← Product Code NIQ · P110013 # RESOLUTE MICROTRAC/RESOLUTE INTEGRITY ZOTAROLIMUS-ELUTING CORONARY STENT SYSTEM (P110013) _Medtronic Vascular · NIQ · Feb 17, 2012 · Cardiovascular · APPR_ **Canonical URL:** https://fda.innolitics.com/device/P110013 ## Device Facts - **Applicant:** Medtronic Vascular - **Product Code:** NIQ - **Decision Date:** Feb 17, 2012 - **Decision:** APPR - **Device Class:** Class 3 - **Review Panel:** Cardiovascular - **Attributes:** Therapeutic ## Intended Use The Resolute MicroTrac and Resolute Integrity Zotarolimus-Eluting Coronary Stent Systems are indicated for improving coronary luminal diameters in patients, including those with diabetes mellitus, with symptomatic ischemic heart disease due to de novo lesions of length ≤27 mm in native coronary arteries with reference vessel diameters of 2.25 mm to 4.2 mm. ## Device Story Drug-eluting coronary stent system (Resolute MicroTrac and Resolute Integrity) used to treat symptomatic ischemic heart disease. Device consists of a cobalt-based alloy (MP35N) stent pre-mounted on a rapid exchange (RX) or over-the-wire (OTW) delivery system. Stent coated with zotarolimus (immunosuppressant) in a BioLinx polymer matrix. Physician delivers stent through coronary vasculature to target lesion; expands via balloon inflation. Zotarolimus elutes from polymer to inhibit smooth muscle cell proliferation, reducing neointimal hyperplasia and restenosis. Used in cardiac catheterization labs by interventional cardiologists. Output is mechanical scaffolding of the vessel lumen; clinical decision-making based on angiographic assessment of lesion. Benefits include improved luminal diameter and reduced restenosis compared to bare metal stents. ## Clinical Evidence Evidence from Global RESOLUTE Clinical Trial Program (RESOLUTE US, AC, Int, FIM, Japan). RESOLUTE US (pivotal) enrolled 1402 subjects; primary endpoint TLF at 12 months. RESOLUTE AC (randomized, 2292 subjects) compared Resolute to Xience V. RESOLUTE Int (observational, 2349 subjects) evaluated real-world performance. RESOLUTE FIM (139 subjects) and Japan (100 subjects) assessed safety/effectiveness. Pooled analysis (5130 subjects) confirmed safety/effectiveness in on-label and complex populations. Primary endpoints (TLF, TVF, late lumen loss) met non-inferiority or superiority goals against historical controls (Endeavor/Taxus/Driver). Stent thrombosis rates were low (ARC definite/probable <1% in on-label pooled analysis). ## Technological Characteristics Stent material: MP35N cobalt-based alloy (ASTM F562). Coating: Parylene C primer, BioLinx polymer (PVP/proprietary components), zotarolimus (1.6 μg/mm²). Delivery system: RX or OTW configuration, Pebax balloon. MR conditional (1.5T/3T). Sterilization: Ethylene oxide. Software: None (mechanical/drug-eluting device). ## Regulatory Identification Stent, coronary, drug-eluting -- a metal scaffold with a drug coating placed via a delivery catheter into the coronary artery or saphenous vein graft to maintain the lumen. The drug coating is intended to inhibit restenosis. ## Predicate Devices - Endeavor Zotarolimus-Eluting Coronary Stent System ([P060033](/device/P060033.md)) - Endeavor Sprint Zotarolimus-Eluting Coronary Stent System ([P060033](/device/P060033.md)/S1) - MicroDriver Bare Metal Stent ([P030009](/device/P030009.md)/S2) - Driver Bare Metal Stent ([P030009](/device/P030009.md)) - Integrity Bare Metal Stent ([P030009](/device/P030009.md)/S039) - Sprinter Legend RX ([P790017](/device/P790017.md)/S96) - NC Sprinter RX ([P790017](/device/P790017.md)/S95) ## Reference Devices - Xience V Everolimus-Eluting Coronary Stent System - Taxus Stent ## Submission Summary (Full Text) > This content was OCRed from public FDA records by [Innolitics](https://innolitics.com). If you use, quote, summarize, crawl, or train on this content, cite Innolitics at https://innolitics.com. > > Innolitics is a medical-device software consultancy. We help companies design, build, and clear FDA-regulated software and AI/ML devices, including [a PMA](https://innolitics.com/services/regulatory/), [a 510(k)](https://innolitics.com/services/510ks/), [a SaMD](https://innolitics.com/services/end-to-end-samd/), [an AI/ML medical device](https://innolitics.com/services/medical-imaging-ai-development/), or [an FDA regulatory strategy](https://innolitics.com/services/regulatory/). SUMMARY OF SAFETY AND EFFECTIVENESS DATA (SSED) I. GENERAL INFORMATION Device Generic Name: Drug-Eluting Coronary Stent System (NIQ) Device Trade Name: Resolute MicroTrac Zotarolimus-Eluting Coronary Stent System Resolute Integrity Zotarolimus-Eluting Coronary Stent System Applicant's Name and Address: Medtronic Vascular 3576 Unocal Place Santa Rosa, CA 95403 USA Date of Panel Recommendation: None Premarket Approval Application (PMA Number): P110013 Date of FDA Notice of Approval: February 17, 2012 Expedited: Not Applicable II. INDICATIONS FOR USE The Resolute MicroTrac and Resolute Integrity Zotarolimus-Eluting Coronary Stent Systems are indicated for improving coronary luminal diameters in patients, including those with diabetes mellitus, with symptomatic ischemic heart disease due to de novo lesions of length ≤27 mm in native coronary arteries with reference vessel diameters of 2.25 mm to 4.2 mm. III. CONTRAINDICATIONS The Resolute MicroTrac and Resolute Integrity stent systems are contraindicated for use in patients with: - Patients with known hypersensitivity or allergies to aspirin, heparin, bivalirudin, clopidogrel, prasugrel, ticagrelor, ticlopidine, drugs such as zotarolimus, tacrolimus, sirolimus, everolimus, or similar drugs or any other analogue or derivative. - Patients with known hypersensitivity to the cobalt-based alloy (cobalt, nickel, chromium, and molybdenum). - Patients with known hypersensitivity to the BioLinx polymer or its individual components. PMA P110013: FDA Summary of Safety and Effectiveness Data Coronary artery stenting is contraindicated for use in: - Patients in whom anti-platelet and/or anticoagulation therapy is contraindicated. - Patients who are judged to have a lesion that prevents complete inflation of an angioplasty balloon or proper placement of the stent or stent delivery system. ## IV. WARNINGS AND PRECAUTIONS The warnings and precautions can be found in the Resolute MicroTrac Zotarolimus-Eluting Coronary Stent System and the Resolute Integrity Zotarolimus-Eluting Coronary Stent System labeling. ## V. DEVICE DESCRIPTION The Resolute MicroTrac Zotarolimus-Eluting Coronary Stent System (Resolute MicroTrac) and Resolute Integrity Zotarolimus-Eluting Coronary Stent System (Resolute Integrity) are device/drug combination products comprised of two regulated components: - A device component, which consists of a Driver™, Micro-Driver™ or Integrity Bare Metal Coronary Stent on the MicroTrac Delivery System. The Resolute MicroTrac utilizes the Driver™ and Micro-Driver™ Bare Metal Stent (BMS), and the Resolute Integrity utilizes the Integrity BMS. The MicroTrac Delivery System is available in a rapid exchange (RX) and an over-the-wire (OTW) configuration. - A drug/polymer coating component, which consists of a formulation of zotarolimus contained in a BioLinx polymer. The characteristics of the Resolute MicroTrac and Resolute Integrity are described in Table 1. PMA P110013: FDA Summary of Safety and Effectiveness Data Table 1: Resolute MicroTrac and Resolute Integrity Product Description | | Resolute MicroTrac RX | Resolute Integrity RX | Resolute MicroTrac OTW | Resolute Integrity OTW | | --- | --- | --- | --- | --- | | Available Stent lengths (mm)¹ | 8, 9, 12, 14, 15, 18, 22, 26, 30 | | | | | Available stent diameters (mm)² | 2.25, 2.5, 2.75, 3.0, 3.5, 4.0 | | | | | Stent Material | A cobalt-based alloy (MP35N) | | | | | Drug Component | A coating of polymers loaded with zotarolimus is applied to the stent at a dose of approximately 1.6μg of zotarolimus per mm² of stent surface area. The maximum nominal drug content on the largest stent (4.0 x 30mm) is 300μg. | | | | | Delivery System Working Length (cm) | 140cm | | | | | Delivery System Adapter Ports | Single access port to inflation lumen. Guidewire exit port is located approximately 25cm from tip. Designed for guidewires ≤0.014". | | Y-Connector (Side arm for access to balloon inflation/deflation lumen. Straight arm is continuous with shaft inner lumen). Designed for guidewires ≤0.014" | | | Stent Delivery Balloon | Single-layer Pebax balloon, wrapped over an inner member tubing with 2 radiopaque marker bands to locate the stent edges. | | | | | Balloon Inflation Pressure | Nominal Inflation Pressure: 9 ATM; Rated Burst Inflation Pressure: 2.25-3.5 mm = 16 ATM, 4.0mm = 15 ATM | | | | | Guide Catheter Compatibility | 0.056" minimum (5F) | | | | | Distal Section Outer Diameter | 2.7F | | 3.4F | | | Proximal Outer Diameter | 2.1F | | | | ¹ 2.25, 2.5 and 2.75mm diameter stents are not available in lengths of 9 and 15mm ² 3.0, 3.5 and 4.0mm diameter stents are not available in lengths of 8 and 14mm ## A. Device Component Description The Resolute MicroTrac device component consists of the Driver™ or Micro-Driver™ Coronary Stent pre-mounted onto an RX or OTW MicroTrac Delivery System. The Resolute Integrity device component consists of the Integrity Coronary Stent pre-mounted onto an RX or OTW MicroTrac Delivery System. The stents are made from a cobalt-based alloy and are coated with a drug/polymer coating, which consists of a Parylene C primer coat, a BioLinx polymer and the active pharmaceutical ingredient (API), zotarolimus. Both the Resolute MicroTrac and Resolute Integrity stents have a drug density of 1.6 μg/mm². The MicroTrac Delivery System provides a means for delivering the stent through the coronary vasculature and, once in the desired location, expands the stent through balloon inflation. PMA P110013: FDA Summary of Safety and Effectiveness Data The Resolute MicroTrac uncoated stent is identical to the MicroDriver (2.25 mm, 2.5 mm and 2.75 mm diameters) (P030009/S2) and Driver (3.0 mm, 3.5 mm and 4.0 mm diameters) bare metal stents (P030009). The Resolute Integrity uncoated stent is identical to the Integrity bare metal stent (P030009/S039). The Resolute MicroTrac and Resolute Integrity stents utilize the same API as the Endeavor (P060033) and Endeavor Sprint (P060033/S1) Zotarolimus-Eluting Stent (DES) Systems, but feature a different polymer coating (BioLinx). The