BioFreedom Drug Coated Coronary Stent System

P190020 · Biosensors International USA, Inc. · NIQ · Apr 14, 2022 · Cardiovascular

Device Facts

• Record ID: P190020
• Device Name: BioFreedom Drug Coated Coronary Stent System
• Applicant: Biosensors International USA, Inc.
• Product Code: NIQ · Cardiovascular
• Decision Date: Apr 14, 2022
• Decision: APWD
• Device Class: Class 3
• Attributes: Therapeutic

Indications for Use

The BioFreedom DCS is indicated for improving coronary luminal diameter in patients at high risk for bleeding with symptomatic ischemic heart disease due to de novo lesions of length ≤ 32 mm in native coronary arteries with a reference diameter ranging between 2.25 mm and 4.0 mm.

Device Story

BioFreedom DCS is a polymer-free, drug-coated coronary stent system consisting of a 316L stainless steel stent abluminally coated with Biolimus A9 (BA9) and a rapid-exchange delivery system. Used in the cardiac catheterization lab by interventional cardiologists to treat coronary artery disease. The stent is deployed via balloon inflation; BA9 is released into the vessel wall to inhibit smooth muscle cell proliferation and reduce restenosis. The device is intended for patients at high bleeding risk who require a shortened (1-month) dual antiplatelet therapy (DAPT) regimen. Clinical output is the mechanical restoration of luminal diameter and pharmacological prevention of neointimal hyperplasia. The device benefits patients by providing an effective anti-restenotic treatment while minimizing the duration of DAPT, thereby reducing bleeding risks associated with long-term antiplatelet therapy.

Clinical Evidence

Evidence based on the prospective, multi-center, single-arm LEADERS FREE II (LFII) trial (N=1203) and historical control data from the LEADERS FREE (LFI) trial. Primary safety endpoint (cardiac death/MI at 6 months) met non-inferiority and superiority vs. historical BMS control (6.5% vs 9.7%, p<0.0001). Primary effectiveness endpoint (clinically-driven TLR at 6 months) met non-inferiority and superiority (3.7% vs 6.1%, p<0.0001). Additional supportive data from LFI, ONYX ONE, and feasibility studies confirm safety and effectiveness in high-bleeding-risk populations.

Technological Characteristics

Stent: 316L stainless steel, 6-crown (2.25-3.0mm) or 9-crown (3.5-4.0mm) pattern. Coating: Polymer-free abluminal Biolimus A9 (BA9). Delivery: Rapid Exchange (RX) semi-compliant balloon catheter. Sterilization: E-beam irradiation. Shelf life: 9 months. Standards: ASTM F138 (material), ASTM F2129/G71 (corrosion), ISO 10555-1 (catheter).

Indications for Use

Indicated for patients at high risk for bleeding with symptomatic ischemic heart disease due to de novo lesions (≤ 32 mm) in native coronary arteries (2.25-4.0 mm reference diameter). Contraindicated in patients unable to receive recommended antiplatelet/anticoagulation therapy, those with lesions preventing complete balloon inflation, or those with known hypersensitivity to BA9, stainless steel, nickel, or contrast agents.

Regulatory Classification

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.

Reference Devices

• Gazelle bare metal stent (BMS)
• Taxus Liberté
• Taxus Express
• Resolute Onyx (Medtronic)

Submission Summary (Full Text)

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SUMMARY OF SAFETY AND EFFECTIVENESS DATA (SSED)

I. GENERAL INFORMATION

Device Generic Name: Coronary Drug Eluting Stent

Device Trade Name: BioFreedom Drug Coated Coronary Stent System (BioFreedom DCS)

Device Procode: NIQ

Applicant’s Name and Address: Biosensors International USA, Inc.
1013 Centre Rd. Suite 228
Wilmington, DE 19805

Date of Panel Recommendation: None

Premarket Approval Application (PMA) Number: P190020

Date of FDA Notice of Approval: April 14, 2022

II. INDICATIONS FOR USE

The BioFreedom DCS is indicated for improving coronary luminal diameter in patients at high risk for bleeding with symptomatic ischemic heart disease due to de novo lesions of length ≤ 32 mm in native coronary arteries with a reference diameter ranging between 2.25 mm and 4.0 mm.

III. CONTRAINDICATIONS

The BioFreedom DCS is contraindicated for use in:

- Patients who cannot receive the recommended antiplatelet therapy (aspirin/P2Y₁₂ platelet inhibitor) and/or anticoagulation therapy (heparin or bivalirudin).
- Patients with lesion(s) that prevent(s) complete inflation of an angioplasty balloon.
- Patients with known hypersensitivity to the BA9 drug or its derivatives.
- Patients with known allergies to stainless steel, nickel or other metal ions found in 316L stainless steel.
- Patients with known sensitivity to contrast agents that cannot be controlled prophylactically prior to BioFreedom stent implantation.

IV. WARNINGS AND PRECAUTIONS

The warnings and precautions can be found in the BioFreedom DCS labeling.

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# V. DEVICE DESCRIPTION

The BioFreedom DCS is a combination product consisting of two key components: the stent coated abluminally with the active ingredient Biolimus A9 (BA9), and the delivery system. The BioFreedom DCS is a polymer-free drug-coated coronary stent system.

The characteristics of the BioFreedom DCS are described in Table 1.

Table 1. BioFreedom DCS Product Characteristics

| Stent Pattern | 6-Crown model | 9-Crown model |
| --- | --- | --- |
| Stent Diameters (mm) | 2.25, 2.5, 2.75, 3.0 | 3.5, 4.0 |
| Stent Strut Thickness (mm) | 0.119 | 0.114 |
| Stent Lengths (mm) | 8, 11, 14, 18, 24, 28 | |
| Stent Material | Stainless Steel 316L | |
| Drug Component | An abluminal (outer surface of the stent) polymer-free coating of BA9 drug applied to the selectively micro-structured surface (SMS) | |
| Delivery System Working Length | 142 cm | |
| Delivery System Design | Rapid Exchange (RX) compatible with guidewires ≤0.014” | |
| Stent Delivery System Balloon | Semi-compliant balloon with two radiopaque markers located on the catheter system balloon shaft to indicate balloon positioning and expanded stent length | |
| Guiding Catheter Compatibility | ≥ 6F (min. guide catheter ID of 0.070”/1.78mm) | |
| Balloon Inflation Pressure | 6-Crown model | 9-Crown-model |
| Nominal Pressure | 7atm/ 709 kPa | 7 atm/ 709 kPa |
| Rated Burst Pressure | 16 atm/ 1621 kPa | 14 atm/ 1418 kPa |
| Catheter Shaft Outer Diameter | Distal: 0.034” (0.86 mm) Proximal: 0.020” (0.51 mm) | Distal: 0.037” (0.94 mm) Proximal: 0.020” (0.51 mm) |
| Shelf Life | 9 months | |

# A. Device Component Description

The BioFreedom stent is made of stainless steel 316L. The stent is laser machined into two patterns that are differentiated by the number of crowns and the number of connectors. The 6-crown pattern is used for $2.25 - 3.0\mathrm{mm}$ diameter stents and the 9-crown stent pattern is used for $3.5 - 4.0\mathrm{mm}$ diameter stents. Each pattern is comprised of a series of corrugated rings aligned along a common longitudinal axis. Each ring is connected to an adjacent ring by two or three curved connectors oriented in the direction of the longitudinal axis. The outer (abluminal) surface of the stent is selectively micro-structured (SMS) prior to drug coating. Figure 1 illustrates a 9-crown BioFreedom stent.

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Figure 1. BioFreedom Stent Drawing

The stent is crimped onto the balloon of the Rapid Exchange (RX) Catheter that combines a single lumen proximal shaft with a single lumen mid-shaft and a coaxial lumen distal shaft to create the rapid exchange capability. Figure 2 provides a pictorial representation of the catheter delivery system.

Figure 2. BioFreedom Delivery System, General View

The commercial size matrix is shown in Table 2.

Table 2. BioFreedom DCS Commercial Matrix

| | Stent Length | | | | | | | |
| --- | --- | --- | --- | --- | --- | --- | --- | --- |
| | | | 8 mm | 11 mm | 14 mm | 18 mm | 24 mm | 28 mm |
| Stent Model/Balloon Diameter | 6-crown | 2.25 mm | X | X | X | X | X | X |
| | | 2.50 mm | X | X | X | X | X | X |
| | | 2.70 mm | X | X | X | X | X | X |
| | | 3.00 mm | X | X | X | X | X | X |
| | 9-crown | 3.50 mm | X | X | X | X | X | X |
| | | 4.00 mm | X | X | X | X | X | X |

# B. Drug Component Description

The BioFreedom DCS is coated with BA9 (also referred to as Biolimus A9 or umirolimus).

1. BA9

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The BA9 drug is the active pharmaceutical ingredient in the BioFreedom DCS. The BA9 chemical name is:

(3S,6R,7E,9R,10R,12R,14S,15E,17E,19E,21S,23S,26R,27R,34aS)-

9,10,12,13,14,21,22,23,24,25,26,27,32,33,34,34a-Hexadecahydro-9,27-dihydroxy-3-

[(1R)-2-[(1S,3R,4R)-4-(2-ethoxyethoxy)-3-methoxycyclohexyl]-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

or

(1R,9S,12S,15R,16E,18R,19R,21R,23S,24E,26E,28E,30S,32S,35R)-1,18-Dihydroxy-

12-[(1R)-2-[(1S,3R,4R)-4-(2-ethoxyethoxy)-3-methoxycyclohexyl]-1-methylethyl]-

19,30-dimethoxy-15,17,21,23,29,35-hexamethyl-11,36-dioxa-4-

azatricyclo[30.3.1.04,9]hexatriaconta-16,24,26,28-tetraene-2,3,10,14,20-pentaone.

The molecular formula of BA9 is C55H87NO14 and its molecular weight is $986.28\mathrm{g / mol}$ . The chemical structure of BA9 is depicted in Figure 3.

Figure 3. Chemical Structure of BA9

The nominal total loaded dose of BA9 per nominal stent length is shown in Table 3.

Table 3. Nominal BA9 Content $\left( {\mu \mathrm{g}}\right)$ per Nominal Stent Length

| | 8 mm | 11 mm | 14 mm | 18 mm | 24 mm | 28 mm |
| --- | --- | --- | --- | --- | --- | --- |
| All diameters (2.25-4.0 mm) | 133 | 178 | 225 | 292 | 384 | 453 |

# 2. Mechanism of Action of BA9

Current understanding suggests that the mechanism of action of the BA9 drug on a molecular level is due to complex formation with cytoplasmic proteins that inhibit the cell cycle between the G0 and G1 phase. This results in interruption of the cascade governing

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cell metabolism, growth, and proliferation, leading to a reversible inhibition of growth-factor-stimulated cell proliferation.

