $97.5\%$ confidence bound on the difference between groups (SurVeil DCB vs. IN.PACT DCB) in is less than $10\%$ (non-inferiority margin). In the ITT group, using multiple imputation, the rate of the primary safety endpoint was $91.7\%$ in the Surveil DCB group compared to $89.6\%$ in the IN.PACT Admiral DCB group. The difference in rates between the groups was $2.1\%$ with one-sided lower $97.5\%$ CL of $-4.0\%$ . Since this is higher than the pre-specified noninferiority margin of $-10.0\%$ , noninferiority is met (P-value for noninferiority $&lt; 0.0001$ ) and the SurVeil DCB is declared noninferior to the IN.PACT Admiral DCB with regards to the primary safety endpoint. A complete case analysis was carried out as a sensitivity analysis on ITT subjects with available data (i.e., subjects who experienced the primary safety composite or had at least 335 days of follow-up) and provided similar results. Kaplan-Meier plot of primary safety through 395 days is presented in Figure 5. Table 12: Primary Safety - Full Cohort, Intent-to-Treat (N=446) PMA P210025: FDA Summary of Safety and Effectiveness Data {29} | Primary Safety Endpoint | SurVeil DCB (N=222 Subjects) | IN.PACT Admiral DCB (N=224 Subjects) | Difference [One-sided Lower 97.5% CL] | Non-inferiority Test P-value1 | | --- | --- | --- | --- | --- | | Composite of freedom from device- and procedure-related death through 30 days and freedom from major target limb amputation and clinically-driven TVR through 12 months (ITT - Multiple Imputations) | 91.7% (87.9%,95.5%) | 89.6% (85.5%,93.7%) | 2.1% [-4.0%] | <0.0001 | | Composite of freedom from device- and procedure-related death through 30 days and freedom from major target limb amputation and clinically-driven TVR through 12 months (ITT - Complete Case) | 92.0% (183/199) | 89.9% (195/217) | 2.1% [-4.0%] | <0.0001 | | Freedom from device- and procedure-related death through 30 days2 | 99.5% (217/218) | 100.0% (223/223) | | | | Freedom from clinically-driven TVR through 12 months3 | 92.4% (183/198) | 89.9% (195/217) | | | | Freedom from major target limb amputation through 12 months4 | 100.0% (196/196) | 100.0% (215/215) | | | | 1 P-value is derived from one-sided Farrington-Manning test with noninferiority margin of 10% and a one-sided significance level of 0.025.2 Denominators include subjects with at least 28 days of follow-up or subjects experiencing device- or procedure-related death through 30 days.3 Denominators include subjects with at least 335 days of follow-up or subjects experiencing clinically-driven TVR through 365 days.4 Denominators include subjects with at least 335 days of follow-up or subjects experiencing target limb amputation through 365 days. | | | | | | Primary Safety Endpoint | 0 | [1, 90] | [91, 180] | [181, 270] | [271, 365] | | --- | --- | --- | --- | --- | --- | | SurVeil DCB (N=222 Subjects) | | | | | | | # Entered | 222 | 222 | 209 | 202 | 193 | | # Censored | 0 | 9 | 5 | 5 | 53 | | # Events | 0 | 4 | 2 | 4 | 6 | | Event-free [%] | 100.0% | 98.1% | 97.2% | 