BioLinx polymer coating is intended to provide extended elution characteristics compared to the Endeavor and Endeavor Sprint products. The MicroTrac delivery system utilizes the same principle of operation and features a similar design as the Sprint delivery system utilized for the Endeavor Sprint product, and the Sprinter Legend RX (P790017/S96) and NC Sprinter RX (P790017/S95) Balloon Dilatation Catheters. ## B. Drug Component Description The drug coating on Resolute MicroTrac and Resolute Integrity stents consists of a Parylene C primer coating, a BioLinx polymer blend (inactive ingredient), and the active pharmaceutical ingredient (API), zotarolimus. Zotarolimus is same API used in the Endeavor Sprint Zotarolimus-Eluting Coronary Stent System (P060033/S001). ## B1. Zotarolimus The active pharmaceutical ingredient utilized in Resolute MicroTrac and Resolute Integrity is zotarolimus. It is a tetrazole-containing macrocyclic immunosuppressant. The Chemical name of zotarolimus is: [3S-[3R*[S*(1R*,3S*,4R*)],6S*, 7E,9S*,10S*,12S*,14R*,15E,17E,19E, 21R*,23R*, 26S*,27S*,34aR*]]-9,10,12,13,14,21,22,23,24,25,26,27, 32,33,34,34a-hexadecahydro-9,27-dihydroxy-3-[2-[3-methoxy-4-(1H-tetrazoyl-1-yl)cyclohexyl]-1-methylethyl]-10,21-dimethoxy-6,8,12,14,20,26-hexamethyl-23,27-epoxy-3H-pyrido[2,1-c] [1,4]oxazacyclohentriacontine-1,5,11,28,29(4H,6H,31H)-pentone. The chemical structure of zotarolimus is shown in Figure 1. The nominal dose of zotarolimus per nominal stent length/diameter for the product matrix is shown in Table 2. PMA P110013: FDA Summary of Safety and Effectiveness Data ![img-0.jpeg](img-0.jpeg) Figure 1: Chemical Structure of Zotarolimus Zotarolimus has extremely low water solubility and is a lipophilic compound that is freely soluble in Propylene glycol, Acetone, Toluene, Acetonitrile, Ethanol, Benzyl alcohol and DMSO. The molecular formula of zotarolimus is $\mathrm{C}_{52}\mathrm{H}_{79}\mathrm{N}_{5}\mathrm{O}_{12}$ and its molecular weight is 966.2. Zotarolimus does not have any ionizable group(s) in the physiological pH range; therefore, its solubility is expected to be unaltered in this range. ## B2. Inactive Ingredient ### BioLinx Polymer Resolute MicroTrac and Resolute Integrity stents are covered with a Parylene C primer coating and a mixture of the drug zotarolimus and the BioLinx polymer. BioLinx is a blend of the Medtronic proprietary components C10 and C19, and PVP (polyvinyl pyrrolidone). The structural formula of the BioLinx polymer subunits is shown in Figure 2. ![img-1.jpeg](img-1.jpeg) Figure 2: Chemical Structure of Biolinx Polymer Sub-units PMA P110013: FDA Summary of Safety and Effectiveness Data Table 2: Product Matrix and Zotarolimus Content | Product Number Resolute MicroTrac OTW | Product Number Resolute MicroTrac RX | Product Number Resolute Integrity OTW | Product Number Resolute Integrity RX | Nominal Expanded Stent ID (mm) | Nominal Unexpanded Stent Length (mm) | Nominal Zotarolimus Content (μg) | | --- | --- | --- | --- | --- | --- | --- | | RSMT22508W | RSMT22508UX | RSINT22508W | RSINT22508UX | 2.25 | 8 | 59 | | RSMT25008W | RSMT25008UX | RSINT25008W | RSINT25008UX | 2.5 | 8 | 59 | | RSMT27508W | RSMT27508UX | RSINT27508W | RSINT27508UX | 2.75 | 8 | 59 | | RSMT30009W | RSMT30009UX | RSINT30009W | RSINT30009UX | 3.0 | 9 | 90 | | RSMT35009W | RSMT35009UX | RSINT35009W | RSINT35009UX | 3.5 | 9 | 90 | | RSMT40009W | RSMT40009UX | RSINT40009W | RSINT40009UX | 4.0 | 9 | 90 | | RSMT22512W | RSMT22512UX | RSINT22512W | RSINT22512UX | 2.25 | 12 | 85 | | RSMT25012W | RSMT25012UX | RSINT25012W | RSINT25012UX | 2.5 | 12 | 85 | | RSMT27512W | RSMT27512UX | RSINT27512W | RSINT27512UX | 2.75 | 12 | 85 | | RSMT30012W | RSMT30012UX | RSINT30012W | RSINT30012UX | 3.0 | 12 | 120 | | RSMT35012W | RSMT35012UX | RSINT35012W | RSINT35012UX | 3.5 | 12 | 120 | | RSMT40012W | RSMT40012UX | RSINT40012W | RSINT40012UX | 4.0 | 12 | 120 | | RSMT22514W | RSMT22514UX | RSINT22514W | RSINT22514UX | 2.25 | 14 | 102 | | RSMT25014W | RSMT25014UX | RSINT25014W | RSINT25014UX | 2.5 | 14 | 102 | | RSMT27514W | RSMT27514UX | RSINT27514W | RSINT27514UX | 2.75 | 14 | 102 | | RSMT30015W | RSMT30015UX | RSINT30015W | RSINT30015UX | 3.0 | 15 | 150 | | RSMT35015W | RSMT35015UX | RSINT35015W | RSINT35015UX | 3.5 | 15 | 150 | | RSMT40015W | RSMT40015UX | RSINT40015W | RSINT40015UX | 4.0 | 15 | 150 | | RSMT22518W | RSMT22518UX | RSINT22518W | RSINT22518UX | 2.25 | 18 | 128 | | RSMT25018W | RSMT25018UX | RSINT25018W | RSINT25018UX | 2.5 | 18 | 128 | | RSMT27518W | RSMT27518UX | RSINT27518W | RSINT27518UX | 2.75 | 18 | 128 | | RSMT30018W | RSMT30018UX | RSINT30018W | RSINT30018UX | 3.0 | 18 | 180 | | RSMT35018W | RSMT35018UX | RSINT35018W | RSINT35018UX | 3.5 | 18 | 180 | | RSMT40018W | RSMT40018UX | RSINT40018W | RSINT40018UX | 4.0 | 18 | 180 | | RSMT22522W | RSMT22522UX | RSINT22522W | RSINT22522UX | 2.25 | 2 | 153 | | RSMT25022W | RSMT25022UX | RSINT25022W | RSINT25022UX | 2.5 | 22 | 153 | | RSMT27522W | RSMT27522UX | RSINT27522W | RSINT27522UX | 2.75 | 22 | 153 | | RSMT30022W | RSMT30022UX | RSINT30022W | RSINT30022UX | 3.0 | 22 | 220 | | RSMT35022W | RSMT35022UX | RSINT35022W | RSINT35022UX | 3.5 | 22 | 220 | | RSMT40022W | RSMT40022UX | RSINT40022W | RSINT40022UX | 4.0 | 22 | 220 | | RSMT22526W | RSMT22526UX | RSINT22526W | RSINT22526UX | 2.25 | 26 | 188 | | RSMT25026W | RSMT25026UX | RSINT25026W | RSINT25026UX | 2.5 | 26 | 188 | | RSMT27526W | RSMT27526UX | RSINT27526W | RSINT27526UX | 2.75 | 26 | 188 | | RSMT30026W | RSMT30026UX | RSINT30026W | RSINT30026UX | 3.0 | 26 | 260 | | RSMT35026W | RSMT35026UX | RSINT35026W | RSINT35026UX | 3.5 | 26 | 260 | | RSMT40026W | RSMT40026UX | RSINT40026W | RSINT40026UX | 4.0 | 26 | 260 | | RSMT22530W | RSMT22530UX | RSINT22530W | RSINT22530UX | 2.25 | 30 | 213 | | RSMT25030W | RSMT25030UX | RSINT25030W | RSINT25030UX | 2.5 | 30 | 213 | | RSMT27530W | RSMT27530UX | RSINT27530W | RSINT27530UX | 2.75 | 30 | 213 | | RSMT30030W | RSMT30030UX | RSINT30030W | RSINT30030UX | 3.0 | 30 | 300 | | RSMT35030W | RSMT35030UX | RSINT35030W | RSINT35030UX | 3.5 | 30 | 300 | | RSMT40030W | RSMT40030UX | RSINT40030W | RSINT40030UX | 4.0 | 30 | 300 | PMA P110013: FDA Summary of Safety and Effectiveness Data page 6 # C. Mechanism of Action The mechanism (or mechanisms) by which Resolute MicroTrac and Resolute Integrity stents affect neointimal production as seen in pre-clinical and clinical studies has not been established conclusively. *In vitro*, zotarolimus inhibited growth factor-induced proliferation of human coronary artery smooth muscle cells, and also demonstrated binding affinity with FKBP-12 (binding protein). The suggested mechanism of action of zotarolimus is to bind to FKBP12, leading to the formation of a trimeric complex with the protein kinase mTOR (mammalian target of rapamycin), inhibiting its activity. Inhibition of mTOR activity leads to inhibition of cell cycle progression from the G1 to the S phase. # VI. ALTERNATIVE PRACTICES AND PROCEDURES There are several other alternatives for the treatment of patients with coronary artery disease including exercise, diet, drug therapy, percutaneous coronary interventions (such as balloon angioplasty, atherectomy, and placement of bare metal stents, coated stents, and other drug eluting stents), and coronary artery bypass surgery (CABG). 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 Resolute MicroTrac Zotarolimus-Eluting Coronary System has not been marketed in the United States or any foreign country. The Resolute Integrity Zotarolimus-Eluting Coronary Stent System is commercially available in the following countries: Table 3: Resolute Integrity Commercial Availability | Algeria | Columbia | Kazakhstan | Nicaragua | Trinidad and Tobago | | --- | --- | --- | --- | --- | | Antigua and Barbuda | Cyprus | Kyrgyzstan | Nigeria | Tunisia | | Armenia | Czech Republic | Korea (South) | Norway | Turkey | | Aruba | Denmark | Kuwait | Pakistan | Uganda | | Australia | Estonia | Laos | Paraguay | Ukraine | | Austria | Finland | Latvia | Philippines | United Kingdom | | Bahamas | France | Lebanon | Poland | Uruguay | | Bahrain | Georgia | Liechtenstein | Portugal | Uzbekistan | | Bangladesh | Germany | Lithuania | Qatar | Vietnam | | Barbados | Ghana | Luxemburg | Romania | Virgin Islands | | Belarus | Greece | Macau | Russia | Yemen | | Belgium | Guyana | Macedonia | Senegal | Zimbabwe | | Belize | Honduras | Malaysia | Serbia | | | Bermuda | Hong Kong | Malta | Slovakia | | | Bolivia | Hungary | Mauritius | Slovenia | | | Bosnia-Herzegovina | Iceland | Montenegro | Spain | | | Botswana | India | Morocco | Sudan | | PMA P110013: FDA Summary of Safety and Effectiveness Data | Brunei | Indonesia | Mozambique | Sweden | | --- | --- | --- | --- | | Bulgaria | Ireland | Myanmar | Switzerland | | Cambodia | Israel | Namibia | Syria | | Cayman Islands | Italy | Netherlands | Taiwan | | Croatia | Jamaica | New Zealand | Thailand | As of January 6, 2012, approximately 261,000 Resolute Integrity Zotarolimus-Eluting Coronary Stent Systems have been distributed outside of the U.S. This product has not been withdrawn from the market in any country for any reason. ## VIII. POTENTIAL ADVERSE EFFECTS OF THE DEVICE ON HEALTH Below is a list of potential adverse effects associated with the use of Resolute MicroTrac and Resolute Integrity Zotarolimus-Eluting Coronary Stent Systems. Adverse events (in alphabetical order) which may be associated with coronary stent use in native coronary arteries include, but are not limited to: - Abrupt vessel closure - Access site pain, hemotoma or hemorrhage - Allergic reaction (to contract, antiplatelet therapy, stent material, or drug and polymer coating) - Aneurysm, pseudoaneurysm, or arteriovenous fistula (AVF) - Arrhythmias including ventricular fibrillation - Balloon rupture - Bleeding - Cardiac tamponade - Coronary artery occlusion, perforation, rupture or dissection - Coronary artery spasm - Death - Embolism (air, tissue, device, or thrombus) - Emergency surgery: peripheral vascular or coronary bypass - Failure to deliver the stent - Hemorrhage requiring transfusion - Hypotension/hypertension - Incomplete stent apposition - Infection or Fever - Myocardial Infarction (MI) - Pericarditis - Peripheral ischemia/peripheral nerve injury - Renal Failure - Restenosis of the stented artery - Shock/pulmonary edema - Stable or Unstable angina - Stent deformation, collapse, or fracture