It is believed that the mechanism of action of the "limus family" is similar, with which the BA9 drug shares a common internal 'rapamycin' ring structure. This rapamycin ring structure is known to bind with the intracellular receptor FKBP-12. The resulting macrolide/FKBP-12 complex subsequently binds to a specific target protein known as mammalian target of rapamycin (mTOR) which is critical for cell cycle progression. Interaction of the macrolide/FKBP-12 complex with mTOR inactivates mTOR resulting in suppression of several specific signal transduction pathways and arrest of the cell cycle at the G1 to S phase.

The BA9 drug coated on the BioFreedom DCS has an ancillary function as an anti-proliferative and anti-restenotic agent due to its ability to interrupt smooth muscle cell migration and proliferation.

## VI. ALTERNATIVE PRACTICES AND PROCEDURES

There are several other alternatives for the correction of coronary artery disease. These may include exercise, diet, smoking cessation, drug therapy, percutaneous coronary interventions (such as angioplasty and placement of other coronary stents), and coronary artery bypass graft 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

As of March 2020, approximately 339,000 BioFreedom DCS devices have been distributed outside the United States (OUS). The countries where the BioFreedom DCS is commercially available are listed below. No products have been withdrawn from the market in any of the following countries.

- Algeria
- Bangladesh
- Brazil
- Chile
- Cyprus
- Ecuador
- Finland
- Greece
- India
- Israel
- Kazakhstan
- Liechtenstein
- Malaysia
- Norway
- Argentina
- Belarus
- Brunei Daruss.
- Colombia
- Czech Republic
- Egypt
- France
- Honduras
- Indonesia
- Italy
- Latvia
- Lithuania
- Mexico
- Oman
- Armenia
- Bolivia
- Bulgaria
- Costa Rica
- Denmark
- El Salvador
- Georgia
- Hong Kong
- Iran
- Japan
- Lebanon
- Macau
- Montenegro
- Palestine
- Austria
- Bosnia-Herz.
- Burma
- Croatia
- Dominican Rep.
- Estonia
- Germany
- Hungary
- Ireland
- Jordan
- Libya
- Macedonia
- Morocco
- Pakistan

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- Panama
- Portugal
- Singapore
- South Korea
- Switzerland
- The Netherlands
- United Kingdom
- Vietnam

- Peru
- Romania
- Slovakia
- Spain
- Syria
- Tunisia
- Utd. Arab Emir.

- Philippines
- Saudi Arabia
- Slovenia
- Sri Lanka
- Taiwan
- Turkey
- Uzbekistan

- Poland
- Serbia
- South Africa
- Sweden
- Thailand
- Ukraine
- Venezuela

# VIII. POTENTIAL ADVERSE EFFECTS OF THE DEVICE ON HEALTH

Adverse events (in alphabetical order) that may be associated with the use of a stent in native coronary arteries include but are not limited to:

- Access site complications (including arteriovenous fistula, hematoma, infection, nerve injury, pain, peripheral ischemia, phlebitis, pseudoaneurysm)
- Acute myocardial infarction
- Allergic reaction or hypersensitivity to anti-coagulation and/or anti-thrombotic therapy, contrast media, or stent components and/or delivery system materials
- Aneurysm
- Angina pectoris (stable or unstable)
- Bleeding complications which may require transfusions or surgical repair
- Cardiac arrhythmias, including ventricular fibrillation and ventricular tachycardia
- Cardiac failure
- Cardiac tamponade
- Cardiogenic shock
- Coronary artery complications (incl. abrupt closure, dissection, embolism, injury, perforation, plaque rupture/shift, restenosis, rupture, spasm, thrombosis, total occlusion)
- Death
- Delayed endothelialization
- Distal emboli
- Endocarditis
- Failure to deliver the stent to the intended site
- Need for emergent or non-emergent coronary artery bypass grafting (CABG)
- Fever or pyrogenic reactions
- Hypotension/hypertension
- Infections
- Myocardial ischemia
- Nausea and vomiting
- Palpitations
- Perforation of the heart or great vessels
- Pericardial effusion
- Pulmonary failure
- Renal failure

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- Stent compression
- Stent misplacement/migration/ embolization
- Stent thrombosis
- Stroke/cerebrovascular accident (CVA)/ transient ischemic attack (TIA)
- Vasovagal reaction
- Vessel spasm
- Volume overload

There may be other potential adverse events that are unforeseen at this time.

Potential adverse events that may be associated with exposure to the BA9 drug include but are not limited to (Steudel et al. 2011):
- Chest heaviness
- Lymphadenopathy
- Nausea
- Mouth ulcers

BA9 drug administration experience is limited to intra-coronary stent delivery. Patient exposure to BA9 is directly related to the total surface area of stents implanted. Consequently, adverse drug effects have not been fully characterized especially at significantly higher systemic doses than what would be delivered via the BioFreedom DCS.

For the specific adverse events that occurred in clinical studies, please see Section X below.

## IX. SUMMARY OF NONCLINICAL STUDIES

A series of non-clinical laboratory studies and pharmacokinetic studies related to the product were performed. Studies included those performed on the drug substance (BA9), the bare metal stent alone, the coated stent alone, the delivery system, and the finished combination product.

## A. Laboratory Studies

### 1. In Vitro Engineering Testing

In vitro engineering testing, in accordance with FDA's “Guidance for Industry and FDA Staff: Non-Clinical Tests and Recommended Labeling for Intravascular Stents and Associated Delivery Systems”, was conducted on test samples representative of the BioFreedom DCS. Specific in vitro engineering tests were performed on the representative uncoated, bare metal version of the BioFreedom stent and the delivery system.

Table 4 summarizes this testing. “Pass” denotes that the test results met product specifications and/or the recommendations in the above referenced guidance document.

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Table 4. Summary of Engineering Testing

| Test | Purpose | Acceptance Criteria | Results |
| --- | --- | --- | --- |
| Material Characterization | | | |
| Stent Material Composition | To confirm the chemical composition of the 316L stainless steel tubing. | Per ASTM F138 | Pass |
| Stent Mechanical Properties | To determine raw material quality and uniformity and predict subsequent thermochemical effects. | Per established standard requirements | Pass |
| Stent Corrosion Resistance | To determine resistance to galvanic and pitting corrosion. | Per ASTM F2129 and ASTM G71 standards | Pass |
| Stent Dimensional and Functional Attributes | | | |
| Dimensional Verification | To ensure accurate stent dimensions. | Meet established design specifications | Pass |
| Percent Surface Area | To determine the surface coverage of the bare stent in the vessel. | The percent contact surface area of the stent at any deployed diameter must not be >20% | Pass |
| Foreshortening | To ensure the foreshortening of the stent falls within acceptable limits. | Foreshortening ≤10% | Pass |
| Recoil | To ensure the amount of elastic recoil after deployment falls within acceptable limits. | Recoil ≤5% | Pass |
| Stent Integrity | To ensure stent defects do not contribute to clinical complications. | No fractures, cracks, or scratches | Pass |
| Radial Stiffness and Radial Strength | To ensure the stent can resist collapse under short-term or long-term external loads. | Radial strength ≥500 mmHg Minimum compression resistance of 0.1 N/mm of stent length at 0.5 mm of stent compression | Pass |
| Stress/Strain and Fatigue Analysis | To determine the stent durability when exposed to worst case physiological loads and configuration by means of a Finite Element Analysis. | N/A | N/A |
| Accelerated Durability | To determine the long-term integrity of the stent under cyclical loading conditions. | No complete segment breakage after 400 million cycles (equivalent to 10 years of implantation) | Pass |
| Particulate Evaluation | To ensure acceptable levels of particulate generated after simulated use. | ≤6000 particles ≥10 μm ≤600 particles ≥25 μm | Pass |

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| Test | Purpose | Acceptance Criteria | Results |
| --- | --- | --- | --- |
| Magnetic Resonance Imaging (MRI) Safety and Compatibility | To determine the effect of MR on the position and temperature of the stent, and to determine the extent of image artifact during MRI. | See product labeling for safe MRI use conditions | Pass |
| Radiopacity | To ensure adequate visibility on X-ray and angiography. | Stents must be adequately visualized on angiogram and have an acceptable contrast value on X-ray | Pass |
| Delivery System Dimensional and Functional Attributes | | | |
| Dimensional Verification | To ensure accurate delivery system dimensions. | Meet established design specifications | Pass |
| Delivery, Deployment and Retraction | To verify the delivery catheter can safely and reliably deliver the stent to the intended location according to the instructions for use, without damage to the stent. | Per validated test protocols | Pass |
| Balloon Rated Burst Pressure | To determine the rated burst pressure (RBP) of the balloon when used with the stent. | 6-crown: ≥16 atm9-crown: ≥14 atmwith 95%/99.9%confidence/reliability | Pass |
| Balloon Fatigue | To ensure the balloon can withstand repeated inflation/deflation cycles. | Withstand 10 cycles at RBP | Pass |
| Balloon Compliance | To determine the relationship between the stent diameter and the balloon inflation pressure. | See compliance chart in device labeling | Pass |
| Balloon Inflation and Deflation Time | To ensure the balloon inflation and deflation time are within acceptable limits for clinical use. | 6-crown:Inflation ≤10 sDeflation ≤15 s9-crown:Inflation ≤15 sDeflation ≤20 s | Pass |
| Catheter Bond Strength and Tip Pull Test | To ensure the bond strength of the joints and/or fixed connections, including the distal tip of the delivery system, are adequate for clinical use. | Per ISO 10555-1 | Pass |
| Flexibility and Kink Test | To ensure the device can withstand flexural forces that are typical of clinical use. | The catheter inflation lumen must be able to flex at the radius of curvature of 15 mm without kinking or exhibiting a diameter of reduction >50% | Pass |
| Catheter Torque | To demonstrate that the delivery | System must withstand ≥2 | Pass |
| | increase in the diameter of the balloon. | increase in the diameter of the balloon. | |
| Fiber Thickness | To measure the thickness of the balloon. | See the following | Pass |
| Fiber Thickness at 1000 mm | To measure the thickness of the balloon. | See the following | Pass |
| Fiber Thickness at 1000 mm | To measure the thickness of the balloon. | See the following | Pass |

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| Test | Purpose | Acceptance Criteria | Results |
| --- | --- | --- | --- |
| Strength | system can withstand torsional forces that are typical of clinical use. | rotations without losing its functional integrity | |
| Coating Integrity | To evaluate the ability of the delivery system coatings to resist damage during clinical use. | For characterization only | Pass |
| Stent Securement | To demonstrate the stent will not dislodge from the delivery system when subjected to forces experienced in typical clinical use. | Force required to dislodge mounted stent ≥1.5 N | Pass |

# 2. Drug Coating Characterization Testing

The drug coating characterization testing conducted on the BioFreedom DCS is summarized in Table 5.