95.2% | 92.0% | | Greenwood SE [%] | 0.0% | 0.9% | 1.1% | 1.5% | 1.9% | | IN.PACT Admiral DCB (N=224 Subjects) | | | | | | | # Entered | 224 | 223 | 220 | 217 | 209 | | # Censored | 1 | 1 | 1 | 1 | 48 | | # Events | 0 | 2 | 2 | 7 | 11 | | Event-free [%] | 100.0% | 99.1% | 98.2% | 95.0% | 89.9% | | Greenwood SE [%] | 0.0% | 0.6% | 0.9% | 1.5% | 2.0% | | Tests Between Groups | Test | Chi-Square | Degree of Freedom | P-value | | | | Log-Rank | 0.5455 | 1 | 0.460 | | Note: The p-value should be interpreted with caution because a hypothesis test for the survival endpoint was not pre-specified and was not adjusted for multiplicity PMA P210025: FDA Summary of Safety and Effectiveness Data {30} ![img-6.jpeg](img-6.jpeg) Figure 5: Kaplan-Meier Curve for the Primary Safety Endpoint to 12 Months - ITT Analysis Population (N=446) # Adverse effects that occurred in the PMA clinical study: Table 13 displays the rates of site reported Serious Adverse Events (SAEs) classified by the MedDRA System Organ Class (SOC) and preferred term. An SAE was defined as an adverse event that leads to: 1. Death 2. A serious deterioration in the health of the subject that either results in: a. life-threatening illness or injury or b. a permanent impairment of a body structure or a body function or c. in-patient hospitalization or prolongation of existing hospitalization or d. medical or surgical intervention to prevent life-threatening illness or injury or permanent impairment to a body structure or a body function 3. Fetal distress, fetal death, or congenital abnormality or birth defect. PMA P210025: FDA Summary of Safety and Effectiveness Data {31} Table 13: Summary of All Site-Reported Serious Adverse Events through 12 Months – ITT Analysis Population (N=446) | Serious Adverse Events | SurVeil DCB (N=222 Subjects) | | IN.PACT Admiral DCB (N=224 Subjects) | | | --- | --- | --- | --- | --- | | | Events | Rate of Subjects with Event | Events | Rate of Subjects with Event | | Any Serious Adverse Event | 176 | 44.6% (99/222) | 193 | 37.9% (85/224) | | Blood and lymphatic system disorders | 6 | 2.7% (6/222) | 1 | 0.4% (1/224) | | Anaemia | 2 | 0.9% (2/222) | 1 | 0.4% (1/224) | | Haemorrhagic anaemia | 3 | 1.4% (3/222) | 0 | 0.0% (0/224) | | Microcytic anaemia | 1 | 0.5% (1/222) | 0 | 0.0% (0/224) | | Cardiac disorders | 27 | 9.5% (21/222) | 31 | 10.7% (24/224) | | Acute myocardial infarction | 5 | 2.3% (5/222) | 7 | 3.1% (7/224) | | Angina pectoris | 4 | 1.8% 4/222) | 2 | 0.9% (2/224) | | Angina unstable | 2 | 0.9% (2/222) | 1 | 0.4% (1/224) | | Aortic valve stenosis | 0 | 0.0% (0/222) | 1 | 0.4% (1/224) | | Atrial fibrillation | 1 | 0.5% (1/222) | 1 | 0.4% (1/224) | | Atrial flutter | 1 | 0.5% (1/222) | 1 | 0.4% (1/224) | | Atrioventricular block | 0 | 0.0% (0/222) | 1 | 0.4% (1/224) | | Atrioventricular block second degree | 0 | 0.0% (0/222) | 2 | 0.9% (2/224) | | Cardiac arrest | 1 | 0.5% (1/222) | 2 | 0.9% (2/224) | | Cardiac failure | 0 | 0.0% (0/222) | 1 | 0.4% (1/224) | | Cardiac failure acute | 0 | 0.0% (0/222) | 1 | 0.4% (1/224) | | Cardiac failure congestive | 8 | 1.8% 4/222) | 3 | 1.3% (3/224) | | Coronary artery disease | 1 | 0.5% (1/222) | 3 | 0.4% (1/224) | | Coronary artery occlusion | 0 | 0.0% (0/222) | 1 | 0.4% (1/224) | | Coronary artery stenosis | 2 | 0.9% (2/222) | 1 | 0.4% (1/224) | | Myocardial ischaemia | 1 | 0.5% (1/222) | 0 | 0.0% (0/224) | | Sinus node dysfunction | 0 | 0.0% (0/222) | 1 | 0.4% (1/224) | | Ventricular extrasystoles | 1 | 0.5% (1/222) | 0 | 0.0% (0/224) | | Ventricular fibrillation | 0 | 0.0% (0/222) | 2 | 0.9% (2/224) | | Eye disorders | 2 | 0.9% (2/222) | 1 | 0.4% (1/224) | | Glaucoma | 1 | 0.5% (1/222) | 0 | 0.0% (0/224) | | Retinal artery occlusion | 0 | 0.0% (0/222) | 1 | 0.4% (1/224) | | Vitreous haemorrhage | 1 | 0.5% (1/222) | 0 | 0.0% (0/224) | | Gastrointestinal disorders | 7 | 2.3% (5/222) | 10 | 4.0% (9/224) | | Abdominal hernia | 1 | 0.5% (1/222) | 0 | 0.0% (0/224) | | Barrett's oesophagus | 0 | 0.0% (0/222) | 1 | 0.4% (1/224) | | Dysphagia | 0 | 0.0% (0/222) | 1 | 0.4% (1/224) | PMA P210025: FDA Summary of Safety and Effectiveness Data Page 32 of 54 {32} PMA P210025: FDA Summary of Safety and Effectiveness Data Page 33 of 54 | Serious Adverse Events | SurVeil DCB (N=222 Subjects) | | IN.PACT Admiral DCB (N=224 Subjects) | | | --- | --- | --- | --- | --- | | | Events | Rate of Subjects with Event | Events | Rate of Subjects with Event | | Gastric ulcer haemorrhage | 0 | 0.0% (0/222) | 1 | 0.4% (1/224) | | Gastritis | 0 | 0.0% (0/222) | 1 | 0.4% (1/224) | | Gastrointestinal haemorrhage | 3 | 0.9% (2/222) | 1 | 0.4% (1/224) | | Inguinal hernia | 0 | 0.0% (0/222) | 1 | 0.4% (1/224) | | Intestinal obstruction | 1 | 0.5% (1/222) | 0 | 0.0% (0/224) | | Lower gastrointestinal haemorrhage | 0 | 0.0% (0/222) | 1 | 0.4% (1/224) | | Nausea | 0 | 0.0% (0/222) | 1 | 0.4% (1/224) | | Retroperitoneal fibrosis | 1 | 0.5% (1/222) | 0 | 0.0% (0/224) | | Umbilical hernia | 1 | 0.5% (1/222) | 1 | 0.4% (1/224) | | Vomiting | 0 | 0.0% (0/222) | 1 | 0.4% (1/224) | | General disorders and administration site conditions | 12 | 5.0% (11/222) | 7 | 2.7% (6/224) | | Catheter site discharge | 2 | 0.9% (2/222) | 0 | 0.0% (0/224) | | Catheter site haematoma | 3 | 1.4% (3/222) | 0 | 0.0% (0/224) | | Catheter site haemorrhage | 0 | 0.0% (0/222) | 1 | 0.4% (1/224) | | Death | 1 | 0.5% (1/222)^{1} | 0 | 0.0% (0/224) | | Drug withdrawal syndrome | 1 | 0.5% (1/222) | 0 | 0.0% (0/224) | | Fatigue | 0 | 0.0% (0/222) | 1 | 0.4% (1/224) | | Non-cardiac chest pain | 3 | 1.4% (3/222) | 2 | 0.4% (1/224) | | Pyrexia | 0 | 0.0% (0/222) | 1 | 0.4% (1/224) | | Vascular stent occlusion | 1 | 0.5% (1/222) | 1 | 0.4% (1/224) | | Vascular stent restenosis | 1 | 0.5% (1/222) | 1 | 0.4% (1/224) | | Hepatobiliary disorders | 1 | 0.5% (1/222) | 0 | 0.0% (0/224) | | Cholelithiasis | 1 | 0.5% (1/222) | 0 | 0.0% (0/224) | | Immune system disorders | 1 | 0.5% (1/222) | 1 | 0.4% (1/224) | | Anaphylactic reaction | 1 | 0.5% (1/222) | 1 | 0.4% (1/224) | | Infections and infestations | 16 | 6.3% (14/222) | 24 | 