PMA P110013: FDA Summary of Safety and Effectiveness Data - Stent migration or embolization - Stent misplacement - Stroke/transient ischemic attack - Thrombosis (acute, subacute or late) Adverse events that have been associated with the intravenous injection of zotarolimus in humans include but are not limited to: - Anemia - Diarrhea - Dry Skin - Headache - Hematuria - Infection - Injection site reaction - Pain (abdominal, arthralgia, injection site) - Rash Potential adverse events related to BioLinx polymer include but are not limited to: - Allergic Reaction - Focal inflammation at the site of stent implantation - Restenosis of the stented artery For the specific adverse events that occurred in the clinical studies, please see Section X below. ## IX. SUMMARY OF NONCLINICAL AND PHARMACOKINETIC STUDIES A series of non-clinical laboratory and pharmacokinetic studies were performed on the Resolute MicroTrac and Resolute Integrity Zotarolimus-Eluting Stent Systems. Studies were performed on the bare metal stent (Driver, MicroDriver or Integrity stent mounted on the stent delivery system), the coated stent alone, the polymer-only coated stent alone, the MicroTrac delivery system, and the finished combination products (i.e., Resolute MicroTrac and Resolute Integrity Coronary Stent Systems). These evaluations included biocompatibility studies, *in vivo* pharmacokinetics, *in vitro* engineering tests, coating characterization, chemistry, manufacturing, and controls (CMC) testing, animal studies, stability and shelf life, and sterilization. PMA P110013: FDA Summary of Safety and Effectiveness Data # A. Biocompatibility A series of biocompatibility tests were conducted to demonstrate that the components of Resolute MicroTrac and Resolute Integrity Zotarolimus-Eluting Coronary Stent System are non-toxic and biocompatible. The Resolute MicroTrac and Resolute Integrity stents were categorized as implant devices with permanent blood contact (>30 days). The MicroTrac Delivery System (used with both Resolute MicroTrac and Resolute Integrity stents) was categorized as an external communicating device in limited contact with circulating blood (<24 hours). All biocompatibility testing was conducted in accordance with: - Good Laboratory Practices Regulations (21 CFR § 58) - Guidance for Industry and FDA Staff, Non-Clinical Tests and Recommended Labeling for Intravascular Stents and Associated Delivery Systems Document (April 18, 2010) - ISO 10993-1, Biological Evaluation of Medical Devices: Evaluation and Testing (2003) With the exception of the stent-only Chromosomal Aberration testing which was conducted on Resolute stents deployed from final, sterilized clinical product mounted on the prior generation Sprint delivery system, all test articles used in the biocompatibility studies were final, sterilized Resolute Zotarolimus-Eluting Coronary Stent Systems on the MicroTrac (RX or OTW) Delivery System. When required per protocol, the stent was aseptically removed from the delivery system prior to testing. Biocompatibility of the Resolute Integrity Zotarolimus-Eluting Coronary Stent System was demonstrated by leveraging testing previously conducted on the Integrity bare metal stent (P030009/S039) and the Resolute MicroTrac stent system. Leveraging this testing information was appropriate because the Resolute Integrity uncoated stent is identical to the Integrity bare metal stent (P030009/S039), and the Resolute Integrity stent system utilizes the same stent coating, delivery system, final packaging, and sterilization method as the Resolute MicroTrac. Two manufacturing changes were made to the MicroTrac Delivery System subsequent to the completion of the biocompatibility testing. These changes did not introduce any new materials and an appropriate justification was provided for leveraging the previously conducted biocompatibility testing. Table 4 provides a summary of the biocompatibility testing conducted to support of Resolute MicroTrac and Resolute Integrity Zotarolimus-Eluting Coronary Stent Systems. Table 4: Summary of Biocompatibility Testing | Test Name | Test Description | Test Article | Result | | --- | --- | --- | --- | | Cytotoxicity | MHLW Cytotoxicity, Colony Assay Method (Extraction) | Resolute Stent MicroTrac Rx Delivery System MicroTrac OTW Delivery System | Pass | | | ISO10993-5 Direct Contact Cytotoxicity (L929 Mouse Fibroblast Cells) | Resolute Stent | Pass | PMA P110013: FDA Summary of Safety and Effectiveness Data Table 4: Summary of Biocompatibility Testing | Test Name | Test Description | Test Article | Result | | --- | --- | --- | --- | | | ISO10993-5 Cytotoxicity (L929 MEM Elution) | MicroTrac RX Delivery System MicroTrac OTW Delivery System | Pass | | Sensitization | ISO10993-10 Murine Local Lymph Node Assay | Resolute Stent MicroTrac RX Delivery System MicroTrac OTW Delivery System | Pass | | | ISO10993-10 ISO Maximization Sensitization | MicroTrac RX Delivery System MicroTrac OTW Delivery System | Pass | | Irritation/Intracutaneous | ISO10993-10 Intracutaneous Reactivity | Resolute Stent MicroTrac RX Delivery System MicroTrac OTW Delivery System | Pass | | Acute System Toxicity | MHLW Acute Systemic Toxicity | Resolute Stent | Pass | | | ISO10993-11 Acute Systemic Toxicity | MicroTrac RX Delivery System MicroTrac OTW Delivery System | Pass | | Pyrogenicity | ISO10993-11 USP <151> Material Medicated Pyrogen | Resolute Stent MicroTrac RX Delivery System MicroTrac OTW Delivery System | Pass | | Subchronic Toxicity | ISO10993-11 4 Week Systemic Toxicity | Resolute Stent | Pass | | Genotoxicity | ISO10993-3 Bacterial Reverse Mutation Study | Resolute Stent | Pass | | | ISO10993-3 In-vivo Mouse Peripheral Blood Micronucleus Study | Resolute Stent | Pass | | | ISO10993-3 Chromosomal Aberration Assay | Resolute Stent | Pass | | Hemocompatibility | ASTM In-vitro Hemolysis, Indirect Method | Resolute Stent MicroTrac RX Delivery System MicroTrac OTW Delivery System | Pass | | | ASTM In-vitro Hemolysis, Direct Method | Resolute Stent | Pass | | | ISO10993-4 Complement Activation C3a and SC5b-9 | Resolute Stent MicroTrac RX Delivery System MicroTrac OTW Delivery System | Pass | | | ISO10993-4 In-vivo Thromboresistance | Resolute MicroTrac RX Delivery System (finished device) | Pass | Table 5 summarizes studies and risk assessment that further support the safety and biocompatibility of the polymer components of the Resolute MicroTrac and Resolute Integrity stent coating. PMA P110013: FDA Summary of Safety and Effectiveness Data Table 5: Summary of Additional Studies on Resolute Polymer Components | Study Category | Study Description | Conclusion | | --- | --- | --- | | In Vitro | Assay for monocyte adhesion | The BioLinx has minimal risk of inducing an inflammatory reaction | | | Assay for monocyte inflammatory activation | | | | Assay for inflammation and activation of coronary vascular cells | The BioLinx polymer has minimal risk of prothrombotic potential | | | Thermal stability as determined by thermogravimetric analysis (TGA) | The BioLinx polymer is biostable under physiologically and clinically relevant environments | | | Hydrolytic stability as determined by BioLinx polymer characterization after PBS incubation at 37°C for 270 days | | In vivo animal testing conducted on the Resolute MicroTrac and Resolute Integrity stent systems evaluated the effects of drug and device exposure in a porcine coronary artery for up to 365 days, in lieu of ISO-10993 chronic toxicity and muscle implantation testing. These studies showed no evidence of local arterial or systemic toxicity. The resulting tissue histology in these studies did not display pathology consistent with drug or polymer-induced toxicity. The animal studies are summarized separately in Section I – Animal Studies, below. Formal carcinogenicity and reproductive toxicity testing was not conducted on the Resolute MicroTrac or Resolute Integrity stents. The carcinogenic potential of the Resolute MicroTrac and Resolute Integrity stents is minimal based on the quantities of materials present (cobalt-chromium alloy, Parylene C primer and BioLinx polymer) and the limited period of zotarolimus release. The genotoxicity and reproductive toxicity of zotarolimus have been investigated in bacterial and mammalian cells in vitro and in laboratory animals in vivo. See Section B – Studies of Drug Substance. Based on in vitro analytical and stability testing results, there is no evidence to suggest that any chemical interactions occur between the BioLinx polymer and zotarolimus drug under established processing and storage conditions that would lead to the formation of covalent bonds or that would alter the structure of the drug in any way to form a new intermediate or molecular entity. ## B. Studies of the Drug Substance Medtronic Vascular provided a letter from the drug substance manufacturer, Abbott Laboratories Inc., authorizing FDA access to a Drug Master File (DMF) in support of this application. In vivo and in vitro pharmacology and toxicology studies as well as animal and human pharmacokinetic studies were conducted on zotarolimus to provide information about systemic and regional toxicity, distribution profiles, end-organ disposition, drug metabolism and potential drug-drug interactions. PMA P110013: FDA Summary of Safety and Effectiveness Data The drug component of the Resolute MicroTrac and Resolute Integrity stent is identical to the active ingredient of the Endeavor Zotarolimus-Eluting Coronary Stent System. Therefore, the information provided for the studies of the drug substance for the Endeavor Zotarolimus-Eluting Coronary Stent System (P060033) is directly applicable to this PMA, and therefore is not repeated here. Details regarding the following: intravenous administration of zotarolimus, safety pharmacology, toxicology, ADME studies and drug interactions, can be found in the SSED for P060033 located at http://www.accessdata.fda.gov/cdrh_docs/pdf6/P060033b.pdf. ## C. In Vivo Pharmacokinetics The pharmacokinetics information for the Resolute MicroTrac and Resolute Integrity stent systems is derived from a study conducted on the Resolute Zotarolimus-Eluting Coronary Stent System (Resolute stent system). The Resolute Integrity stent system is similar to the Resolute stent system with regard to the stent design, and the stent coating technology (dosing and drug to polymer ratio) and delivery system design and