Table 5. Drug Coating Characterization Testing

| Test | Purpose | Acceptance Criteria | Results |
| --- | --- | --- | --- |
| Acute Coating Integrity | To evaluate drug coating integrity of the stent. | Characterization only | Pass |
| Coating Thickness and Uniformity | To demonstrate that drug coating thickness is uniform along the length of the stent. | Characterization only | Pass |
| Longitudinal Coating Uniformity | To characterize the coating uniformity along the length of the stent. | Characterization only | Pass |
| Acute Coating Durability Test | To demonstrate the ability of the coating to resist delamination when subjected to simulated clinical use conditions. | Characterization only | Pass |

# 3. Chemistry Manufacturing and Controls (CMC) Testing

Where applicable, International Conference on Harmonization (ICH) guidelines were followed for the testing routinely performed on the BioFreedom DCS system. This testing is summarized in Table 6.

Table 6. CMC Release Testing

| Test | Test Description |
| --- | --- |
| Drug content | Assay is conducted to quantitatively verify that the total amount of drug on the stent is within the specifications established for the finished product. |
| BA9 Identification, Degradation Products & Impurities | Assay is conducted to verify the identity of the drug substance (BA9) and quantitatively verify the amount and type of degradation products on the stent are within the specifications established for the finished product. |
| Drug Release | The in vitro release profile for BA9 is measured on the stent to |

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| Test | Test Description |
| --- | --- |
| | verify that the drug release is within the specifications established for the finished product. |
| Endotoxin | The amount of bacterial endotoxins is verified to be within the specification limits established for the finished product. |
| Particulates | Particulate levels are measured to verify that they remain below the specifications established for the finished product. |
| Appearance | A visual inspection is conducted to verify that the product’s appearance specifications are met. |
| Content Uniformity | Multiple stents are assayed to verify the uniformity of the drug content between individual stents is within the specifications established for the finished product. |
| Residual Solvent: Acetone | The amount of acetone on the BioFreedom DCS is determined to verify that the residual level of the solvent used in the manufacturing process is within the specification limits established for the finished product. |

4. Stability and Shelf Life

Stability/shelf-life studies were conducted to establish a shelf life for the BioFreedom DCS. The stability testing included BA9 drug content, identification, degradation products and impurities, drug release, endotoxin, particulates, drug weight loss, appearance, content uniformity, and residual solvent testing. Appropriate mechanical engineering tests were also performed on aged product and packaging to ensure that the finished product continues to meet specifications throughout its expiration dating. The data generated supports a product shelf life of 9 months.

5. Packaging and Sterilization

Packaging verification testing was performed to demonstrate that the design of the BioFreedom DCS packaging can withstand the hazards of the distribution environment and that the sterility of the device is maintained throughout the labeled shelf life. The BioFreedom DCS is sterilized using electron beam (E-beam) irradiation. The sterilization validation and dose audit verifications were performed 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” and ISO 11137-2 “Sterilization of health care products – Radiation – Part 2: Establishing the sterilization dose”. The validation and dose audit verifications confirm that the E-beam sterilization process achieves a minimum sterility assurance level (SAL) of $10^{-6}$. In addition, the quantity of bacterial endotoxins was verified to be within the specification limits.

6. Biocompatibility

A series of Good Laboratory Practice (GLP) biocompatibility tests were conducted to demonstrate that the components of the BioFreedom DCS are non-toxic and biocompatible. Tests were conducted on final, E-beam-sterilized BioFreedom DCS, selectively-microstructured bare metal stents, and stent delivery systems. These test articles were processed in the same manner as the finished BioFreedom DCS. The

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results of the biocompatibility studies indicated that the BioFreedom DCS was biologically safe and acceptable for clinical use.

All biocompatibility testing was conducted in accordance with one or more of the following general regulations, standards and guidance documents:

Good Laboratory Practices Regulations (21 CFR § 58)
- Guidance for Industry: "Coronary Drug-Eluting Stents-Nonclinical and Clinical Studies" (March 2008)
- Guidance for Industry and FDA Staff: "Select Updates for Non-Clinical Engineering Tests and Recommended Labeling for Intravascular Stents and Associated Delivery Systems"
- Guidance for Industry and FDA Staff: "Use of International Standard ISO 10993-1, Biological Evaluation of Medical Devices Part 1: Evaluation and Testing" (April 2013)
- ISO 10993-1, "Biological Evaluation of Medical Devices: Evaluation and Testing within a Risk Management Process"
- ISO 14971, Medical devices: "Application of Risk Management to Medical Devices"

Table 7 provides a summary of the biocompatibility testing conducted to support the BioFreedom DCS.

Table 7. Summary of Biocompatibility Testing

| Test Name | Test Description | Test Article | Results |
| --- | --- | --- | --- |
| Cytotoxicity | ISO 10993-5: Direct Contact Cytotoxicity (L929 MEM Elution) | Drug coated stent SMS bare metal stent Delivery system | Pass (non-cytotoxic) |
| | ISO 10993-5: MEM Elution Assay with L-929 | SMS bare metal stent Delivery System | Pass (non-cytotoxic) |
| | ISO 10993-5: MEM Endpoint Dilution Using L-929 | Drug coated stent | Pass (non-cytotoxic) |
| Pyrogenicity | ISO 10993-11: Materials Mediated Rabbit Pyrogenicity Test | Drug coated stent SMS bare metal stent Delivery System | Pass (non-pyrogenic) |
| Sensitization | ISO 10993-10: Sensitization (Guinea Pig Maximization) | Drug coated stent SMS bare metal stent Delivery System | Pass (non-sensitizing) |
| | MHLW Sensitization (Guinea Pig Maximization) | SMS bare metal stent | Pass (non-sensitizing) |
| Intracutaneous Reactivity | ISO 10993-10: Irritation Test | Drug coated stent SMS bare metal stent Delivery System | Pass (non-irritant) |
| Subchronic/ Subacute Toxicity | ISO 10993-11: Subchronic Intravenous Toxicity Study in | Drug coated stent SMS bare metal stent | Pass (non-toxic) |

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| Test Name | Test Description | Test Article | Results |
| --- | --- | --- | --- |
| | Mice (14 Dose Exposure) | | |
| | ISO 10993-11: Subacute Intraperitoneal Toxicity Study in Mice (14 Dose Exposure) | • Drug coated stent
• SMS bare metal stent | Pass (non-toxic) |
| Acute Systemic Toxicity | ISO 10993-11: Acute Systemic Injection Test | • Drug coated stent
• SMS bare metal stent
• Delivery System | Pass (non-toxic) |
| Hemocompatability /Hemolysis | ASTM F756 Hemolysis Assay – Direct Contact Method | • Drug coated stent
• SMS bare metal stent
• Delivery system | Pass (non-hemolytic) |
| | ASTM F756 Hemolysis Assay – Extract Method | • Drug coated stent
• SMS bare metal stent
• Delivery system | Pass (non-hemolytic) |
| Complement Activation | ISO 10993-4: Complement Activation Test (C3a and SC5b-9) | • Drug coated stent
• SMS bare metal stent
• Delivery system | Pass |
| Implantation | ISO 10993-6: Intramuscular Implantation with Histopathology (2 week) | • Drug coated stent | Pass |
| | ISO 10993-6: Intramuscular Implantation with Histopathology (13 week) | • Drug coated stent | Pass |
| Genotoxicity | ISO 10993-3: Bacterial Mutagenicity Test – Ames Assay | • Drug coated stent
• SMS bare metal stent | Pass (non-mutagenic) |
| | ISO 10993-3: In Vitro Mouse Lymphoma Assay with Extended Treatment | • Drug coated stent
• SMS bare metal stent | Pass (non-mutagenic) |
| | ISO 10993-3: In Vivo Mouse Micronucleus Assay | • Drug coated stent
• SMS bare metal stent | Pass (non-mutagenic) |
| | MHLW Bacterial Mutagenicity Test – Ames Assay | • SMS bare metal stent | Pass (non-mutagenic) |
| | MHLW In Vitro Chromosome Aberration Analysis | • SMS bare metal stent | Pass (non-mutagenic) |
| | ISO 10993-3: In Vitro Chromosome Aberration Analysis | • SMS bare metal stent | Pass (non-mutagenic) |
| | MHLW In Vivo Mouse Micronucleus Assay with Exhaustive Extraction | • SMS bare metal stent | Pass (non-mutagenic) |
| Subchronic/Chronic Toxicity, Genotoxicity, Carcinogenicity | Chemical Characterization Testing and Toxicological Risk Assessment | • Drug coated stent | Pass |

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A risk assessment was performed for the potential toxicity of the BioFreedom DCS. No major concerns regarding the BioFreedom DCS toxicity were found.

## B. Animal Studies

Detailed arterial histopathology and histomorphometry are not obtainable through human clinical trials. Consequently, a series of animal studies were conducted to evaluate safety, efficacy (proof of concept dosing), and overall product performance.

Animal studies (feasibility, safety, and acute) were conducted in accordance with §21CFR 58 (Good Laboratory Practices). The results of these studies support the safety and biocompatibility of the BioFreedom DCS. Table 8 includes summaries of the major animal studies performed to support product safety.

Table 8. Summary of Major Supportive Animal Studies

| Study Type | # of Stents | Testing Summary | Results |
| --- | --- | --- | --- |
| GLP Safety and PK Study | Histo-pathology cohort: Test: 25 DCS Control: 24 BioFlex II 37 Cypher PK cohort: 12 DCS. | Single (non-overlapped) stents were implanted into 51 Yucatan mini swine. Histopathology was performed at day 28, 90, and 180. In the PK cohort, BA9 concentrations were measured in the systemic circulation and the myocardium. | At 28 days, all DCS stents showed the anti-proliferative coatings to be efficacious compared to bare metal stent controls while maintaining a similar safety profile. At 90 and 180 days, DCS stents had less stenosis than the Cypher DES. In the PK cohort, BA9 concentrations reached a maximum within 1 to 2 hours following implantation and dropped to near undetectable levels within 2 days. At 180 days all samples from blood and myocardium were below the limit of quantitation. |
| GLP Overlapped Safety Study | Test: 12 DCS Control: 12 BioFlex II | To evaluate the vascular response to overlapped BioFreedom stents, 19 Yucatan mini swine were implanted with either DCS or bare metal stents in overlapped configurations. Histo-pathology was evaluated at 28 and 180 days. | Medial area, neointimal area, and neointimal thickness were similar between groups, with percent stenosis lower in the overlapped portions of DCS stents compared to bare metal controls at 28 days. At 180 days, the two groups demonstrated comparable vascular responses. |
| GLP Acute PK Study | 42 DCS | To assess coronary tissue and residual BA9 concentrations on the stent, 14 Yorkshire swine were implanted with DCS in each of the three main coronary arteries and evaluated at 1, 2, 4, and 24 hours, and 2, 3, and 7 | BA9 reached maximum concentration in the target tissue within 2 hours. Tissue concentrations dropped approximately 88% by 4 hours and remained constant for the remainder of the 7 days. |

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| Study Type | # of Stents | Testing Summary | Results |
| --- | --- | --- | --- |
| | | days post-implantation | |
| GLP Acute & Short-term Safety Study | Test: 5 DCS Control: 3 BioFlex II | To demonstrate the rapid drug release profile of the BioFreedom DCS does not cause local cellular toxicity at the stented site, 8 Yorkshire swine were implanted with non-overlapping DCS or bare metal control stents and evaluated at 3 and 28 days. | All animals survived to the designated timepoint. No evidence of necrosis or toxicity or adverse reaction was observed within the myocardium or organs. |

X. SUMMARY OF PRIMARY CLINICAL STUDY

The applicant performed a clinical study, LEADERS FREE II (LFII) to establish a reasonable assurance of safety and effectiveness of the BioFreedom DCS in patients considered high bleeding risk (HBR) in the US, Canada, Denmark, France, Germany, Italy, and the United Kingdom under IDE G130034. Data from this study was the basis for the PMA approval decision. A summary of the clinical study is presented below.