5.8% (13/224) | | Bronchitis | 0 | 0.0% (0/222) | 2 | 0.4% (1/224) | | Bronchitis bacterial | 0 | 0.0% (0/222) | 1 | 0.4% (1/224) | | Cellulitis | 1 | 0.5% (1/222) | 0 | 0.0% (0/224) | | Diverticulitis | 0 | 0.0% (0/222) | 1 | 0.4% (1/224) | | Endocarditis bacterial | 0 | 0.0% (0/222) | 1 | 0.4% (1/224) | | Enterococcal bacteraemia | 0 | 0.0% (0/222) | 1 | 0.4% (1/224) | | Epididymitis | 1 | 0.5% (1/222) | 0 | 0.0% (0/224) | | Gastroenteritis | 0 | 0.0% (0/222) | 1 | 0.4% (1/224) | | Infected skin ulcer | 0 | 0.0% (0/222) | 1 | 0.4% (1/224) | | Infection | 1 | 0.5% (1/222) | 0 | 0.0% (0/224) | {33} PMA P210025: FDA Summary of Safety and Effectiveness Data Page 34 of 54 | Serious Adverse Events | SurVeil DCB (N=222 Subjects) | | IN.PACT Admiral DCB (N=224 Subjects) | | | --- | --- | --- | --- | --- | | | Events | Rate of Subjects with Event | Events | Rate of Subjects with Event | | Infective exacerbation of chronic obstructive airways disease | 0 | 0.0% (0/222) | 1 | 0.4% (1/224) | | Influenza | 0 | 0.0% (0/222) | 1 | 0.4% (1/224) | | Localized infection | 0 | 0.0% (0/222) | 1 | 0.4% (1/224) | | Lung infection | 1 | 0.5% (1/222) | 0 | 0.0% (0/224) | | Osteomyelitis | 0 | 0.0% (0/222) | 1 | 0.4% (1/224) | | Pneumonia | 6 | 2.7% (6/222) | 8 | 2.7% (6/224) | | Postoperative wound infection | 1 | 0.5% (1/222) | 0 | 0.0% (0/224) | | Pyelonephritis | 1 | 0.5% (1/222) | 0 | 0.0% (0/224) | | Pyelonephritis acute | 1 | 0.5% (1/222) | 0 | 0.0% (0/224) | | Sepsis | 1 | 0.5% (1/222) | 2 | 0.9% (2/224) | | Septic shock | 0 | 0.0% (0/222) | 1 | 0.4% (1/224) | | Staphylococcal infection | 1 | 0.5% (1/222) | 0 | 0.0% (0/224) | | Urinary tract infection | 1 | 0.5% (1/222) | 0 | 0.0% (0/224) | | Wound infection | 0 | 0.0% (0/222) | 1 | 0.4% (1/224) | | Injury, poisoning and procedural complications | 22 | 9.0% (20/222) | 16 | 6.7% (15/224) | | Ankle fracture | 2 | 0.9% (2/222) | 0 | 0.0% (0/224) | | Arterial bypass thrombosis | 0 | 0.0% (0/222) | 1 | 0.4% (1/224) | | Femoral neck fracture | 1 | 0.5% (1/222) | 2 | 0.9% (2/224) | | Hip fracture | 1 | 0.5% (1/222) | 0 | 0.0% (0/224) | | Meniscus injury | 0 | 0.0% (0/222) | 1 | 0.4% (1/224) | | Overdose | 1 | 0.5% (1/222) | 0 | 0.0% (0/224) | | Peripheral artery restenosis | 9 | 3.6% 8/222) | 6 | 2.2% (5/224) | | Procedural hypotension | 1 | 0.5% (1/222) | 0 | 0.0% (0/224) | | Pubis fracture | 0 | 0.0% (0/222) | 1 | 0.4% (1/224) | | Rib fracture | 1 | 0.5% (1/222) | 0 | 0.0% (0/224) | | Scar | 0 | 0.0% (0/222) | 1 | 0.4% (1/224) | | Spinal compression fracture | 0 | 0.0% (0/222) | 1 | 0.4% (1/224) | | Transplant failure | 0 | 0.0% (0/222) | 1 | 0.4% (1/224) | | Upper limb fracture | 1 | 0.5% (1/222) | 0 | 0.0% (0/224) | | Vascular access site pseudoaneurysm | 3 | 1.4% (3/222) | 2 | 0.9% (2/224) | | Vascular pseudoaneurysm | 2 | 0.9% (2/222) | 0 | 0.0% (0/224) | | Investigations | 0 | 0.0% (0/222) | 1 | 0.4% (1/224) | | Blood pressure systolic increased | 0 | 0.0% (0/222) | 1 | 0.4% (1/224) | | Metabolism and nutrition disorders | 2 | 0.9% (2/222) | 3 | 