materials. Given these similarities and supportive bench and animal study information, the findings from the RESOLUTE First In Man (FIM) PK Sub-study, as described below, are applicable to both the Resolute MicroTrac and Resolute Integrity stent systems. The pharmacokinetics (PK) of zotarolimus delivered from the Resolute Stent has been determined in subjects with coronary artery disease after stent implantation. Twenty-two subjects in the RESOLUTE-FIM Clinical Trial were enrolled in a pharmacokinetic (PK) sub-study. The RESOLUTE-FIM Clinical Trial was a prospective, multi-center, controlled trial, which took place in New Zealand and Australia. The pharmacokinetic sub-study was designed to assess the acute pharmacokinetics and safety of zotarolimus administered using the Resolute Zotarolimus-Eluting Coronary Stent System for the treatment of single de novo lesions in native coronary arteries. Blood samples (5 mL) were collected at 30 days post-procedure. Selected pharmacokinetic parameters for the RESOLUTE PK sub-study analysis are provided in Table 6. PMA P110013: FDA Summary of Safety and Effectiveness Data Table 6: Zotarolimus Pharmacokinetics in the RESOLUTE FIM Clinical Trial PK Sub-Study Patients After Implantation of Resolute Zotarolimus-Eluting Coronary Stents | PK Parameter | Units | Group I (128 μg) N = 11 | Group IIa (180 μg) N = 11 | Group IIIa (240 μg) N = 7 | Group IVa (300 μg) N = 3 | | --- | --- | --- | --- | --- | --- | | C_{max} | (ng/mL) | 0.129 | 0.210 ±0.062 | 0.300 ±0.075 | 0.346 ±0.133 | | T_{max} | (h) | 1.00 | 0.9 ±0.7 | 0.9 ±0.5 | 0.8 ±0.5 | | AUC_{0-last} | (ng·h/mL) | 15.08 | 16.04 ±4.74 | 35.89 ±12.79 | 31.19 ±17.69 | | AUC_{0-inf}§ | (ng·h/mL) | 41.89 | 39.09 ±11.77 | 52.41 ±12.57 | 80.12 ±51.00 | | B§ | (1/h) | 0.003 | 0.004 ±0.001 | 0.004 ±0.001 | 0.003 ±0.002 | | t_{1/2}# | (h) | 263.4 | 195.5 ±74.4 | 167.4 ±29.7 | 208.3 ±144.4 | | CL/F§ | (L/h) | 3.06 | 5.23 ±2.55 | 4.80 ±1.11 | 5.14 ±3.55 | | Vd_{0}/F§ | (L) | 1161.2 | 1449.3 ±221.6 | 1181.2 ±336.4 | 1658.6 ±494.8 | Notes: Cmax = Maximum volume of distribution Tmax = Time to Cmax AUC0-last = Area under the blood concentration-time curve (AUC) from time 0 to time of last measurable concentration AUC0-inf = AUC from time 0 to infinity (AUC0-inf). t1/2 = Harmonic mean half-life CL/F = Mean apparent clearance Vd0/F = Apparent volume of distribution a Primary dose groups † No SD was reported when N = 1 ‡ Harmonic mean ±pseudo-standard deviation # Not a true estimate of the elimination half-life as the drug release from the stent was not complete during the course of the pharmacokinetic sampling § Not a true sample The results in Table 6 show that the pharmacokinetics of zotarolimus were linear in the primary dose-proportionality evaluation (including dose groups with N > 1), 180, 240 and 300 μg, following the implantation of the Resolute stents as illustrated by dose proportional increases in maximum blood concentration (Cmax), area under the blood concentration-time curve (AUC) from time 0 to time of last measurable concentration (AUC0-last) and AUC from time 0 to infinity (AUC0-inf). The mean apparent clearance (CL/F) and harmonic mean half-life (t1/2) for the primary dose groups ranged from 4.80 to 5.23 L/h and 167.4 to 208.3 h, respectively. The mean time to reach peak systemic concentration (Tmax) ranged from 0.8 to 0.9 h after stent implantation. The data demonstrate dose proportionality and linearity similar to that seen with increasing zotarolimus doses from the Endeavor stent (P060033) and intravenous administration. Based on available zotarolimus pharmacokinetic data, systemic safety margins at multiples of ≥78-fold has been established for the Resolute stent at 300 μg due to the extended elution of Implants in the Magnetic zotarolimus from the BioLinx polymer. ## D. In Vitro Engineering Testing In vitro engineering testing has been completed in accordance with the following: - FDA Guidance for Industry and Staff: Non-Clinical Engineering Tests and Recommended Labeling for Intravascular Stents and Associated Delivery Systems, April 18, 2010 - FDA Guidance for Industry and Staff: Establishing Safety and Compatibility of Passive Resonance (MR) Environment, August 2008 PMA P110013: FDA Summary of Safety and Effectiveness Data Testing was conducted on devices representative of Resolute MicroTrac and Resolute Integrity, except where testing could be leveraged from the Integrity (P03009/S39), Driver (P030009) and Micro-Driver (P030009/S2) Bare Metal Coronary Stent Systems. Leveraging this testing information was appropriate because the Resolute Integrity uncoated stent is identical to the Integrity bare metal stent (P030009/S039), and the Resolute MicroTrac uncoated stent is identical to the Driver and MicroDriver bare metal stent. The applicant provided an appropriate rationale where the testing was leveraged or representative devices were used for each attribute evaluated. In addition, two manufacturing changes were made to the MicroTrac Delivery System subsequent to the completion of the *in vitro* testing. Several *in vitro* tests were repeated to support these changes, and an appropriate justification was provided for leveraging the other tests. The delivery system with the manufacturing changes implemented is referred to as “Modified MicroTrac” or “Commercial MicroTrac.” The *in vitro* engineering studies, which support the performance of Resolute MicroTrac and Resolute Integrity, are provided in Table 7. In the table below, “Resolute stent” means the stent used in the Resolute MicroTrac system. “Pass” denotes that the test results met product specifications and/or the recommendations in the above-referenced guidance document. PMA P110013: FDA Summary of Safety and Effectiveness Data page 15 page 16 PMA P110013: FDA Summary of Safety and Effectiveness Data Table 7: In Vitro Testing Supporting the Performance of Resolute MicroTrac and Resolute Integrity | Test | Description of Test | Test Article | Results | | --- | --- | --- | --- | | Stent Integrity, Dimensional and Functional Attributes | | | | | Fretting Corrosion | This test evaluated the risk of stent failure caused by fretting corrosion of Driver, MicroDriver, Integrity, Resolute and Resolute Integrity stents deployed in an overlapped configuration in a 1.5 cm radius bend after 420 million cycles. The results met all acceptance criteria and indicated that the stents possess a high resistance to fretting corrosion. | Resolute Integrity Stent; Resolute Stent | Pass | | Deployed Stent Length | This test demonstrated that the stent length is consistent with labeling when deployed at nominal pressure. Each stent was deployed to nominal pressure, and the stent length was measured. The results indicated that the length of Resolute and Resolute Integrity stents is consistent with labeling. | Resolute Integrity Stent; Resolute Stent | Pass | | Foreshortening at Nominal | The test measured the change in stent length from the catheter-loaded condition to deployment at nominal pressure. Testing was conducted with consideration of the methods described in ASTM F2081-06. All samples met product specifications. | Resolute Integrity Stent; Resolute Stent | Pass | | Foreshortening at Maximum | The test measured the change in stent length from the catheter-loaded condition to deployment at the maximum labeled diameter. Testing was conducted with consideration of the methods described in ASTM F2081-06. All samples met product specifications. | Resolute Integrity Stent; Resolute Stent | Pass | | Stent Recoil | This test quantified the amount of elastic recoil for the stent and correlated this parameter to the recommended sizing procedures. The stent delivery system was inflated to nominal pressure and the stent was removed allowing for recoil to occur. The inner diameter was recorded at the distal, middle and proximal sections of the stent. Recoil was calculated by subtracting the recoiled stent inner diameter from the pre-recoil inner diameter. All samples met the acceptance criteria. | Resolute Integrity Stent; Resolute Stent | Pass | | Stent ID | This test demonstrated that the stent inner diameter is consistent with labeling when deployed at nominal pressure. Each stent was deployed to nominal pressure, and the stent inner diameter was measured at the distal, middle and proximal sections of the stent. The results indicated that the inner diameter of Resolute and Resolute Integrity stents is consistent with labeling. | Resolute Integrity Stent; Resolute Stent | Pass | | Stent ID Uniformity | This test demonstrated stent inner diameter uniformity when deployed at nominal pressure. Testing was conducted with consideration of the methods described in ASTM F2081. All samples met the acceptance criteria. | Resolute Integrity Stent; Resolute Stent | Pass | | Stent Integrity | The test determined if the plastic deformation experienced by the stent when expanded from the compressed profile to the final maximum deployed diameter can produce crack initiation for the stent. Samples were deployed to their largest possible diameters by inflating each delivery system to maximum labeled diameter. Each stent was examined under magnification for potential cracks. All samples met the acceptance criteria with no visible cracks or notches. | Integrity Bare Metal Stent; Driver Bare Metal Stent | Pass | | Stent Crossing Profile | This test verified that the stent crossing profiles of Resolute and Resolute Integrity are consistent with label claims. Testing was conducted with considerations of the methods described in ASTM F2081. All samples met product specifications. | Resolute Integrity Stent; Resolute Stent | Pass | | Accelerated Durability Testing | This test evaluated the risk of stent failure caused by fretting, abrasion, and wear of Integrity and Driver bare metal stents deployed in an overlapped configuration in a 1.5cm radius bend after 420 million cycles. Stents were deployed to the largest intended diameter and tested through a simulated 10 year life. After the | Integrity Bare Metal Stent; Driver Bare Metal Stent | Pass | page 17 PMA P110013: FDA Summary of Safety and Effectiveness Data Table 7: In Vitro Testing Supporting the Performance of Resolute MicroTrac and Resolute Integrity | Test | Description of Test | Test Article | Results | | --- | --- | --- | --- | | | completion of the 10 year simulated durability testing, the stents were