A. Study Design

Patients were enrolled between February 14, 2017 and September 5, 2017. The database for this PMA reflected data collected through February 18, 2019 and included 2449 patients. There were 66 investigational sites.

This study was a prospective, single arm, multi-center, multi-national, open label trial to evaluate the safety and effectiveness of the BioFreedom DCS in patients with coronary artery disease who were at high risk of bleeding. Patients received percutaneous coronary intervention (PCI) with the BioFreedom DCS followed by one month of dual antiplatelet therapy (DAPT).

The results were compared to a historical control, the Gazelle bare metal stent (BMS) used as the control arm in the earlier LEADERS FREE (LFI) trial (described further in Section XI). Identical inclusion/exclusion criteria, case report forms, angiographic core laboratory, and clinical events committee (CEC) adjudication rules, processes and committee members as the LFI trial were utilized. A 5-strata level propensity analysis was utilized for the statistical analysis plan comparing the LFII DCS cohort to the LFI BMS historical control.

Choice of Control: In most pivotal trials, the control treatment represents a contemporary standard of care that is approved in the US. However, the Gazelle BMS used as the historical control is not an FDA-approved device and has never been used in the US. The applicant believed that conducting a randomized trial with a BMS arm would present an equipoise problem and safety concern as the results of LFI in

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Europe had already initially demonstrated superiority of the BioFreedom DCS to the BMS control, and at the time the LFII trial was being planned, no drug eluting stents (DES) marketed in the US had been studied for use in patients at high risk of bleeding, making any DES also unsuitable as a control.

Nonclinical and clinical information about the Gazelle BMS, as well as a white paper defending the choice of the Gazelle BMS as a historical control for the LFII study, were reviewed as part of the PMA. In summary, the Gazelle BMS uses a very similar stainless-steel platform as the BioFreedom DCS, with the same strut thickness of 120 µm. Apart from the lack of drug coating, the only difference between the platforms is a modification of the connectors, which are straight in the Gazelle BMS, and S-shaped in the BioFreedom DCS. Gazelle received CE-mark approval in 2005 and has been commercialized by the applicant since then in Europe, Asia, and Latin America. Gazelle was used as the control in the LFI study, and because it cannot be distinguished from the BioFreedom DCS by the naked eye, that trial was able to be performed in a double-blind fashion (further discussed in the Supplemental Clinical Information section below). To demonstrate that the thicker struts of the Gazelle BMS compared to more modern BMS would not bias LFII in favor of the BioFreedom DCS arm, the applicant provided analyses that favorably compared the performance of the Gazelle BMS in LFI with that of other contemporary BMS used in similar patient cohorts (Mehran et al. 2009; Räber et al. 2012; Sabaté et al. 2014; Spaulding et al. 2011; Valgimigli et al. 2015).

1. Clinical Inclusion and Exclusion Criteria

Enrollment in the LEADERS FREE II study was limited to patients who met the following inclusion criteria:

Any indication for PCI in patients deemed at high risk for bleeding and candidates for 1-month DAPT. This includes candidates with stable angina, silent ischemia, acute coronary syndrome (ACS) including ST-segment elevation myocardial infarction (STEMI) and non-STEMI, non-native lesions, and in-stent restenosis. Reasons for unsuitability for &gt;1 month DAPT included at least one of the following:

1. Adjunctive oral anticoagulation treatment planned to continue after PCI
2. Age ≥75 years old
3. Baseline Hemoglobin (Hgb) &lt;11 g/dl (or anemia requiring transfusion during the 4 weeks prior to the index procedure)
4. Any prior intracerebral bleed
5. Any stroke in the last 12 months
6. Hospital admission for bleeding during the prior 12 months
7. Non-skin cancer diagnosed or treated &lt;3 years with a perceived increased risk of bleeding
8. Planned daily non-steroidal anti-inflammatory drugs (NSAID) (other than aspirin) or steroids for &gt;30 days after PCI

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9. Planned surgery that would require interruption of DAPT (within next 6 months)
10. Renal failure defined as creatinine clearance &lt;40 ml/min
11. Thrombocytopenia (platelet count (PLT) &lt;100,000/mm³)
12. Severe chronic liver disease defined as patients who have developed any of the following: variceal hemorrhage, ascites, hepatic encephalopathy or jaundice
13. Expected non-compliance to prolonged DAPT for other medical reasons

Patients were not permitted to enroll in the LEADERS FREE II study if they met any of the following exclusion criteria:

1. Pregnant and breastfeeding women
2. Patients expected not to comply with 1-month DAPT
3. Patients requiring a planned staged PCI procedure more than one week after the index procedure
4. Procedure planned to require non-study stents, or stand-alone balloon angioplasty (POBA) or stand-alone atherectomy
5. Active bleeding at the time of inclusion
6. Reference vessel diameter &lt;2.25 mm or &gt;4.0 mm
7. Cardiogenic shock
8. Compliance with long-term single anti-platelet therapy unlikely
9. A known hypersensitivity or contraindication to aspirin, clopidogrel (or prasugrel, or ticagrelor if applicable), stainless steel, zinc, Biolimus A9 or a sensitivity to contrast media, which cannot be adequately pre-medicated
10. PCI during the previous 12 months for a lesion other than the target lesion of the index procedure
11. Participation in another clinical trial (12 months after index procedure)
12. Patients with a life expectancy of &lt;12 months

To support the propensity analysis comparing the LFII cohort to the historical BMS arm of LFI, study enrollment caps were placed on the criteria listed in Table 9.

Table 9. Enrollment Caps in LFII

| Inclusion Criteria | Max # Patients |
| --- | --- |
| Candidates with STEMI | 50 |
| Candidates meeting only the criteria: Age ≥75 years old | 250 |
| Candidates meeting only the criteria: Expected non-compliance to prolonged DAPT for other medical reasons | 10 |

2. Follow-up Schedule

All patients were scheduled to return for follow-up examinations at 30 days, 6 months, and 1 year after the index procedure. Telephone contact was initiated with the patients at 2 months and will also be conducted at 2- and 3-years post-procedure.

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Preoperatively, patients received physical examinations, angina status was recorded, routine laboratory tests including Creatine kinase (CK) and/or Creatine kinase myocardial band (CK-MB) or troponin were conducted, and 12-lead electrocardiograms were performed. Postoperatively, an ECG was performed prior to discharge, with a 12-lead ECG required to document any suspicious cardiac ischemic episode. Troponin or CK and CK-MB (per institutional standard) were measured in the case of signs/symptoms of MI and at least once post-procedure with one of the measurements at 18-24 hours post-procedure. At follow-up visits, angina assessment, any adverse events, cardiovascular and other important medication intake, and any hospitalizations were recorded.

The key timepoints are shown below in the tables summarizing safety and effectiveness.

## 3. Clinical Endpoints

With regards to safety, the primary safety endpoint was the composite of cardiac death and MI at 6 months. Secondary safety endpoints were assessed at all follow-up time points and included:

- Composite of cardiac death and MI at 1 and 2 months and 1, 2 and 3 years
- The composite of cardiac death, myocardial infarction (MI) and stent thrombosis (Definite/Probable)
- Bleeding per Bleeding Academic Research Consortium (BARC) criteria (BARC 3 to 5, all BARC, by access site)
- All individual components of the primary endpoint
- Cardiac death
- Myocardial infarction (according to the Third Universal Definition¹)
- Q wave, Non-Q wave, and all myocardial infarction
- Stent thrombosis per Academic Research Consortium (ARC) definition²
- All-cause mortality

With regards to effectiveness, the primary effectiveness endpoint was the incidence of clinically-driven target lesion revascularization (CD-TLR) at 6 months. Secondary effectiveness endpoints were assessed at all follow-up time points and included:

- Urgent TLR
- CD-TLR at time points other than the primary endpoint
- Clinically-driven target vessel revascularization

With regard to success/failure criteria, non-inferiority testing of the primary safety and primary effectiveness endpoints was planned. If non-inferiority was shown, both

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the primary safety and primary effectiveness endpoints would be then tested for superiority (first safety, then effectiveness).

Protocol Definition of MI: The protocol definition of MI was the third Universal Definition and included Q wave, non-Q wave, and all myocardial infarctions. Periprocedural PCI was defined as detection of a rise of troponin &gt; 3X of the upper reference limit (URL) or a rise in CK-MB &gt; 3X URL. Spontaneous MI was defined as the detection of a rise in troponin &gt; URL or CK-MB &gt; URL (Cutlip et al. 2007).

## B. Accountability of PMA Cohort

At the time of database lock, of 1203 patients enrolled and found to be eligible for the PMA study, 91.4% patients are available for analysis at the completion of the study, the 12-month post-index procedure visit. The disposition of the patients is summarized in Table 10.

Table 10. Patient Disposition
| Parameter | LFII DCS | LFI BMS |
| --- | --- | --- |
| Signed Informed Consent (enrolled) | 2449 | 1227 |
| Screen Failures | 1246 | 16 |
| Intention-to-Treat (ITT) Population* | 1203 | 1211 |
| 30-Day Landmark Analysis Population‡ | 87.7% (1055/1203) | 85.1% (1031/1211) |
| Deaths prior to 12-Month Visit | 7.6% (91/1203) | 8.7% (105/1211) |
| Withdrawals Prior to 12-Month Visit | 1.1% (13/1203) | 0.9% (11/1211) |
| Completed 12-Month Visit | 91.4% (1099/1203) | 90.4% (1095/1211) |

* The intention-to-treat (ITT) population includes patients who met all the study eligibility criteria. The lesions were deemed treatable and the guidewire crossed the lesion. All subsequent percentages are based on this population.
‡ All ITT patients who were event-free through 30 days and followed up thereafter.

## C. Study Population Demographics and Baseline Characteristics

Table 11 presents demographics for the BioFreedom DCS ITT population and the historical control group. The mean age of the DCS patients was 74.6 years and 31.3% were female. Subjects were predominantly white (at least 75.0%; race data not available for approximately 20% of DCS patients) and overweight (mean body mass index (BMI) 28.7).