0.4% (1/224) | | Dehydration | 0 | 0.0% (0/222) | 2 | 0.4% (1/224) | | Hyperkalaemia | 0 | 0.0% (0/222) | 1 | 0.4% (1/224) | {34} PMA P210025: FDA Summary of Safety and Effectiveness Data Page 35 of 54 | Serious Adverse Events | SurVeil DCB (N=222 Subjects) | | IN.PACT Admiral DCB (N=224 Subjects) | | | --- | --- | --- | --- | --- | | | Events | Rate of Subjects with Event | Events | Rate of Subjects with Event | | Hyperlipidaemia | 1 | 0.5% (1/222) | 0 | 0.0% (0/224) | | Hypoglycaemia | 1 | 0.5% (1/222) | 0 | 0.0% (0/224) | | **Musculoskeletal and connective tissue disorders** | **7** | **3.2%** (7/222) | **11** | **4.9%** (11/224) | | Arthralgia | 1 | 0.5% (1/222) | 0 | 0.0% (0/224) | | Back disorder | 0 | 0.0% (0/222) | 1 | 0.4% (1/224) | | Back pain | 0 | 0.0% (0/222) | 1 | 0.4% (1/224) | | Compartment syndrome | 0 | 0.0% (0/222) | 1 | 0.4% (1/224) | | Dupuytren's contracture | 1 | 0.5% (1/222) | 0 | 0.0% (0/224) | | Haemarthrosis | 0 | 0.0% (0/222) | 1 | 0.4% (1/224) | | Intervertebral disc protrusion | 1 | 0.5% (1/222) | 0 | 0.0% (0/224) | | Lumbar spinal stenosis | 1 | 0.5% (1/222) | 2 | 0.9% (2/224) | | Muscle spasms | 1 | 0.5% (1/222) | 0 | 0.0% (0/224) | | Osteoarthritis | 0 | 0.0% (0/222) | 1 | 0.4% (1/224) | | Pain in extremity | 1 | 0.5% (1/222) | 2 | 0.9% (2/224) | | Rotator cuff syndrome | 0 | 0.0% (0/222) | 1 | 0.4% (1/224) | | Spinal osteoarthritis | 1 | 0.5% (1/222) | 0 | 0.0% (0/224) | | Spondylolysis | 0 | 0.0% (0/222) | 1 | 0.4% (1/224) | | **Neoplasms benign, malignant and unspecified (incl cysts and polyps)** | **4** | **1.8%** (4/222) | **6** | **2.7%** (6/224) | | Carcinoid tumour of the small bowel | 0 | 0.0% (0/222) | 1 | 0.4% (1/224) | | Cholesteatoma | 1 | 0.5% (1/222) | 0 | 0.0% (0/224) | | Gastroesophageal cancer | 0 | 0.0% (0/222) | 1 | 0.4% (1/224) | | Laryngeal cancer metastatic | 0 | 0.0% (0/222) | 1 | 0.4% (1/224) | | Lung neoplasm malignant | 1 | 0.5% (1/222) | 0 | 0.0% (0/224) | | Neoplasm skin | 0 | 0.0% (0/222) | 1 | 0.4% (1/224) | | Papillary thyroid cancer | 0 | 0.0% (0/222) | 1 | 0.4% (1/224) | | Salivary gland neoplasm | 1 | 0.5% (1/222) | 0 | 0.0% (0/224) | | Squamous cell carcinoma | 1 | 0.5% (1/222) | 0 | 0.0% (0/224) | | Squamous cell carcinoma of lung | 0 | 0.0% (0/222) | 1 | 0.4% (1/224) | | **Nervous system disorders** | **8** | **3.2%** (7/222) | **10** | **4.0%** (9/224) | | Carotid artery stenosis | 1 | 0.5% (1/222) | 2 | 0.9% (2/224) | | Cerebrovascular accident | 0 | 0.0% (0/222) | 1 | 0.4% (1/224) | | Embolic stroke | 1 | 0.5% (1/222) | 1 | 0.4% (1/224) | | Encephalopathy | 0 | 0.0% (0/222) | 2 | 0.9% (2/224) | | Epidural lipomatosis | 1 | 0.5% (1/222) | 0 | 0.0% (0/224) | | Haemorrhagic stroke | 1 | 0.5% (1/222) | 0 | 0.0% (0/224) | | Metabolic encephalopathy | 0 | 0.0% (0/222) | 3 | 1.3% (3/224) | {35} PMA P210025: FDA Summary of Safety and Effectiveness Data Page 36 of 54 | Serious Adverse Events | SurVeil DCB (N=222 Subjects) | | IN.PACT Admiral DCB (N=224 Subjects) | | | --- | --- | --- | --- | --- | | | Events | Rate of Subjects with