visually inspected using optical microscopy for cracks or fractures. All samples tested were free from cracks or fractures. There were no stent failures noted after 420 million cycles. Additionally stents were analyzed using SEM for fretting corrosion. | | | | Stent Material Analysis (Chemical Analysis) | This test confirmed that Resolute and Resolute Integrity stents are produced from material that conforms in chemical composition to ASTM F562-07. Chemical analysis was conducted on the Co-Ni-Cr-Mo alloy provided by the material supplier to confirm chemical analysis and inclusion/ impurity content as provided by ASTM F562 "Standard Specification for Wrought Cobalt-35 Nickel-20 Chromium-10 Molybdenum Alloy for Surgical Implant Applications." | Integrity Bare Metal Stent; Driver Bare Metal Stent | Pass | | Pitting and Crevice Corrosion Potential | This test evaluated the relative susceptibility to pitting/crevice corrosion of the Resolute stent compared to the Driver stent. Testing was conducted after scoring the Resolute coating down to the base metal and utilized the methods described in ASTM F746 and the experimental setup described in ASTM F2129. Results for the Resolute stent were comparable to the marketed Driver stent. This testing was also conducted on the Integrity stent. | Integrity Bare Metal Stent; Driver Bare Metal Stent Resolute Stent | N/A – Characterization Only | | Galvanic Corrosion | This test evaluated whether galvanically coupling the uncoated Resolute and Resolute Integrity stents (Driver and Integrity stents) to stents constructed from 316L stainless steel may promote accelerated corrosion of either stent as measured through galvanic coupling in a physiological saline solution. The results met all acceptance criteria and indicated a high resistance to galvanic corrosion. | Integrity Bare Metal Stent; Driver Bare Metal Stent | N/A – Characterization Only | | Percent Surface Area (Stent Free Area) | This test determined the percentage stent free area of the Resolute and Resolute Integrity stents. This value was calculated using stent nominal dimensional values and is based on the ratio of stent area to the area of the vessel. Metal to artery percentage ratios were calculated for all of the stent diameters recommended in the product labeling. | Integrity Bare Metal Stent; Driver Bare Metal Stent | N/A – Characterization Only | | Radial Stiffness and Radial Strength | This test determined stent resistance to radial load. The stents were deployed to nominal stent diameter and placed in a radial crush tester. All samples met the acceptance criteria. | Integrity Bare Metal Stent; Driver Bare Metal Stent | Pass | | Mechanical Properties | This test characterized the following properties of the annealed Co-Ni-Cr-Mo alloy bars conforming to ASTM F562. The bars were tensile tested to failure while engineering stress and strain were continuously recorded. The results were in conformance with ASTM F562 | Integrity Bare Metal Stent; Driver Bare Metal Stent | N/A – Characterization Only | | Fatigue and Stress Analysis | This test analyzed each stent design using a finite element analysis model to ensure that the implant conditions to which the stent would be subjected would not result in failure due to fatigue. The FEA evaluated the structural integrity of the stent when subjected to the expected loading conditions generated in coronary arteries. The analysis took into account manufacturing, delivery, implantation and clinical loading over the implant life, and predicted that fatigue failures will not likely occur. | Integrity Bare Metal Stent; Driver Bare Metal Stent | Pass | | MRI Safety | The following is included in the instructions for use: This test demonstrated that the Resolute MicroTrac and Resolute stent (up to a total length of 104 mm) and Resolute Integrity stents (up to a total length of 120 mm) are MR conditional. The stent (s) can be scanned safely under the following conditions: -Static magnetic field of 1.5 and 3 Telsa -Spatial gradient field of 1000 G/cm or less | Integrity Bare Metal Stent; Resolute Stent | Pass | page 18 PMA P110013: FDA Summary of Safety and Effectiveness Data Table 7: In Vitro Testing Supporting the Performance of Resolute MicroTrac and Resolute Integrity | Test | Description of Test | Test Article | Results | | --- | --- | --- | --- | | | Maximum whole body averaged specific absorption rate (SAR) of 2.0 W/kg or less under normal operating mode only, for 15 minutes of scanning. 1.5T Resolute Integrity Based on non-clinical testing and modeling, a 38 mm Resolute Integrity Stent was calculated to produce an in-vivo temperature rise of less than 2.35 °C and overlapped stents with a maximum length of 120 mm was calculated to produce an in-vivo temperature rise of less than 3.87 °C at a maximum whole body averaged specific absorption rate (SAR) of 2.0 W/kg for 15 minutes of MR scanning per sequence in a 64 MHz whole body transmit coil, which corresponds to a static field of 1.5 Tesla. These calculations do not take into consideration the cooling effects of perfusion and blood flow. The maximum whole body averaged specific absorption rate (SAR) was derived by calculation. Resolute MicroTrac Based on non-clinical testing and modeling, a 38 mm Resolute MicroTrac stent was calculated to produce an in-vivo temperature rise of less than 1.6°C and overlapped stents with a maximum length of 104 mm was calculated to produce an in-vivo temperature rise of less than 2.0°C at a maximum whole body averaged specific absorption rate (SAR) of 2.0 W/kg for 15 minutes of MR scanning in a 64 MHz whole body transmit coil, which corresponds to a static field of 1.5 Tesla. These calculations do not take into consideration the cooling effects of perfusion and blood flow. The maximum whole body averaged specific absorption rate (SAR) was derived by calculation. 3T: Resolute Integrity Based on non-clinical testing and modeling, a 38 mm Resolute Integrity Stent was calculated to produce an in-vivo temperature rise of less than 3.29 °C and overlapped stents with a maximum length of 120 mm was calculated to produce an in-vivo temperature rise of less than 3.95 °C at a maximum whole body averaged specific absorption rate (SAR) of 2.0 W/kg for 15 minutes of MR scanning per sequence in a 3 T GE SIGNA HDx with software version 14LX/MR release 14.0.M5A.0828.b. These calculations do not take into consideration the cooling effects of perfusion and blood flow. The maximum whole body averaged specific absorption rate (SAR) was derived by calculation. Resolute MicroTrac Based on non-clinical testing and modeling, a 38 mm Resolute MicroTrac stent was calculated to produce an in-vivo temperature rise of less than 1.5°C and overlapped stents with a maximum length of 104 mm was calculated to produce an in-vivo temperature rise of less than 3.0°C at a maximum whole body averaged specific absorption rate (SAR) of 2.0 W/kg for 15 minutes of MR scanning in a 3.0 T Siemens TrioTIM whole body MR system using software version syngo MR B13 4VB13A. These calculations do not take into consideration the cooling effects of perfusion and blood flow. The maximum whole body averaged specific absorption rate (SAR) was derived by calculation. | | | Table 7: In Vitro Testing Supporting the Performance of Resolute MicroTrac and Resolute Integrity | Test | Description of Test | Test Article | Results | | --- | --- | --- | --- | | | 1.5T and 3T The Resolute MicroTrac or Resolute Integrity stent should not move or migrate when exposed to MR scanning immediately post-implantation. MRI at 3 Telsa and 1.5 Telsa may be performed immediately following the implantation of the stent. Non-clinical testing at field strength greater than 3 Telsa has not been performed to evaluate stent migration and heating. MR image quality may be compromised if the area of interest is in the same area or relatively close to the position of the device. Therefore, it may be necessary to optimize MR imaging parameters for the presence of the implant. The image artifact extends approximately 1cm from the device, both inside and outside the delice lumen when scanned in non-clinical testing using the spin echo and gradient echo sequences specified in ASM F2119-01; the device lumen was always observed during scanning. | | | | Radiopacity | This test evaluated the radiopacity of the Resolute stents prior to deployment and angiographic appearance of the stent post-deployment. Resolute and Resolute Integrity stents must have adequate radiopacity to ensure safe and effective delivery of the stents to the target vessel location. | Resolute Integrity Stent; Resolute Stent | Pass | | Delivery System Dimensional and Functional Attributes | | | | | Delivery System Crossing Profile | This test verified that the crossing profile of the MicroTrac system is consistent with label claims. All samples met product specifications. | MicroTrac and Commercial MicroTrac delivery systems | Pass | | Catheter Effective Length | This test measured the catheter effective length. All samples met product specifications. | MicroTrac delivery system | Pass | | Distal Shaft Marker Distance | This test measured the distance of the distal shaft marker. All samples met product specifications. | MicroTrac delivery system | Pass | | Delivery, Deployment and Retraction | This test assessed the ability of the delivery system to be prepared and tracked through a tortuous path and simulated vessel. This test also measured the retraction forces of the delivery system after deployment of the stent. Results indicated that the delivery system performed as intended and no damage to the stent was noted. | Resolute Integrity Stent on MicroTrac and Commercial MicroTrac delivery systems; Resolute Stent on MicroTrac delivery system | N/A – Characterization Only | | Balloon Rated Burst Pressure | This test demonstrated that the delivery system (with mounted stent) does not experience loss of integrity of balloon, shaft, proximal adapter or proximal/distal seal at or below the pressure required to expand the stent to the Rated Burst Pressure (RBP). The results demonstrated with 95% confidence that at least 99.9% of the delivery systems will not experience loss of integrity at or below the rated burst pressure. | Resolute Integrity Stent on MicroTrac and Commercial MicroTrac delivery systems; Resolute Stent on MicroTrac delivery system | Pass | | Balloon Fatigue | This test demonstrated the repeatability (to 10 inflations) of successful unconstrained balloon inflation to RBP. The stent/balloon burst results show statistically that, with 95% confidence, 90% of the delivery systems will not experience balloon, shaft, or proximal/distal loss of integrity at or below the maximum recommended RBP. | Resolute Integrity Stent on MicroTrac and Commercial MicroTrac delivery systems; Resolute Stent on MicroTrac delivery system | Pass | PMA P110013: FDA Summary of Safety and Effectiveness Data page 20 PMA P110013: FDA Summary of Safety and Effectiveness Data Table 7: In Vitro Testing Supporting the Performance of Resolute MicroTrac and Resolute Integrity | Test | Description of Test | Test Article | Results | | --- | --- | --- | --- | | Stent Diameter vs. Balloon Pressure (Compliance) | This test quantified the stent inner diameter as a function of balloon inflation pressure. The stent sizing results verify that the stent systems meet the labeled compliance curves. | Resolute Integrity Stent on MicroTrac delivery system; Resolute Stent on MicroTrac delivery system | N/A – Characterization Only | | Balloon Bond Tensile and Yield | This test demonstrated that the delivery system meets the product specifications for balloon bond tensile and yield. | MicroTrac and Commercial MicroTrac delivery systems | Pass | | Catheter Bond Tensile | This test demonstrated that each delivery system meets the design requirements for catheter bond tensile. All bonds were loaded into the tensile tester and pulled to failure. All samples met the acceptance criteria. | MicroTrac and Commercial MicroTrac delivery systems | Pass | | Exchange Joint Distance | This test measured the distance from the balloon bond to the exchange joint for the RX delivery system. All samples met the acceptance criteria. | MicroTrac delivery system | Pass | | Balloon Inflation and Deflation Time | This test characterized the inflation time to RBP, by evaluating the time needed to manually inflate the product to RBP and the time required for the product to deflate from RBP. All samples met the product specification. | MicroTrac and Commercial MicroTrac delivery systems | Pass | | Stent Securement (Distal and Proximal) | This test measured the force required to remove a stent distally and proximally from a balloon. All samples met the product specifications. | MicroTrac delivery system | Pass | | Lesion Crossability and Guide Catheter Pullback | This test characterized the ability of the stent to resist shifting/dislodgement while passing through a simulated lesion. This test also evaluated stent dislodgement by reverse motion when the stent is withdrawn into a guide catheter with a minimum guide catheter inner diameter in accordance with label claim. All samples met the acceptance criteria. | MicroTrac and Commercial MicroTrac delivery systems | Pass | | Catheter Torque Testing | This test demonstrated the number of rotations the catheter can withstand prior to fracture. | MicroTrac and Commercial MicroTrac delivery systems | N/A – Characterization Only | | Catheter Kink Testing | This test demonstrated the smallest radius that the catheter can conform to prior to kinking. | MicroTrac and Commercial MicroTrac delivery systems | N/A – Characterization Only | E. Coating Characterization Testing The following methods were used to characterize and set initial specifications for Resolute MicroTrac and Resolute Integrity Zotarolimus-Eluting Coronary Stent Systems. The coating characterization testing conducted includes the tests summarized in Table 8. Table 8: Coating Characterization Testing | Test | Description of Test | Test Article | Results | | --- | --- | --- | --- | | Particulate (Submerge and Deploy) | This test determined particulate matter after deployment of a single stent in an aqueous solution in two configurations: -to nominal (baseline) -to maximum labeled diameter (over expansion) | Resolute Integrity Stent; Resolute Stent | N/A – Characterization Only | | Particulate (Bent and Overlapped) | This test determined particulate matter after two stents have been tracked through a tortuous fixture and deployed in a bent and overlapped configuration in a simulated vessel (simulated use). | Resolute Integrity Stent on MicroTrac and Commercial MicroTrac delivery systems; Resolute Stent on MicroTrac delivery system | N/A – Characterization Only | | Particulate (Acute Track and Deploy) | The test used light obscuration particle count method to determine the particulate matter after a single stent has been tracked, deployed in a bent configuration and expanded to rated burst pressure (RBP), simulating clinical procedure. | Resolute Integrity Stent on MicroTrac and Commercial MicroTrac delivery systems; Resolute Stent on MicroTrac delivery system | Pass | | Acute Coating Integrity | This test visually assessed the coating integrity of a single stent deployed in two configurations: -to nominal in an aqueous solution (baseline) -to maximum labeled diameter in a mock vessel after tracking through a tortuous fixture simulated use | Resolute Integrity Stent on MicroTrac delivery system; Resolute Stent on MicroTrac delivery system | N/A – Characterization Only | | Chronic Coating Integrity Test | This test characterized the chronic coating integrity of overlapped Resolute stents after 420 million cycles (equivalent to ten years in vivo) of radial pulsation in a bent configuration. Chronic coating integrity of the Resolute stents was visually assessed by SEM imaging. | Resolute Integrity Stent; Resolute Stent | N/A – Characterization Only | | Physical Structure and Chemical properties of coating components | This test described the physical and chemical properties of the Resolute Coating Components | MicroTrac delivery system | N/A – Characterization Only | | Chronic Coating Fatigue particulate testing | This test determined the particulate matter of the Resolute stent after being subjected to up to 420 million cycles of heated radial fatigue post tracking and deployment in an overlapped configuration. | Resolute Integrity Stent; Resolute Stent | N/A – Characterization Only | | Coating Thickness | This test characterized the coating thickness along the stent length of the Resolute stent via Scanning | Resolute Integrity Stent; | N/A – | 27 page 21 PMA P110013: FDA Summary of Safety and Effectiveness Data PMA P110013: FDA Summary of Safety and Effectiveness Data page 22 28 | Test | Description of Test | Test Article | Results | | --- | --- | --- | --- | | Testing | Electron Microscope (SEM) cross sectional imaging. | Resolute Stent | Characterization Only | | Coating Adhesion Testing | This test quantitatively characterized the adhesion strength for each coating layer of the Resolute stent. | Resolute Integrity Stent; Resolute Stent | N/A – Characterization Only | | Coating Stress Analysis (Finite Element Analysis) | The finite element analysis (FEA) model represented the Resolute coating experiencing the stresses and strains related to maximum diameter and cyclic loading in the straight and 1.5cm radius curvature positions. | Resolute Stent | N/A – Characterization Only | | Chemical Identification Testing | This test characterized and identified particulate that had been recovered from Resolute stents that had been tracked through a clinically relevant tortuous fixture and deployed around a 1.5cm radius bend to the maximum labeled diameter in an overlapped configuration. Particulate was characterized and identified via Raman spectrometry, staining and SEM imaging | Resolute Integrity Stent on MicroTrac delivery system; Resolute Stent | N/A – Characterization Only | 29 PMA P110013: FDA Summary of Safety and Effectiveness Data page 23 # F. Chemistry Manufacturing and Control (CMC) Testing Each batch of finished product undergoes CMC testing. This testing is summarized in Table 9. Where applicable, the test methods follow International Conference on Harmonization (ICH) Guidelines. All testing must meet the specifications established for finished goods release. Information to support the stability of the Resolute and Resolute Integrity stents is summarized separately in Section G, Stability and Shelf Life. Table 9: CMC Release Testing | Test | Description of Test | Test Article | | --- | --- | --- | | Determination of Total Drug Content (Potency and Content Uniformity) | The objective of this test is to identify and quantify zotarolimus in Resolute and Resolute Integrity stents. Tracked drug content is performed to simulate the in vivo tracking and deployment of the finished Resolute device. | Resolute Integrity Stent; Resolute Stent | | Determination of Total Drug Related Substances | The objective of this test is to quantify related substances (degradation products) on the finished Resolute and Resolute Integrity stents. | Resolute Integrity Stent; Resolute Stent | | Determination of Butylated Hydroxytoluene (BHT) | The objective of this test is to quantify the BHT content of the finished Resolute and Resolute Integrity stents. | Resolute Integrity Stent; Resolute Stent | | Determination of Residual Solvents | The objective of this test is to quantify the residual solvents, used in manufacturing of finished Resolute and Resolute Integrity stents. | Resolute Integrity Stent; Resolute Stent | | Elution Testing | The objective of this test is to characterize the in vitro elution profile of Resolute and Resolute Integrity stents. | Resolute Integrity Stent; Resolute Stent | | Particulate (regulatory method) | The objective of this test is to use the light obscuration particle count method for the determination of particulate matter on Coronary Stent Systems that have been tracked, deployed and expanded to rated burst pressure (RBP), simulating clinical procedure. | Resolute Integrity Stent on Commercial MicroTrac delivery system; Resolute Stent on Commercial MicroTrac delivery system | PMA P110013: FDA Summary of Safety and Effectiveness Data page 24 ## G. Stability and Shelf Life Manufacturing site-specific stability studies were conducted to establish a shelf-life/expiration date for Resolute MicroTrac and Resolute Integrity Zotarolimus-Eluting Coronary Stent Systems. Testing in support of package integrity and functional testing of the stent systems was conducted on aged product. The testing evaluation includes drug identity, assay, degradants, *in vitro* elution, particulates, sterility, drug