Table 11. LFII and Historical Control Demographics
| Characteristic | LFII DCS (N=1203) | LF1 BMS (N=1211) |
| --- | --- | --- |
| Sex | | |
| Male | 68.7% (826/1203) | 69.1% (837/1211) |
| Female | 31.3% (377/1203) | 30.9% (374/1211) |
| Age (years) | 74.6 ± 9.7 (1203) (43.0, 96.0) | 75.7 ± 9.3 (1211) (37.8, 99.5) |
| Race | | |

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Table 12 shows the baseline clinical characteristics and medical history for the patient population. Thirty-four percent of BioFreedom DCS patients had diabetes, $24.1\%$ had prior MI, and $45.2\%$ presented with an acute coronary syndrome (ACS). In general, baseline clinical characteristics were comparable between the BioFreedom DCS and historical control groups. Any imbalances were mitigated after propensity score stratification.

Table 12. Baseline Clinical Characteristics

| Parameter | LFII DCS (N=1203) | LFI BMS (N=1211) |
| --- | --- | --- |
| Current Smoker | 12.2% (144/1180) | 11.4% (137/1203) |
| Diabetes Mellitus | 34.5% (414/1201) | 32.3% (391/1210) |
| Diabetic (Medically Treated) | 30.7% (369/1201) | 29.4% (356/1210) |
| Diabetic (Insulin Dependent) | 11.2% (135/1201) | 11.3% (137/1210) |
| Hypercholesterolemia | 74.4% (892/1199) | 62.7% (746/1189) |
| Hypertension | 86.5% (1039/1201) | 79.6% (961/1208) |
| Renal Insufficiency at Screening† | 21.2% (255/1201) | 23.1% (278/1206) |
| History of MI | 24.1% (287/1189) | 21.4% (258/1203) |
| Prior CABG | 15.5% (186/1202) | 10.1% (122/1209) |
| ACS at Presentation | 45.2% (544/1203) | 43.1% (522/1211) |
| STEMI | 2.33% (28/1203) | 4.0% (48/1211) |
| NSTEMI | 22.4% (270/1203) | 23.2% (281/1211) |
| Unstable angina | 20.4% (246/1203) | 15.9% (193/1211) |
| History of Stroke | 14.6% (175/1200) | 9.1% (110/1208) |
| History of Malignancy | 9.4% (112/1194) | 9.8% (119/1210) |
| Hypothyroidism | 1.6% (19/1203) | 0.9% (11/1209) |
| Hypothyroidism (HLA) | 1.6% (19/1203) | 0.9% (11/1209) |
| Hypothyroidism (HLA+) | 1.6% (19/1203) | 0.9% (11/1209) |

LFI and LFI were partially conducted in regions outside of the US that do not permit the collection of racial demographic data.
\*\*Ethnicity demographic data for LFI was not provided.

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| Parameter | LFII DCS (N=1203) | LFI BMS (N=1211) |
| --- | --- | --- |
| Congestive Heart Failure | 19.7% (237/1201) | 12.4% (150/1211) |
| Previous PCI | 38.1% (456/1198) | 21.9% (265/1208) |
| Stent in Target Lesion | 11.4% (137/1198) | NA |
| Peripheral Vascular Disease | 17.4% (209/1198) | 15.8% (190/1201) |
| Single vessel disease | 23.8% (283/1189) | 38.4% (460/1198) |
| Multiple vessel disease | 76.2% (906/1189) | 61.6% (738/1198) |
| Blood Disorder | 16.5% (198/1202) | 9.3% (112/1208) |
| Anemia | 12.2% (147/1203) | 6.9% (83/1211) |
| Thrombocytopenia | 1.7% (20/1203) | 1.2% (14/1211) |
| Other | 2.6% (31/1203) | 1.2% (15/1211) |
| Atrial Fibrillation | 35.0% (420/1201) | 34.6% (418/1209) |
| Chronic Obstructive Pulmonary Disease | 14.0% (168/1201) | 11.7% (141/1202) |

NA= Not Available
† Per lab normal for creatinine

Key Baseline Lesion Characteristics: In BioFreedom DCS patients, visually estimated mean reference vessel diameter was 3.0 ± 0.5 mm, mean lesion length was 18.6 ± 10.6 mm, and mean percent diameter stenosis was 83.7 ± 12.4%. The target lesion location distribution is generally reflective of patients presenting for PCI with approximately 50% in the LAD, 29% in the LCX, and 34% in the RCA. Approximately half of lesions were classified as complex (B2/C). Additional baseline lesion characteristics can be found in Table 13.

Table 13. Baseline Lesion Characteristics

| | LFII DCS (N=1203 Subjects N=1945 Lesions) | LFI BMS (N=1211 Subjects N=1909 Lesions) |
| --- | --- | --- |
| Pre-Procedure | | |
| Target Vessel | | |
| Left Anterior Descending (LAD) | 49.9% (641/1284) | 51.8% (666/1287) |
| Left Circumflex Artery (LCX) | 29.1% (374/1284) | 28.9% (371/1287) |
| Right Coronary Artery (RCA) | 33.9% (435/1284) | 35.1% (451/1287) |
| Left Main | 5.0% (64/1284) | 3.9% (50/1287) |
| Graft | 0.2% (2) | 0.2% (2) |
| Mean Lesion Length (mm) | 18.56 ± 10.59 (1945) | 17.22 ± 9.07 (1905) |
| Mean RVD (mm) | 3.01 ± 0.52 (1945) | 2.99 ± 0.49 (1905) |
| % Diameter Stenosis (DS) | 83.69 ± 12.42 (1945) | 81.65 ± 12.31 (1907) |
| TIMI Flow | | |
| 0 | 9.2% (178/1945) | 7.2% (138/1909) |
| 1 | 4.5% (87/1945) | 3.6% (68/1909) |
| 2 | 7.9% (154/1945) | 6.2% (119/1909) |

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| | LFII DCS (N=1203 Subjects N=1945 Lesions) | LFI BMS (N=1211 Subjects N=1909 Lesions) |
| --- | --- | --- |
| 3 | 82.9% (1613/1945) | 86.4% (1650/1909) |
| B2/C Lesion | 52.0% (1011/1945) | 46.1% (881/1909) |
| In-stent Restenosis | 8.2% (160/1945) | 2.0% (38/1909) |
| Bifurcation | 13.4% (261/1945) | 12.6% (240/1907) |
| Total Occlusion | 5.0% (98/1945) | 3.4% (64/1907) |
| Post-Procedure | | |
| Lesion Success* | 96.7% (1880/1945) | 98.0% (1841/1878) |
| Dissection | 0.9% (11/1203) | 1.0% (13/1211) |
| Perforation | 0.2% (2/1203) | 0.0% (0/1211) |

*Lesion success was defined as the attainment of &lt;20% residual stenosis by visual estimate and either TIMI flow 3 or consistent TIMI flow 2 before and after the procedure with any percutaneous method.

Key Procedural Characteristics: The majority of the BioFreedom DCS patients had one lesion treated (64.1%) and one vessel treated (77.9%). Approximately half of patients had one stent implanted (53.2%). Additional procedural characteristics can be found in Table 14.

Table 14. Procedural Characteristics

| | LFII DCS (N=1203 Subjects N=1287 Procedures) | LFI BMS (N=1211 Subjects N=1287 Procedures) |
| --- | --- | --- |
| Type of Procedure | | |
| Index | 93.5% (1203) | 94.1% (1211) |
| Staged | 6.5% (84) | 5.9% (76) |
| Number Lesions Treated/Subject | 1.57 (1203) | 1.59 (1211) |
| 0 | 0.2% (3/1203) | 0% (0/1211) |
| 1 | 60.4% (727/1203) | 61.4% (744/1211) |
| 2 | 25.6% (308/1203) | 25.7% (311/1211) |
| 3 | 9.4% (113/1203) | 8.7% (105/1211) |
| 4 or more | 4.3% (52/1203) | 4.2% (51/1211) |
| Number of Vessels Treated/Subject | 1.32 (1203) | 1.07 (1211) |
| 0 | 0.2% (3/1203) | 0% (0/1211) |
| 1 | 71.9% (865/1203) | 73.2% (886/1211) |
| 2 | 22.9% (276/1203) | 22.5% (273/1211) |
| 3 | 4.9% (59/1203) | 3.8% (46/1211) |
| 4 | 0% (0/1203) | 0.5% (6/1211) |
| Number of Stents Placed/Subject | 1.8 (1203) | 1.7 (1211) |
| 0 | 1.0% (12/1203) | 0.5% (6/1211) |

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| | LFII DCS (N=1203 Subjects N=1287 Procedures) | LFI BMS (N=1211 Subjects N=1287 Procedures) |
| --- | --- | --- |
| 1 | 53.2% (683/1203) | 55.3% (712/1211) |
| 2 | 26.2% (337/1203) | 27.4% (352/1211) |
| 3 | 12.1% (155/1203) | 11.6% (149/1211) |
| 4 | 4.2% (54/1203) | 3% (38/1211) |
| 5 or more | 3.4% (44/1203) | 2.3% (30/1211) |
| Total Stent Length (mm)/Subject | 34.6 ± 23.3 (1275) | 31.60 ± 20.98 (1269) |
| Any overlapping stent | 18.6% (239/1284) | 13% (167/1283) |

HBR Characteristics of Patients Enrolled in LFII: Table 15 below provides an overview of the study HBR criteria met by all registered subjects. The mean number of HBR criteria met per BioFreedom DCS patient was 1.74. The most common HBR criteria met were age $\geq 75$ years (64.1% of all DCS patients) and adjunctive oral anticoagulation treatment planned to continue after PCI (35.6% of all DCS patients). Most of the HBR criteria in LFII are very similar to the LFI BMS historical control arm.