Event | Events | Rate of Subjects with Event | | Post herpetic neuralgia | 1 | 0.5% (1/222) | 0 | 0.0% (0/224) | | Presyncope | 1 | 0.5% (1/222) | 1 | 0.4% (1/224) | | Syncope | 1 | 0.5% (1/222) | 0 | 0.0% (0/224) | | Transient ischaemic attack | 1 | 0.5% (1/222) | 0 | 0.0% (0/224) | | **Product issues** | **0** | **0.0%** (0/222) | **1** | **0.4%** (1/224) | | Device malfunction | 0 | 0.0% (0/222) | 1 | 0.4% (1/224) | | **Psychiatric disorders** | **0** | **0.0%** (0/222) | **2** | **0.9%** (2/224) | | Completed suicide | 0 | 0.0% (0/222) | 1 | 0.4% (1/224) | | Mental disorder | 0 | 0.0% (0/222) | 1 | 0.4% (1/224) | | **Renal and urinary disorders** | **3** | **1.4%** (3/222) | **4** | **1.8%** (4/224) | | Acute kidney injury | 1 | 0.5% (1/222) | 3 | 1.3% (3/224) | | Chronic kidney disease | 0 | 0.0% (0/222) | 1 | 0.4% (1/224) | | Nephrolithiasis | 1 | 0.5% (1/222) | 0 | 0.0% (0/224) | | Renal mass | 1 | 0.5% (1/222) | 0 | 0.0% (0/224) | | **Reproductive system and breast disorders** | **1** | **0.5%** (1/222) | **1** | **0.4%** (1/224) | | Genital erosion | 1 | 0.5% (1/222) | 0 | 0.0% (0/224) | | Vaginal prolapse | 0 | 0.0% (0/222) | 1 | 0.4% (1/224) | | **Respiratory, thoracic and mediastinal disorders** | **3** | **1.4%** (3/222) | **17** | **4.0%** (9/224) | | Acute respiratory failure | 0 | 0.0% (0/222) | 3 | 1.3% (3/224) | | Aspiration | 1 | 0.5% (1/222) | 0 | 0.0% (0/224) | | Chronic obstructive pulmonary disease | 1 | 0.5% (1/222) | 4 | 0.4% (1/224) | | Dyspnoea | 1 | 0.5% (1/222) | 1 | 0.4% (1/224) | | Emphysema | 0 | 0.0% (0/222) | 1 | 0.4% (1/224) | | Epistaxis | 0 | 0.0% (0/222) | 2 | 0.4% (1/224) | | Hypoxia | 0 | 0.0% (0/222) | 1 | 0.4% (1/224) | | Pulmonary mass | 0 | 0.0% (0/222) | 1 | 0.4% (1/224) | | Respiratory failure | 0 | 0.0% (0/222) | 4 | 1.3% (3/224) | | **Skin and subcutaneous tissue disorders** | **1** | **0.5%** (1/222) | **0** | **0.0%** (0/224) | | Neuropathic ulcer | 1 | 0.5% (1/222) | 0 | 0.0% (0/224) | | **Vascular disorders** | **53** | **18.9%** (42/222) | **46** | **15.2%** (34/224) | | Aortic aneurysm | 1 | 0.5% (1/222) | 1 | 0.4% (1/224) | | Arterial spasm | 1 | 0.5% (1/222) | 0 | 0.0% (0/224) | | Arteriovenous fistula | 0 | 0.0% (0/222) | 1 | 0.4% (1/224) | {36} | Serious Adverse Events | SurVeil DCB (N=222 Subjects) | | IN.PACT Admiral DCB (N=224 Subjects) | | | --- | --- | --- | --- | --- | | | Events | Rate of Subjects with Event | Events | Rate of Subjects with Event | | Deep vein thrombosis | 1 | 0.5% (1/222) | 1 | 0.4% (1/224) | | Haematoma | 1 | 0.5% (1/222) | 0 | 0.0% (0/224) | | Haemorrhage | 1 | 0.5% (1/222) | 0 | 0.0% (0/224) | | Hypertension | 1 | 0.5% (1/222) | 0 | 0.0% (0/224) | | Hypertensive emergency | 0 | 0.0% (0/222) | 1 | 0.4% (1/224) | | Hypotension | 1 | 0.5% (1/222) | 1 | 0.4% (1/224) | | Iliac artery occlusion | 0 | 0.0% (0/222) | 1 | 0.4% (1/224) | | Orthostatic hypotension | 0 | 0.0% (0/222) | 1 | 0.4% (1/224) | | Peripheral arterial occlusive disease | 2 | 0.9% (2/222) | 2 | 0.9% (2/224) | | Peripheral artery aneurysm | 3 | 0.5% (1/222) | 0 | 0.0% (0/224) | | Peripheral artery dissection | 1 | 0.5% (1/222) | 1 | 0.4% (1/224) | | Peripheral artery occlusion | 12 | 4.5% (10/222) | 17 | 5.8% (13/224) | | Peripheral artery stenosis | 23 | 9.9% (22/222) | 15 | 5.4% (12/224) | | Peripheral embolism | 1 | 0.5% (1/222) | 1 | 0.4% (1/224) | | Peripheral ischaemia | 1 | 0.5% (1/222) | 0 | 0.0% (0/224) | | Peripheral vascular disorder | 1 | 0.5% (1/222) | 0 | 0.0% (0/224) | | Peripheral venous disease | 0 | 0.0% (0/222) | 1 | 0.4% (1/224) | | Subclavian steal syndrome | 0 | 0.0% (0/222) | 1 | 0.4% (1/224) | | Varicose vein | 2 | 0.5% (1/222) | 1 | 0.4% (1/224) | This table presents serious adverse events starting from the index procedure through 365 days post procedure. One Subject expired at home of unknown cause. ## 2. Effectiveness Results The analysis of effectiveness was based on the ITT full study cohort of 222 SurVeil DCB subjects and 224 IN.PACT Admiral DCB subjects available for the 12- month time point. Table 14 presents the primary effectiveness results for the full study cohort. The SurVeil™ Drug-Coated Balloon was concluded to be non-inferior to the IN.PACT® Admiral® Drug-Coated Balloon for the primary effectiveness endpoint of primary patency if the one-sided lower 97.5% confidence bound on the difference between groups (SurVeil DCB vs. IN.PACT DCB) is less than 15% (non-inferiority margin). In the ITT group, using multiple imputation, the rate of primary patency at 12 months was 81.7% in the Surveil DCB group compared to 85.9% in the IN.PACT Admiral DCB group. The difference in rates between the groups was -4.2% with one-sided lower 97.5% CL of -12.0%. Since this is higher than the pre-specified noninferiority margin of -15.0%, noninferiority is met (P-value for noninferiority 0.0035) and the SurVeil DCB is declared noninferior to IN.PACT Admiral DCB with respect to the primary effectiveness endpoint. A complete case analysis was carried out as a sensitivity analysis on ITT subjects with available data (i.e., subjects who experienced the primary effectiveness composite or had at least 335 days of follow-up) and provided PMA P210025: FDA Summary of Safety and Effectiveness Data {37} similar results. Kaplan-Meier plot of primary patency through 12 months is presented in Figure 6. Table 14: Primary Effectiveness – Full Cohort, Intent-to-Treat (N=446) | Primary Effectiveness Endpoint | SurVeil DCB (N=222 Subjects) | IN.PACT Admiral DCB (N=224 Subjects) | Difference [One-sided Lower 97.5% CL] | Non-inferiority Test P-value1 | | --- | --- | --- | --- | --- | | Primary patency through 12 months (ITT – Multiple Imputation) | 81.7% (75.9%,87.4%) | 85.9% (80.9%,90.9%) | -4.2% [-12.0%] | 0.0035 | | Primary patency through 12 months (ITT - Complete Case) | 82.2% (139/169) | 86.7% (163/188) | -4.5% [-12.3%] | 0.0041 | | Freedom from clinically driven TLR through 12 months2 | 91.9% (182/198) | 94.4% (203/215) | | | | Freedom from binary restenosis through 12 mon…
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