content uniformity, residual solvents, and endotoxins. Appropriate engineering tests were also performed on aged product and compared to baseline to ensure that Resolute MicroTrac and Resolute Integrity Coronary Stent Systems meet specifications throughout the shelf life. The data generated from the stability studies, coupled with the data generated from the in vitro shelf life studies, support an 18 month label claim and associated shelf life for both products. ## H. Sterilization Resolute MicroTrac and Resolute Integrity Coronary Stent Systems are sterilized using ethylene oxide sterilization, and have been validated per AAMI/ISO 11135-1:2007 “Sterilization of health care products-Ethylene Oxide – Part 1: Requirements for development, validation and routine control of a sterilization process for medical devices” and EN556-1:2002 “Sterilization of Medical Devices – Requirements for medical devices to be designated STERILE – Part 1: Requirements for terminally sterilized medical devices.” Results obtained from the sterilization studies show that the product satisfies a minimum Sterility Assurance Level (SAL) of $10^{-6}$. The amounts of bacterial endotoxin were verified to be within the specification limits. ## I. Animal Studies Because important arterial histopathology, histomorphometry, and tissue and stent-based pharmacokinetic data cannot be obtained from human clinical studies, a series of animal experiments using a porcine coronary artery model of stent implantation were conducted to evaluate safety, vascular compatibility, drug bioequivalence, and acute product performance. All animal studies (feasibility, safety, pharmacokinetic and acute) were conducted in accordance with § 21CFR 58 (Good Laboratory Practices), except where noted. Non-GLP studies were conducted in order to provide additional background data on non-safety related issues. Animal testing included studies that evaluated the safety and device performance of the Resolute stent mounted on FDA-approved earlier generation catheter delivery systems (Sprint and AV100 delivery systems) and mounted on the MicroTrac delivery system. Additional studies evaluated the Resolute Integrity stent mounted on the MicroTrac delivery system. The initial animal studies conducted on the Resolute stent mounted on the MicroTrac delivery system showed larger and more frequent myocardial ischemic lesions compared to those studies conducted on the Resolute stent mounted on earlier generation delivery catheters. To address these findings, manufacturing changes were made to the MicroTrac delivery system. An additional animal study (FS212) was conducted on the Resolute Integrity stent mounted on the modified MicroTrac delivery system (also referred to as Commercial MicroTrac). In this study, myocardial histology in animals implanted with the Resolute Integrity stent mounted on the modified MicroTrac delivery system demonstrated very few myocardial lesions, and the findings were comparable to the control articles, which consisted of FDA-approved earlier generation delivery catheters. Animal testing also included bioequivalency studies that demonstrated bioequivalency (with respect to residual drug on the stent and drug in the treated tissue) of Resolute Integrity stents mounted on the MicroTrac delivery system and Resolute stents mounted on the MicroTrac delivery system compared to the same stent systems manufactured at an alternate site. Summaries of the major animal studies performed to support product safety are included in Table 10. PMA P110013: FDA Summary of Safety and Effectiveness Data page 25 Table 10: Summary of In Vivo Testing | Study | Stent Design | Stent Size (mm) | Type/Number of animals | Number of Stents | Follow-up duration | Major Endpoints | | --- | --- | --- | --- | --- | --- | --- | | FS192 | Test Article: Resolute Integrity RX Control: Resolute MicroTrac GLP: Yes | Diameters: 3.0 mm Length: 18 mm | Domestic Farm Swine/49 | Test: 48 Control: 48 | Up to 60 days | Comparison of the amount of released drug from the Resolute Integrity stent and Resolute MicroTrac stent at various time points between 0 and 60 days, through determination of residual drug content on explanted stents and drug in treated arterial tissue. | | FS193 | Test Article: Resolute Integrity Control: Resolute MicroTrac and Integrity Bare Metal Stent GLP: Yes | Diameters: 3.0, 3.5 mm Lengths: 12, 18 mm | Yucatan Mini Swine/28 | Test: 28 Control: 53 | 90 days | Angiographic analysis Morphometric analysis Histopathology SEM analysis | | FS194 | Test Article: Resolute Integrity Control: Resolute MicroTrac and Integrity Bare Metal Stent GLP: Yes | Diameters: 3.0, 3.5 mm Lengths: 12, 18 mm | Yucatan Mini Swine/29 | Test: 29 Control: 52 | 28 days | Angiographic analysis Morphometric analysis Histopathology SEM analysis | | FS195 | Test Article: Resolute Integrity Control: Resolute MicroTrac and Integrity Bare Metal Stent GLP: Yes | Diameters: 3.0, 3.5 mm Lengths: 12, 18 mm | Yucatan Mini Swine/31 | Test: 26 Control: 47 | 5 days | Angiographic analysis Morphometric analysis Histopathology SEM analysis | | FS196 | Test Article: Resolute Integrity Control: Resolute MicroTrac and Integrity Bare Metal Stent GLP: Yes | Diameters: 2.25, 2.5, 2.75 mm Lengths: 8 mm | Yucatan Mini Swine/14 | Test: 14 Control: 28 | 28 days | Angiographic analysis Morphometric analysis Histopathology SEM analysis Radiopacity | | FS197 | Test Article: Resolute Integrity Control: Resolute AV100³, Endeavor Sprint OTW, Resolute Sprint | Diameters: 2.25, 3.5, 4.0 mm Lengths: 8, 30, 35 mm | Domestic Farm Swine/4 | Test: 56 Control: 30 | Acute | Acute performance, including: System introduction, Guide Catheter and Guide Wire Compatibility, Deliverability, Trackability, Pushability, Pullback into the guide catheter (of the undeployed | Resolute AV100 is a predicate device, which has the identical bare metal stent and drug coating to Resolute MicroTrac but utilizes a different delivery system PMA P110013: FDA Summary of Safety and Effectiveness Data Table 10: Summary of In Vivo Testing | Study | Stent Design | Stent Size (mm) | Type/Number of animals | Number of Stents | Follow-up duration | Major Endpoints | | --- | --- | --- | --- | --- | --- | --- | | | RX, Endeavor Sprint RX GLP: Yes | | | | | and deployed stents), Deployment Inflation/deflation performance, Radiopacity, and Overall performance | | PS255 | Test Article: Resolute AV100 and Polymer-coated Stents Control: Driver Bare Metal Stent GLP: No | Diameters: 3.0, 3.5 mm Lengths: 18 mm | Domestic Farm Swine/11 | Test: 20 Control: 9 | 28 Days | Acute performance Angiographic analysis Morphometric analysis Histopathology | | FS125 | Test Article: Resolute AV100 and Polymer-coated Stents Control: Driver Bare Metal Stents GLP: Yes | Diameters: 3.0, 3.5 mm Lengths: 12, 18 mm | Domestic Farm Swine/49 | Test: 102 Control: 63 | 28 Days | Acute performance Angiographic analysis Morphometric analysis Histopathology | | FS127 | Test Article: Polymer Coated Stents Control: Driver Bare Metal Stents GLP: Yes | Diameters: 3.0, 3.5 mm Lengths: 18 mm | Domestic Farm Swine/10 | Test: 13 Control: 12 | 28 Days | Acute performance Angiographic analysis Morphometric analysis Histopathology | | FS128 | Test Article: Resolute AV100 and Polymer-coated Stents Control: Driver Bare Metal Stent GLP: Yes | Diameters: 3.0, 3.5 mm Lengths: 12, 18 mm | Yucatan mini Swine/46 | Test: 88 Control: 65 | 90 Days | Acute performance Angiographic analysis Morphometric analysis Histopathology SEM Analysis | | FS129 | Test Article: Resolute AV100 and Polymer-coated Stents Control: Driver Bare Metal Stent GLP: Yes | Diameters: 3.0, 3.5 mm Lengths: 12, 18 mm | Yucatan mini Swine/45 | Test: 89 Control: 63 | 180 Days | Acute performance Angiographic analysis Morphometric analysis Histopathology SEM Analysis | | FS138 | Test Article: Resolute AV100 Control: Driver Bare Metal Stent GLP: Yes | Diameters: 3.0, 3.5 mm Lengths: 12, 18 mm | Domestic Farm Swine/18 | Test: 41 Control: 27 | 7 Days | Acute performance Angiographic analysis Morphometric analysis Histopathology Cellular proliferation (BrdU Analysis) | | PS320 | Test Article: Resolute AV100 | Diameters: 3.0, 3.5 mm | Domestic Farm Swine/27 | Test: 44 Control: 27 | 7 Days | Acute performance Angiographic analysis | PMA P110013: FDA Summary of Safety and Effectiveness Data 34 page 28 PMA P110013: FDA Summary of Safety and Effectiveness Data Table 10: Summary of In Vivo Testing | Study | Stent Design | Stent Size (mm) | Type/Number of animals | Number of Stents | Follow-up duration | Major Endpoints | | --- | --- | --- | --- | --- | --- | --- | | | Control: Driver Bare Metal Stent GLP: No | Lengths: 18 mm | | | | Morphometric analysis Histopathology | | FS149 | Test Article: Resolute AV100 Control: Driver Bare Metal Stent GLP: Yes | Diameters: 3.0, 3.5 mm Lengths: 12, 18 mm | Domestic Farm Swine/18 | Test: 34 Control: 26 | 7 Days | Acute performance Angiographic analysis Morphometric analysis Histopathology | | FS132 | Test Article: Resolute AV100 Control: Polymer Coated Stents GLP: Yes | Diameter: 3.0 mm Length: 18 mm | Yucatan mini swine/30 | Test: 54 Control: 4 | Up to 180 Days | Zotarolimus concentration - blood Zotarolimus concentration - arterial tissue Zotarolimus concentration - myocardial tissue Zotarolimus concentration - non-target organs Stent drug content at explant | | FS142 | Test Article: Resolute AV100 and Polymer-coated Stents Control: Driver Bare Metal Stent GLP: Yes | Diameters: 3.0, 3.5 mm Length: 12, 18 mm | Yucatan mini swine/63 | Test: 108 Control: 91 | 365 Days | Acute performance Angiographic analysis Morphometric analysis Histopathology SEM analysis | | FS144 | Test Article: Resolute AV100 and Polymer-coated Stents Control: Driver Bare Metal Stent GLP: Yes | Diameters: 2.25, 2.5 mm Length: 8 mm | Domestic Farm Swine/34 | Test: 52 Control: 34 | 28 Days | Acute performance Angiographic analysis Morphometric analysis Histopathology SEM analysis | | FS165 | Test Article: Resolute Sprint Control: Resolute AV100,Driver Bare Metal Stent GLP: Yes | Diameters: 3.0, 3.5 mm Length: 18 mm | Domestic Farm Swine/16 | Test: 11 Control: 26 | 7 Days | Acute performance Angiographic analysis Morphometric analysis Histopathology SEM analysis | | FS166 | Test Article: Resolute Sprint Control: Resolute AV100,Driver Bare Metal Stent | Diameters: 3.0, 3.5 mm Length: 18 mm | Domestic Farm Swine/16 | Test: 12 Control: 27 | 28 Days | Acute performance Angiographic analysis Morphometric analysis Histopathology SEM analysis | PMA P110013: FDA Summary of Safety and Effectiveness Data page 29 Table 10: Summary of In Vivo Testing | Study | Stent Design | Stent Size (mm) | Type/Number of animals | Number of Stents | Follow-up duration | Major Endpoints | | --- | --- | --- | --- | --- | --- | --- | | | GLP: Yes | | | | | | | FS169 | Test Article: Resolute Sprint Control: Resolute AV100 GLP: Yes | Diameter: 4.0 mm Length: 30 mm | Domestic Farm Swine/2 | Test: 30 Control: 28 | Acute | Acute performance including: System compatibility, Guide wire compatibility, Deliverability, Trackability, Pushability, Pullback into the guide catheter (of the undeployed stent), Deployment inflation/deflation performance, Radiopacity, Pullback into the guide catheter (of the deployed stent delivery system) | | FS170 | Test Article: Resolute Sprint and Polymer-coated Stents Control: Micro-Driver Bare Metal Stent GLP: Yes | Diameters: 2.25, 2.5 mm Length: 8 mm | Yucatan Mini Swine/21 | Test: 33 Control: 21 | 180 Days | Acute performance Angiographic analysis Morphometric analysis Histopathology SEM analysis | | FS180 | Test Article: Resolute Sprint GLP: Yes | Diameter: 3.0 mm Length: 30 mm | Domestic Farm Swine/48 | Test: 96 | Up to 60 Days | Comparison of stent drug content at explant Comparison of cumulative drug elution rate | | FS185 | Test Article: Resolute MicroTrac Control: Resolute AV100 GLP: Yes | Diameters: 4.0 mm Length: 38 mm | Domestic Farm Swine/1 | Test: 10 Control: 10 | Acute | Acute performance including: Guide Catheter compatibility, Guide Wire compatibility, Deliverability, Trackability, Pushability, Deployment inflation/deflation performance, Radiopacity, Pullback into the guide catheter (of the deployed stent delivery system), Overall performance | | FS187 | Test Article: Resolute MicroTrac Control: Endeavor Sprint GLP: Yes | Diameters: 3.5 mm Length: 30 mm | Domestic Farm Swine/1 | Test: 10 Control: 10 | Acute | Acute performance including: Guide Catheter compatibility, Guide Wire compatibility, Deliverability, Trackability, Pushability, Deployment inflation/deflation performance, Radiopacity, Pullback into the guide catheter (of the deployed stent delivery system), Overall performance | | FS190 | Test Article: Resolute MicroTrac Control: Resolute Sprint. | Diameters: 3.0, 3.5 mm Length: | Yucatan Mini Swine/16 | Test: 14 Control: 27 | 28 Days | Acute performance Angiographic analysis Morphometric analysis | PMA P110013: FDA Summary of Safety and Effectiveness Data page 30 Table 10: Summary of In Vivo Testing | Study | Stent Design | Stent Size (mm) | Type/Number of animals | Number of Stents | Follow-up duration | Major Endpoints | | --- | --- | --- | --- | --- | --- | --- | | | Driver Bare Metal Stents | 18 mm | | | | Histopathology SEM analysis | | FS212 | Test Article: Resolute Integrity Stent on the commercial MicroTrac RX Delivery System Controls: Resolute Stent on the Sprint RX Delivery System Endeavor Stent on the Sprint RX Delivery System | Diameters: 3.0, 3.5 mm Length: 18 mm | Yucatan Mini Swine/30 | Test: 20 Controls: 40 | 28 Days | Angiographic analysis Histopathology Morphometric analysis | PMA P110013: FDA Summary of Safety and Effectiveness Data page 31 # X. SUMMARY OF CLINICAL STUDIES ## A. Overview of Clinical Studies The principal safety and effectiveness information for the RESOLUTE MicroTrac and RESOLUTE Integrity Zotarolimus-Eluting Coronary Stent Systems is derived from a series of clinical trials conducted on the Resolute Zotarolimus-Eluting Coronary Stent System (Resolute stent system). The Resolute stent system consists of the cobalt alloy bare metal stent, the zotarolimus and BioLinx stent coating, and the Sprint delivery system. The Resolute MicroTrac stent system features the same coated stent as the Resolute stent system, but on a different delivery system (MicroTrac). The Resolute Integrity stent mounted on the MicroTrac delivery system is similar to the Resolute stent mounted on the Sprint delivery system with regard to the stent design, the stent coating technology (drug concentration and drug to polymer ratio), and delivery system design and materials. The Resolute Integrity stent is manufactured from a single wire whereas the Resolute stent is formed from laser fused elements. The Resolute Integrity stent is mounted on the MicroTrac delivery system, which differs from the Sprint delivery system with regard to the catheter manufacturing, shaft and tip design, and stent crimping process. Given the similarities between the Resolute stent system and the Resolute Integrity stent system, and supportive bench and animal study information, the findings from the RESOLUTE clinical studies, as described below, are applicable to the Resolute MicroTrac and Resolute Integrity stent systems. The principal safety and effectiveness information for the Resolute stent was derived from the Global RESOLUTE Clinical Trial Program, which consists of the following clinical trials – the RESOLUTE United States Clinical Trial, the RESOLUTE All-Comers Clinical Trial, the RESOLUTE International Study, the RESOLUTE First-in-Man (FIM) Clinical Trial and the RESOLUTE Japan Clinical Trial. These five studies evaluated the performance of the Resolute stent in improving coronary luminal diameters in patients, including those with diabetes mellitus, with symptomatic ischemic heart disease due to de novo lesions of length $\leq 27$ mm in native coronary arteries with reference vessel diameters of $2.25\mathrm{mm}$ to $4.2\mathrm{mm}$. Key elements of these studies are summarized below in Table 11. The RESOLUTE United States (RESOLUTE US) Clinical Trial is a prospective, multicenter, non-randomized trial that evaluated the safety and effectiveness of the Resolute stent for treatment of de novo lesions in native coronary artery(ies) with reference vessel diameters (RVD) ranging from $2.25\mathrm{mm}$ to $4.2\mathrm{mm}$. The RESOLUTE US Clinical Trial is the pivotal trial of the overall Global RESOLUTE Clinical Trial Program. The RESOLUTE US trial included the following: - The $2.25\mathrm{mm}$ to $3.5\mathrm{mm}$ Main Study: The primary endpoint was Target Lesion Failure (TLF) at 12 months post-procedure, defined as Cardiac Death, Target Vessel Myocardial Infarction (MI), or clinically driven Target Lesion Revascularization (TLR). - The 2.25 mm Cohort, in which the cohort was derived from subjects treated with the 2.25 mm Resolute stent in the 2.25 mm to 3.5 mm Main Study and the 2.25 to 3.5 mm Angio/IVUS sub-study. The primary endpoint was TLF at 12 months post-procedure. - The 2.25 mm to 3.5 mm Angio/IVUS Sub-study: The primary endpoint was in-stent late lumen loss (LL) at 8 months post-procedure as measured by quantitative coronary angiography (QCA). - The 4.0 mm stent Sub-study. The primary endpoint was in-segment late LL at 8 months post-procedure as measured by QCA. The total study population of the primary enrollment group (consisting of all subjects enrolled in the four studies listed above) consisted of 1402 subjects at 116 investigational sites in the United States. Post-procedure, subjects were to receive aspirin indefinitely and clopidogrel/ticlopidine for a minimum of six months and up to 12 months in subjects who were not at a high risk of bleeding. The RESOLUTE All-Comers (RESOLUTE AC) Clinical Trial is a prospective, multi-center, two-arm randomized, non-inferiority trial that compared the Resolute stent to a control DES (the Xience V® stent). The eligibility criteria reflected an ‘all-comers’ population. A total of 2292 subjects were enrolled at 17 clinical research sites from 11 countries in Western Europe (Switzerland, Belgium, Netherlands, Denmark, France, Germany, Italy, Spain, United Kingdom, Israel, and Poland). The primary endpoint was TLF, defined as the composite of Cardiac Death, MI (not clearly attributable to a non-target vessel), or and clinically indicated TLR within 12 months post-implantation. Post-procedure, subjects were to receive aspirin indefinitely and clopidogrel/ticlopidine for a minimum of six months and up to 12 months in subjects who were not at a high risk of bleeding. The RESOLUTE International (RESOLUTE Int) study is a prospective, multi-center, non-randomized, single-arm observational study with all enrolled subjects treated according to routine practices at participating hospitals. A total of 2349 subjects were enrolled at 88 clinical research sites from 17 countries distributed over Europe, Asia, Africa and South America. The primary objective of this study was to evaluate the safety and clinical performance of the Resolute stent in an ‘all-comers’ patient population. The primary endpoint was the composite of Cardiac Death and MI (not clearly attributable to a non-target vessel) at 12 months post-implantation. Post-procedure, subjects were to receive aspirin indefinitely and clopidogrel/ticlopidine for a minimum of six months and up to 12 months in subjects who were not at a high risk of bleeding. The RESOLUTE FIM Clinical Trial is the first-in-human study evaluating the Resolute stent. RESOLUTE FIM is a non-randomized, prospective, multi-center, single-arm trial. The purpose of the trial was to assess the initial safety of the Resolute stent. A total of 139 subjects were enrolled at 12 investigative sites in Australia and New Zealand. The primary endpoint was in-stent late lumen loss (LL) at nine months post-implantation measured by QCA. Post-procedure, subjects were to receive aspirin indefinitely and clopidogrel/ticlopidine for a minimum of six months. This trial had a subset of subjects undergoing pharmacokinetic (PK) assessments (see Section IX C for the pharmacokinetic profile of the Resolute stent). PMA P110013: FDA Summary of Safety and Effectiveness Data page 32 The RESOLUTE Japan Clinical Trial is a prospective, multi-center, non-randomized, single-arm trial. A total of 100 subjects were enrolled at 14 investigational sites in Japan. The primary endpoint was in-stent late… --- **Source:** [https://fda.innolitics.com/device/P110013](https://fda.innolitics.com/device/P110013) **Published by [Innolitics](https://innolitics.com)** — a medical-device software consultancy. We help companies design, build, and clear FDA-regulated software and AI/ML devices. 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