Table 15. Patients Meeting One or More of the HBR Inclusion Criteria

| HBR Inclusion Criteria | LFII DCS (N=1203) | LFI BMS (N=1211) |
| --- | --- | --- |
| Patients satisfying one or more of the following criteria: | | |
| Oral anticoagulation after PCI | 34.1% (410/1203) | 35.6% (431/1211) |
| ≥ 75 years old | 60.7% (730/1203) | 64.1% (776/1211) |
| Anemia or recent transfusion | 16.3% (196/1203) | 16.0% (194/1211) |
| Prior intracerebral bleed | 1.2% (15/1203) | 1.6% (19/1211) |
| Stroke <1 year | 2.3% (28/1203) | 2.0% (24/1211) |
| Hospital for bleeding <1 year | 3.9% (47/1203) | 2.7% (33/1211) |
| Non-skin cancer <3 years | 7.8% (94/1203) | 9.9% (120/1211) |
| NSAID or steroids ≥30 days post PCI | 9.2% (111/1203) | 2.8% (34/1211) |
| Planned major surgery <6 months | 12.1% (146/1203) | 17.4% (211/1211) |
| Renal failure (Cr. Clearance <40 ml/min) | 14.7% (177/1203) | 20.2% (245/1211) |
| Thrombocytopenia (<100,000 mm3) | 2.7% (32/1203) | 1.5% (18/1211) |
| Severe chronic liver disease | 1.2% (14/1203) | 0.8% (10/1211) |
| Expected DAPT non-compliance | 3.5% (42/1203) | 3.9% (47/1211) |
| Number of HBR criteria met (mean) | 1.74 | 1.78 (all LFI patients) |

Antiplatelet Medication Usage: Use of dual antiplatelet therapy (aspirin plus a $\mathrm{P2Y}_{12}$ inhibitor) at discharge, 1 month, 6 months, and 12 months is summarized in Table 16. All

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patients were required to be on DAPT for one month and single antiplatelet therapy indefinitely (either aspirin or any $\mathrm{P2Y}_{12}$ inhibitor). Antiplatelet compliance was generally good, with $1.2\%$ (15/1203) BioFreedom DCS patients discontinuing DAPT prior to 23 days and $7.1\%$ (86/1203) prolonging DAPT beyond 37 days. Clopidogrel was the predominant $\mathrm{P2Y}_{12}$ inhibitor ( $78.9\%$ usage) used at discharge in DCS patients. In all, $84.1\%$ of DCS patients (1012/1203) were on DAPT at the time of discharge. At discharge, $33.5\%$ of DCS patients (403/1203) were on oral anticoagulants. The date of DAPT discontinuation was recorded differently in the two studies, however, the percentage of patients who had discontinued DAPT within the acceptable window ( $30 \pm 7$ days) was similar in the two groups ( $86.9\%$ of LFII DCS patients and $90.2\%$ of BMS).

Table 16. Antiplatelet Medication Usage

| | LFII DCS (N=1203) | LFI BMS (N=1211) |
| --- | --- | --- |
| Discharge | | |
| P2Y12 Inhibitor | 93.1% (1120/1203) | 99.5% (1205/1211) |
| Clopidogrel | 78.9% (949/1203) | 93.8% (1134/1211) |
| Prasugrel | 1.4% (17/1203) | 1.3% (16/1211) |
| Ticagrelor | 12.8% (154/1203) | 4.5% (54/1211) |
| Aspirin | 84.6% (1018/1203) | 97% (1173/1211) |
| DAPT (Aspirin and P2Y12) | 84.1% (1012/1203) | 96.9% (1172/1211) |
| Oral Anticoagulation | 33.5% (403/1203) | 34.6% (418/1211) |
| 1 month | | |
| P2Y12 Inhibitor | 98.2% (1156/1177) | 77.1% (921/1196) |
| Clopidogrel | 84.8% (998/1177) | 73.9% (866/1196) |
| Prasugrel | 1.6% (19/1177) | 1.2% (14/1196) |
| Ticagrelor | 12.4% (146/1177) | 3.4% (40/1196) |
| Aspirin | 93.8% (1104/1177) | 93.1% (1091/1196) |
| DAPT (Aspirin and P2Y12) | 92.3% (1086/1177) | 72.7% (852/1196) |
| Oral Anticoagulation | 36.7% (432/1177) | 32.7% (383/1196) |
| 6 months | | |
| P2Y12 Inhibitor | 31.4% (348/1110) | NA* |
| Clopidogrel | 27.8% (309/1110) | NA |
| Prasugrel | 0.4% (4/1110) | NA |
| Ticagrelor | 3.2% (36/1110) | NA |
| Aspirin | 74.1% (822/1110) | NA |
| DAPT (Aspirin and P2Y12) | 8.6% (95/1110) | NA |
| Oral Anticoagulation | 37.9% (421/1110) | NA |
| 12 months | | |
| P2Y12 Inhibitor | 31.5% (341/1083) | 21.2% (235/1088) |
| Clopidogrel | 27.4% (297/1083) | 19.8% (215/1088) |
| Prasugrel | 0.8% (9/1083) | 0.6% (6/1088) |
| Ticagrelor | 3.5% (38/1083) | 1.3% (14/1088) |
| Aspirin | 75.6% (819/1083) | 81.3% (884/1088) |

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| DAPT (Aspirin and P2Y12) | 12.0% (130/1083) | 9.7% (106/1088) |
| --- | --- | --- |
| Oral Anticoagulation | 38.0% (412/1083) | 36.5% (397/1088) |

*NA=Not Available

## D. Safety and Effectiveness Results

### 1. Safety Results

The analysis of safety was based on the 1203 ITT patients. Key safety outcomes are presented in Table 17. Adverse effects are reported in Table 18 and Table 19.

**Primary Endpoint (Safety):** The primary safety endpoint of cardiac death and MI was met. Non-inferiority of the primary endpoint of cardiac death or all MI (3rd Universal Definition) 6 months following BioFreedom DCS implantation in HBR patients compared to the LF II Gazelle BMS historical control arm was demonstrated after propensity score adjustment (as pre-specified in the LF II SAP). Propensity score stratification was performed by an independent statistician.

The 6-month Kaplan-Meier (KM) estimated rate for cardiac death/all MI was 6.5% for the BioFreedom DCS group and 9.7% for the BMS historical control group. Based on the number of patients and observed rates in each stratum, the results show that the stratified difference between BioFreedom DCS and Gazelle BMS KM estimated rates of cardiac death/all MI at 6 months was -3.5% with a 97.5% confidence interval upper limit of -1.2%, which was well below the prespecified non-inferiority margin of 3.92%. The -3.5% difference was also statistically significant for superiority, with the upper limit of the 2-sided 95% confidence interval (-5.8%, -1.2%) less than zero.

**Secondary Endpoints (Safety):** At 1-year follow-up, the composite safety endpoint (cardiac death and MI) occurred at a 9.3% KM estimated rate in the BioFreedom DCS group, and at a 12.4% KM estimated rate in the BMS group (p=0.0150, log-rank test) with a hazard ratio of 0.72 (95% CI 0.55, 0.94), as shown in the propensity-stratified adjusted KM curves below (Figure 4).

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Figure 4. Kaplan-Meier Plot of Cardiac Death and MI Through 1 Year

Other supportive individual and composite safety endpoints between 1 and 12 months are listed in Table 17. The values provided are KM estimated rates without propensity score adjustment. Major bleeding (BARC 3-5) at 1 year was high but similar in both groups, occurring in 82 BioFreedom DCS patients $(7.0\%)$ vs. 85 BMS patients $(7.3\%)$ . ARC definite/probable stent thrombosis occurred in 22 patients $(1.9\%)$ receiving BioFreedom DCS stents, versus 26 patients $(2.2\%)$ in the BMS historical control arm.

Table 17. Summary of Secondary Safety Endpoints

| Endpoints | Study Device | KM Estimated Event Rate (N=1203) | | | |
| --- | --- | --- | --- | --- | --- |
| | | 1 Month | 2 Months | 6 Months | 12 Months |
| Cardiac Death or MI (3rdUniversal) | LFII DCS | 2.7% (33) | 3.6% (43) | 6.5% (78) | 9.3% (110) |
| | LFI BMS | 3.2% (39) | 4.5% (54) | 9.7% (117) | 12.3% (147) |
| Cardiac Death, MI or StentThrombosis (ARCDefinite/Probable) | LFII DCS | 2.7% (33) | 3.6% (43) | 6.6% (79) | 9.4% (111) |
| | LFI BMS | 3.4% (41) | 4.6% (56) | 9.9% (119) | 12.6% (150) |
| All Death | LFII DCS | 1.0% (12) | 2.1% (25) | 4.6% (55) | 7.6% (91) |
| | LFI BMS | 1.0% (12) | 1.8% (22) | NA | 8.7% (105) |
| Cardiac Death | LFII DCS | 0.9% (11) | 1.1% (13) | 2.5% (30) | 3.5% (41) |
| | LFI BMS | 0.8% (10) | 1.4% (17) | NA | 5.1% (61) |
| Non-cardiac Death | LFII DCS | 0.1% (1) | 1.0% (12) | 2.1% (25) | 4.3% (50) |
| | LFI BMS | NA | NA | NA | NA |
| All MI (3rdUniversal) | LFII DCS | 1.9% (23) | 2.7% (32) | 4.4% (52) | 6.5% (75) |
| | LFI BMS | 2.6% (31) | 3.7% (44) | 5.9% (70) | 8.8% (103) |
| Target Vessel MI | LFII DCS | 1.8% (22) | 2.1% (25) | 3.4% (40) | 4.5% (52) |

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| Endpoints | Study Device | KM Estimated Event Rate (N=1203) | | | |
| --- | --- | --- | --- | --- | --- |
| | | 1 Month | 2 Months | 6 Months | 12 Months |
| | LFI BMS | 1.5% (18) | 2.5% (30) | 4.1% (48) | 6.3% (73) |
| All Bleeding | LFII DCS | 10.1% (121) | 12.6% (151) | 16.7% (198) | 21.2% (249) |
| | LFI BMS | 10.5% (126) | 11.9% (142) | 14.5% (173) | 19.1% (225) |
| Major Bleeding (BARC 3-5) | LFII DCS | 3.2% (38) | 4.5% (54) | 5.4% (64) | 7.0% (82) |
| | LFI BMS | 3.0% (36) | 3.3% (40) | 4.9% (58) | 7.3% (85) |
| Stent Thrombosis (ARC Definite/Probable) | LFII DCS | 1.1% (13) | 1.3% (16) | 1.5% (18) | 1.8% (21) |
| | LFI BMS | 1.1% (13) | 1.6% (19) | 1.6% (19) | 2.2% (26) |

# Adverse effects that occurred in the PMA clinical study:

A summary of adverse events is presented below in Table 18. Adverse events were reported using MedDRA preferred terms. Only adverse events occurring at a rate of $\geq 1\%$ in either treatment group are reported.

There was a total of 3301 adverse events reported in 860 patients in the BioFreedom DCS group, compared to a total of 2325 adverse events reported in 822 patients in the historical control BMS group. The frequency and nature of adverse events observed in the LEADERS FREE II trial were similar to those observed for other drug-eluting stents approved in the US. Note that events were not always coded consistently across the LFII and LFI trials, so direct comparisons are not necessarily informative. The below table combines related terms where appropriate.

Table 18. All Adverse Events Occurring in $&gt; {1}\%$ of Patients

| | LF II DCS (N=1203 Subjects) % Subjects (# of Events) | LFI BMS (N=1211 Subjects) % Subjects (# of Events) |
| --- | --- | --- |
| Any Adverse Event to 365 Days | 71.5% (3301) | 67.9% (2325) |
| Blood and lymphatic system disorders | | |
| Anaemia | 2.8% (37) | 2.9% (44) |
| Cardiac disorders | | |
| Acute myocardial infarction | 4.1% (55) | 4.8% (79) |
| Angina pectoris | 2.7% (34) | 4.3% (59) |
| Angina unstable | 1.0% (12) | 1.9% (25) |
| Atrial fibrillation | 5.7% (78) | 3.4% (42) |
| Bradycardia | 1.3% (17) | 0.6% (7) |
| Cardiac failure | 1.7% (24) | 3.7% (55) |
| Cardiac failure congestive | 3.2% (46) | 1.3% (20) |
| Coronary artery dissection | 0.9% (11) | 1.0% (13) |
| Coronary artery stenosis | 4.6% (61) | 0.2% (2) |
| Dizziness | 3.4% (44) | 1.0% (12) |
| Myocardial infarction | 2.2% (31) | 2.1% (29) |

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| | LF II DCS (N=1203 Subjects) % Subjects (# of Events) | LFI BMS (N=1211 Subjects) % Subjects (# of Events) |
| --- | --- | --- |
| Palpitations | 1.0% (12) | 0.4% (5) |
| **Gastrointestinal disorders** | | |
| Abdominal pain | 1.6% (19) | 0.3% (4) |
| Abdominal pain upper | 1.2% (18) | 0.7% (8) |
| Diarrhoea | 2.1% (27) | 0.9% (11) |
| Gastrointestinal haemorrhage | 1.8% (23) | 1.3% (16) |
| Nausea | 1.5% (20) | 0.3% (4) |
| Rectal haemorrhage | 1.2% (16) | 1.3% (22) |
| **General disorders and administration site conditions** | | |
| Asthenia | 1.4% (18) | 0.7% (9) |
| Chest pain | 11.1% (167) | 6.5% (89) |
| Coronary artery restenosis | 0.2% (5) | 4.0% (60) |
| Death | 1.4% (17) | 1.0% (13) |
| Fatigue | 2.0% (25) | 0.7% (8) |
| Non-cardiac chest pain | 1.2% (14) | 0.7% (9) |
| Oedema peripheral | 1.8% (22) | 0.9% (12) |
| Pain | 1.2% (15) | 0.0% (0) |
| Thrombosis in device or Vascular stent thrombosis | 1.8% (35) | 2.3% (32) |
| **Infections and infestations** | | |
| Bronchitis | 1.1% (15) | 0.7% (8) |
| Lower respiratory tract infection | 0.3% (4) | 1.0% (12) |
| Pneumonia | 2.1% (30) | 2.3% (30) |
| Respiratory tract infection | 0.4% (5) | 1.2% (14) |
| Upper respiratory tract infection | 1.1% (13) | 0.1% (1) |
| Urinary tract infection | 2.9% (39) | 2.3% (28) |
| **Injury, poisoning and procedural complications** | | |
| Fall | 1.2% (15) | 0.9% (11) |
| Post procedural myocardial infarction | 0.3% (4) | 1.2% (16) |
| Vascular access site haemorrhage | 1.3% (17) | 0.0% (0) |
| Vessel puncture site haematoma or Vascular access site haematoma | 2.2% (27) | 2.1% (25) |
| **Investigations** | | |
| Cardiac enzymes increased or Myocardial necrosis marker increased | 0.9% (12) | 1.8% (23) |
| Troponin I increased or Troponin T increased or Troponin increased | 0.8% (10) | 1.3% (16) |
| **Metabolism and nutrition disorders** | | |
| Hypokalaemia | 1.1% (14) | 0.1% (1) |
| **Musculoskeletal and connective tissue disorders** | | |

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| | LF II DCS (N=1203 Subjects) % Subjects (# of Events) | LFI BMS (N=1211 Subjects) % Subjects (# of Events) |
| --- | --- | --- |
| Arthralgia | 1.7% (24) | 0.3% (4) |
| Back pain | 2.8% (34) | 0.6% (7) |
| Musculoskeletal discomfort or Musculoskeletal pain or Musculoskeletal stiffness or Myalgia | 1.8% (13) | 0.7% (2) |
| Pain in extremity | 1.9% (26) | 1.0% (13) |
| **Nervous system disorders** | | |
| Cerebrovascular accident | 0.5% (6) | 1.2% (15) |
| Headache | 1.6% (19) | 0.3% (4) |
| Ischaemic stroke or Brain stem infarction or Cerebellar infarction or Cerebral infarction or Cerebral ischaemia or Ischaemic cerebral infarction | 1.1% (13) | 0.9% (11) |
| Syncope | 2.3% (29) | 0.9% (13) |
| **Renal and urinary disorders** | | |
| Acute kidney injury or Renal injury | 2.8% (37) | 0.1% (1) |
| Haematuria (blood in urine) | 2.0% (28) | 1.7% (23) |
| Renal failure or Renal failure acute or Renal failure chronic | 0.7% (9) | 2.7% (35) |
| **Respiratory, thoracic and mediastinal disorders** | | |
| Acute pulmonary oedema or Pulmonary oedema | 1.2% (16) | 1.7% (21) |
| Chest discomfort | 2.1% (28) | 0.0% (0) |
| Chronic obstructive pulmonary disease | 1.9% (26) | 0.7% (14) |
| Cough | 1.7% (23) | 1.2% (14) |
| Dyspnoea | 8.0% (102) | 6.1% (79) |
| Dyspnoea exertional | 1.1% (14) | 0.5% (6) |
| Epistaxis (nosebleed) | 2.1% (30) | 2.7% (42) |
| Respiratory failure | 1.2% (17) | 0.1% (1) |
| **Skin and subcutaneous tissue disorders** | | |
| Cellulitis | 1.2% (14) | 0.1% (1) |
| Contusion | 1.8% (22) | 0.0% (0) |
| Laceration | 1.5% (19) | 0.0% (0) |
| Rash or Rash generalized or Rash popular | 1.2% (14) | 0.4% (5) |
| **Surgical and medical procedures** | | |
| Coronary revascularization or Percutaneous coronary intervention or Vascular stent restenosis | 3.5% (46) | 1.7% (22) |
| **Vascular disorders** | | |
| Haematoma or Traumatic haematoma | 1.6% (19) | 0.9% (11) |
| Hypertension | 2.7% (33) | 0.8% (10) |

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| | LF II DCS
(N=1203 Subjects)
% Subjects
(# of Events) | LFI BMS
(N=1211 Subjects)
% Subjects
(# of Events) |
| --- | --- | --- |
| Hypotension | 2.3% (28) | 0.9% (12) |
| Peripheral arterial occlusive disease | 1.0% (16) | 0.4% (9) |

A summary of device/procedure-related serious adverse events is presented below in Table 19. A serious adverse event either resulted in death, was life-threatening, required inpatient hospitalization or caused prolongation of existing hospitalization, resulted in persistent or significant disability/incapacity, or required intervention to prevent permanent impairment or damage. Serious adverse events were reported using MedDRA preferred terms. Only serious adverse events occurring at a rate of $\geq 1\%$ in either treatment group are reported.

There was a total of 210 device/procedure-related serious adverse events reported in 134 patients in the BioFreedom DCS group, compared to a total of 376 serious adverse events reported in 211 patients in the historical control BMS group. The below table combines related terms where appropriate.

Table 19. Device or Procedure-Related Serious Adverse Events

| | LF II DCS
(N=1203 Subjects)
% Subjects
(# of Events) | LFI BMS
(N=1211 Subjects)
% Subjects
(# of Events) |
| --- | --- | --- |
| Any Device/Procedure-Related Serious Adverse Event to 365 Days | 11.1% (210) | 17.4% (376) |
| Acute myocardial infarction or Acute coronary syndrome or Myocardial infarction or Post procedural myocardial infarction | 3.4% (44) | 5.1% (77) |
| Angina pectoris or Angina unstable or Chest pain | 1.1% (14) | 4.3% (56) |
| Coronary angioplasty or Coronary artery bypass or Coronary artery restenosis or Coronary revascularisation or Percutaneous coronary intervention or Vascular stent restenosis | 2.7% (35) | 5.1% (75) |
| Coronary artery thrombosis or Thrombosis in device or Vascular stent thrombosis | 1.9% (33) | 2.2% (32) |

2. Effectiveness Results

The analysis of effectiveness was based on the 1203 ITT patients. Key effectiveness outcomes are presented in Table 20 to Table 22.

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Primary Endpoint (Effectiveness): The primary effectiveness endpoint of CD-TLR was met (Table 20). Non-inferiority of the primary endpoint of CD-TLR 6 months following BioFreedom DCS implantation in HBR patients compared to the LF II Gazelle BMS historical control arm was demonstrated after propensity score adjustment (as pre-specified in the LF II SAP). The same propensity score stratification as the primary safety endpoint analysis was used.

The 6-month Kaplan-Meier (KM) estimated rate for CD-TLR was 3.7% for the BioFreedom DCS group and 6.1% for the BMS historical control group. Based on the number of patients and observed rates in each stratum, the results show that the stratified difference between BioFreedom DCS and Gazelle BMS KM estimated rates of CD-TLR at 6 months was -2.2% with a 97.5% confidence interval upper limit of -0.4%, which was well below the prespecified non-inferiority margin of 2.48%. The -2.2% difference was also statistically significant for superiority, with the upper limit of the 2-sided 95% confidence interval (-4.1%, -0.4%) less than zero.

Table 20. Analyses of Primary Endpoints at 6 Months

| Endpoint | LFII DCS KM Estimate (N=1203) | LFI BMS KM Estimate (N=1211) | Stratified KM Difference | P value |
| --- | --- | --- | --- | --- |
| Cardiac Death and MI at 6 Months | 6.5% | 9.7% | Non-inferiority -3.5% [-1.2%]* | <0.0001 |
| | | | Superiority -3.5% [-5.8%, -1.2%]** | 0.0033 |
| Clinically Driven Target Lesion Revascularization | 3.7% | 6.1% | Non-inferiority -2.2% [-0.4%]* | <0.0001 |
| | | | Superiority -2.2% [-4.1%, -0.4%]** | 0.0175 |

*Upper 97.5% confidence interval
**95% confidence interval

To examine events occurring after DAPT discontinuation at one month, the 30-day landmark analysis population, consisting of all ITT patients that did not experience any events prior to 30 days, was also evaluated for the primary endpoints (Table 21).

Table 21. 30-Day Landmark Population Primary Endpoints at 6 Months

| Endpoint | LFII DCS KM Estimate (N=1054) | LFI BMS KM Estimate (N=1031) | Stratified KM Difference | P value |
| --- | --- | --- | --- | --- |
| Cardiac Death and MI | 3.8% | 6.9% | Non-inferiority -3.5% [-1.47%]* | <0.0001 |
| | | | Superiority -3.5% [-5.53%, -1.47%]** | 0.0013 |

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| Clinically Driven Target Lesion Revascularization | 2.9% | 5.4% | Non-inferiority -2.41% [-0.53%]* | <0.0001 |
| --- | --- | --- | --- | --- |
| | | | Superiority -2.41% [-4.3%, -0.53%]** | 0.0157 |

*Upper 97.5% confidence interval
**95% confidence interval

Secondary Endpoints (Effectiveness): At 1-year follow-up, the effectiveness endpoint (CD-TLR) occurred at a $7.2\%$ KM estimated rate in the BioFreedom DCS group, and at a $9.2\%$ KM estimated rate in the BMS historical control group $(p = 0.0388$ , log-rank test) with a hazard ratio of 0.72 (95% CI 0.52, 0.98), as shown in the propensity-stratified adjusted KM curves below (Figure 5).

Figure 5. Kaplan-Meier Plot of CD-TLR Through 1 Year

Other supportive composite effectiveness endpoints between 1 and 12 months are listed in Table 22. The values provided are KM estimated rates without propensity score adjustment. Revascularization rates after 2 months consistently favored the DCS group compared with the historical BMS control.

Table 22. Secondary Effectiveness Endpoints

| Endpoints | Study Device | KM Estimated Event Rate (N=1203) | | | |
| --- | --- | --- | --- | --- | --- |
| | | 1 Month | 2 Months | 6 Months | 12 Months |
| Urgent TLR | LFII DCS | 0.7% (9) | 0.9% (11) | 2.6% (30) | 3.9% (45) |
| | LFI BMS | 0.5% (6) | 1.3% (16) | 4.4% (52) | 5.6% (65) |
| Clinically Driven TLR | LFII DCS | 0.8% (10) | 1.1% (13) | 3.7% (43) | 7.2% (82) |
| | LFI BMS | 0.5% (6) | 1.4% (17) | 6.1% (71) | 9.3% (107) |

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| Endpoints | Study Device | KM Estimated Event Rate (N=1203) | | | |
| --- | --- | --- | --- | --- | --- |
| | | 1 Month | 2 Months | 6 Months | 12 Months |
| Clinically Driven TVR | LFII DCS | 1.1% (13) | 1.4% (17) | 4.1% (48) | 7.7% (88) |
| | LFI BMS | 0.5% (6) | 1.4% (17) | 6.3% (73) | 10.0% (115) |

# 3. Subgroup Analyses

The following preoperative characteristics were evaluated for potential association with outcomes:

# Sex/Gender

Although not powered to evaluate safety or effectiveness of the BioFreedom DCS in sex- or gender-specific subgroups, outcomes for male and female patients from the LFII trial at one year are available (Table 23).

The composite rate of cardiac death/all MI in LFII DCS patients at one year was $9.62\%$ in male patients and $8.72\%$ in female patients.

The stent thrombosis rate at one year was $1.96\%$ in males and $1.94\%$ in females. The major bleeding rate (BARC 3-5) was $6.09\%$ in male patients and $9.77\%$ in female patients.

Table 233. Primary and Secondary Endpoints by Sex/Gender

| Endpoint | Male (N=826) | Female (N=377) |
| --- | --- | --- |
| Cardiac Death / All MI | 78 (9.62%) | 32 (8.72%) |
| All Death | 62 (7.59%) | 29 (7.78%) |
| Cardiovascular Death | 28 (3.46%) | 13 (3.54%) |
| Non-cardiac Death | 34 (4.27%) | 16 (4.4%) |
| All MI | 53 (6.62%) | 22 (6.08%) |
| Target-Vessel MI | 37 (4.61%) | 15 (4.11%) |
| Major Bleeding (BARC 3-5) | 49 (6.09%) | 36 (9.77%) |
| Definite or Probable Stent Thrombosis | 16 (1.96%) | 7 (1.94%) |
| Clinically-indicated Target Lesion Revascularization | 60 (7.66%) | 22 (6.19%) |
| Clinically-indicated Target Vessel Revascularization | 64 (8.14%) | 24 (6.75%) |
| Target Lesion Failure | 97 (12.04%) | 38 (10.36%) |
| Target Vessel Failure | 100 (12.41%) | 40 (10.91%) |

The overall conclusions of the trial regarding the safety and effectiveness of the BioFreedom DCS when used with one month of DAPT in patients at high risk of bleeding can be generalized to males and females.

# Age

Of the 1203 patients in LFII, 988 were $&gt;65$ years old at the time of registration. The rates of cardiac death/all MI, BARC 3-5 bleeding, and stent thrombosis at one year in patients $&gt;65$ years old were $9.52\%$ , $7.99\%$ , and $2.08\%$ , respectively.

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These rates were comparable to those observed in the overall LFII population. Table 24 summarizes event rates at one year in patients $&gt;65$ and $\leq 65$ years old in the LFII study.

Table 24. Primary and Secondary Endpoints By Age

| Endpoint | ≤65 (N=215) | >65 (N=988) |
| --- | --- | --- |
| Cardiac Death / All MI | 18 (8.49%) | 92 (9.52%) |
| All death | 11 (5.21%) | 80 (8.19%) |
| Cardiovascular Death | 6 (2.86%) | 35 (3.63%) |
| Non-cardiac Death | 5 (2.42%) | 45 (4.73%) |
| All MI | 13 (6.18%) | 62 (6.51%) |
| Target-Vessel MI | 9 (4.25%) | 43 (4.5%) |
| Major Bleeding (BARC 3-5) | 8 (3.83%) | 77 (7.99%) |
| Definite or Probable Stent Thrombosis | 3 (1.41%) | 20 (2.08%) |
| Clinically-indicated Target Lesion Revascularization | 12 (5.74%) | 70 (7.52%) |
| Clinically-indicated Target Vessel Revascularization | 15 (7.16%) | 73 (7.82%) |
| Target Lesion Failure | 20 (9.44%) | 115 (11.99%) |
| Target Vessel Failure | 23 (10.84%) | 117 (12.19%) |

# Race and Ethnicity

Outcomes by race and ethnicity in the LFII study are presented in Table 25. Of the 1203 patients, 902 were white (75.0%) and 45 were Black or African American (3.7%), while 19 (1.6%) were Hispanic or Latino. The available race and ethnicity information is too limited to comment on any potential associations.

Table 25. Primary and Secondary Endpoints By Race and Ethnicity

| Endpoint | White (N=902) | American Indian or Alaska Native (N=3) | Asian (N=8) | Black or African American (N=45) | Hispanic or Latino (N=19) |
| --- | --- | --- | --- | --- | --- |
| Cardiac Death / All MI | 75 (8.5%) | 0 (0%) | 0 (0%) | 5 (11.17%) | 2 (10.53%) |
| All death | 63 (7.08%) | 0 (0%) | 0 (0%) | 4 (8.89%) | 2 (10.53%) |
| Cardiovascular Death | 26 (2.97%) | 0 (0%) | 0 (0%) | 2 (4.44%) | 1 (5.26%) |
| Non-cardiac Death | 37 (4.24%) | 0 (0%) | 0 (0%) | 2 (4.65%) | 1 (5.88%) |
| All MI | 50 (5.73%) | 0 (0%) | 0 (0%) | 5 (11.17%) | 1 (5.26%) |
| Target-Vessel MI | 32 (3.65%) | 0 (0%) | 0 (0%) | 4 (9.15%) | 1 (5.88%) |
| Major Bleeding (BARC 3-5) | 63 (7.12%) | 0 (0%) | 0 (0%) | 6 (13.78%) | 3 (17.11%) |
| Definite or Probable Stent Thrombosis | 15 (1.7%) | 0 (0%) | 0 (0%) | 1 (2.27%) | 0 (0%) |
| Clinically-indicated Target Lesion Revascularization | 60 (7.01%) | 0 (0%) | 1 (12.5%) | 4 (9.09%) | 2 (10.53%) |
| Clinically-indicated Target Vessel Revascularization | 64 (7.46%) | 0 (0%) | 1 (12.5%) | 4 (9.09%) | 2 (10.53%) |
| Target Lesion Failure | 96 (10.94%) | 0 (0%) | 1 (12.5%) | 6 (13.33%) | 3 (15.79%) |

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| Endpoint | White (N=902) | American Indian or Alaska Native (N=3) | Asian (N=8) | Black or African American (N=45) | Hispanic or Latino (N=19) |
| --- | --- | --- | --- | --- | --- |
| Target Vessel Failure | 100 (11.38%) | 0 (0%) | 1 (12.5%) | 6 (13.33%) | 3 (15.79%) |

## 4. Poolability Analyses

As LF II combined subjects from the US, Canada, and Europe, the study SAP specified that the primary endpoints would be presented by region and by site, and that heterogeneity of treatment effects with respect to sites would be explored. Table 256 presents primary endpoint results by region. Effectiveness results did appear to vary by region, with US patients experiencing fewer CD-TLR events than OUS patients at 6 months. However, this does not raise a concern for the performance of the BioFreedom DCS in US patients. For the multiple center effect analysis, a logistic regression model including an intercept term and fixed effect for sites showed no issues of poolability between investigational sites for the primary safety or primary effectiveness endpoints.

Table 25. Geographic Poolability Evaluation

| | KM Estimated Rate of Death or MI at 6 Months (N=1203) | KM Estimated Rate of CD-TLR at 6 Months (N=1203) |
| --- | --- | --- |
| US | 3.1% (18/594) | 4.4% (26/594) |
| OUS | 4.3% (25/609) | 8.6% (52/609) |

## 5. Pediatric Extrapolation

In this premarket application, existing clinical data was not leveraged to support approval of a pediatric patient population.

## E. Financial Disclosure

The Financial Disclosure by Clinical Investigators regulation (21 CFR 54) requires applicants who submit a marketing application to include certain information concerning the compensation to, and financial interests and arrangement of, any clinical investigator conducting clinical studies covered by the regulation. The pivotal LFII clinical study included 413 investigators. None of the clinical investigators had disclosable financial interests/arrangements as defined in sections 54.2(a), (b), (c), and (f). The information provided does not raise any questions regarding the reliability of the data.

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# XI. SUMMARY OF SUPPLEMENTAL CLINICAL INFORMATION

LFII was the pivotal trial used to support this PMA. Several additional clinical studies have been conducted on the BioFreedom DCS as chronologically outlined in Table 267.

Table 26. Summary of Additional Clinical Studies

| Study | # of Patients | Type | DAPT | Endpoints | Duration |
| --- | --- | --- | --- | --- | --- |
| BioFreedom First in Human (2008-2014) | 60 BioFreedom DCS60 Taxus Liberté | Prospective, randomized, 4 German sites | 6 mo | Late lumen loss at 12 months | 5 years |
| Summary of Results | This first-in-human study demonstrated non-inferiority to Taxus Liberté for the primary endpoint and demonstrated comparable MACE rates through 5 years of follow up. | | | | |
| LEADERS FREE (LFI) (2012-2016) | 1,239 BioFreedom DCS1,227 Gazelle BMS | Prospective, randomized, double blind, 68 sites in 20 OUS countries | 1 mo | 1. MACE2. Clini…