WallFlex Biliary RX Fully Covered Stent System RMV

DEN150040 · Boston Scientific · PNB · Jun 3, 2016 · Gastroenterology, Urology

Device Facts

• Record ID: DEN150040
• Device Name: WallFlex Biliary RX Fully Covered Stent System RMV
• Applicant: Boston Scientific
• Product Code: PNB · Gastroenterology, Urology
• Decision Date: Jun 3, 2016
• Decision: DENG
• Submission Type: Direct
• Regulation: 21 CFR 876.5011
• Device Class: Class 2
• Attributes: Therapeutic

Intended Use

The WallFlex Biliary RX Fully Covered Stent System RMV is indicated for indwell up to 12 months in the treatment of benign biliary strictures secondary to chronic pancreatitis.

Device Story

The WallFlex Biliary RX Fully Covered Stent System RMV is a prescription-only, single-use device for treating benign biliary strictures. It consists of a self-expanding Nitinol metallic stent with a platinum core, fully covered by Permalume silicone, and a coaxial Rapid Exchange (RX) delivery system. The stent features proximal/distal flares and a retrieval loop to facilitate placement and removal. Used in clinical settings by physicians, the device is deployed under fluoroscopic guidance using radiopaque markers on the delivery system. The stent remains indwelling for up to 12 months to maintain duct patency, after which it is removed endoscopically. By providing mechanical support to the stricture, the device aims to resolve biliary obstruction, improve liver function, and reduce obstructive symptoms, benefiting patients with chronic pancreatitis.

Clinical Evidence

Prospective, nonrandomized multinational study (NCT01014390) of 127 chronic pancreatitis patients. Primary endpoint: stent removability. Results: 100% technical placement success. Stent removability successful in 72.4% (ITT) and 78.0% (PP). Removal success (including spontaneous passage) 84.3% (ITT) and 90.7% (PP). Stricture resolution 74.0% (ITT) and 79.7% (PP). No stricture recurrence in 85.1% of patients over median 19-month follow-up. SAEs occurred in 36.2% of patients, primarily pancreatitis (10.2%) and cholangitis (7.1%).

Technological Characteristics

Nitinol monofilament wire with platinum core; Permalume silicone covering. Coaxial RX delivery system with 0.035-inch guidewire compatibility. Radiopaque markers for fluoroscopic visualization. Sterilized via ethylene oxide. MRI conditional. Dimensions: 8-10 mm diameter, 40-80 mm length.

Indications for Use

Indicated for patients with benign biliary strictures secondary to chronic pancreatitis requiring temporary stent placement for up to 12 months.

Regulatory Classification

Identification

A metallic biliary stent system for benign strictures is a prescription device intended for the treatment of benign biliary strictures. The biliary stents are intended to be left indwelling for a limited amount of time and subsequently removed. The device consists of a metallic stent and a delivery system intended to place the biliary stent in the bile duct. This device type is not intended for use in the vasculature.

Special Controls

In combination with the general controls of the FD&C Act, the Metallic Biliary Stent System for Benign Strictures is subject to the following special controls:

*Classification.* Class II (special controls). The special controls for this device are:(1) Clinical performance testing must demonstrate or provide the following: (i) The ability to safely place and subsequently remove the stent after the maximum labeled indwell period. (ii) All adverse event data including bile duct obstruction and trauma to the bile duct. (iii) The stent resolves strictures during the maximum labeled indwell period. (iv) Stricture resolution is maintained post-stent removal. (2) Non-clinical performance testing must demonstrate that the device performs as intended under anticipated conditions of use. The following performance characteristics must be demonstrated: (i) Corrosion testing to demonstrate that the stent maintains its integrity during indwell and does not release potentially toxic levels of leachables. (ii) Stent dimensional testing supports the intended use. (iii) Compression and expansion forces must be characterized. (iv) The delivery catheter must deliver the stent to the intended location and the stent must not be adversely impacted by the delivery catheter during deployment and catheter withdrawal. (v) The delivery system must withstand clinically anticipated forces. (vi) Compatibility in a magnetic resonance environment. (3) All patient contacting components of the device must be demonstrated to be biocompatible. (4) Performance data must demonstrate the sterility of the device components intended to be provided sterile. (5) Shelf life testing must demonstrate that the device maintains its performance characteristics and that packaging maintains sterility for the duration of the labeled shelf life. (6) Labeling for the device must include: (i) A detailed summary of the clinical testing including device effectiveness, and device- and procedure-related adverse events. (ii) Appropriate warning(s) to accurately ensure usage of the device for the intended patient population. (iii) Shelf life. (iv) Compatibility information for use in the magnetic resonance environment. (v) Stent foreshortening information supported by dimensional testing.

Submission Summary (Full Text)

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#### DE NOVO CLASSIFICATION REQUEST FOR WALLFLEX BILIARY RX FULLY COVERED STENT SYSTEM RMV

#### REGULATORY INFORMATION

FDA identifies this generic type of device as:

Metallic Biliary Stent System for Benign Strictures: A metallic biliary stent system for benign strictures is a prescription device intended for the treatment of benign biliary strictures. The biliary stents are intended to be left indwelling for a limited amount of time and subsequently removed. The device consists of a metallic stent and a delivery system intended to place the biliary stent in the bile duct. This device type is not intended for use in the vasculature.

NEW REGULATION NUMBER: 21 CFR 876.5011

CLASSIFICATION: II

PRODUCT CODE: PNB

#### BACKGROUND

DEVICE NAME: WallFlex Biliary RX Fully Covered Stent System RMV

SUBMISSION NUMBER: DEN150040

DATE OF DE NOVO: August 28, 2015

- BOSTON SCIENTIFIC CORPORATION CONTACT: 100 BOSTON SCIENTIFIC WAY MARLBOROUGH, MA 01752
#### REQUESTER'S RECOMMENDED CLASSIFICATION: Class II

#### INDICATIONS FOR USE

The WallFlex Biliary RX Fully Covered Stent System RMV is indicated for indwell up to 12 months in the treatment of benign biliary strictures secondary to chronic pancreatitis.

#### LIMITATIONS

The sale, distribution, and use of the device are restricted to prescription use in accordance with 21 CFR §801.109.

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## Contraindications:

- The WallFlex Biliary RX Fully Covered Stent should not be placed in strictures that cannot be dilated enough to pass the delivery system, in a perforated duct, or in very small intrahepatic ducts.
- The WallFlex Biliary RX Fully Covered Stent System RMV should not be used in patients for whom endoscopic techniques are contraindicated.

#### Warnings:

The safety and effectiveness of the stent has not been established for indwell periods exceeding 12 months.

The WallFlex Biliary RX Fully Covered Stent System RMV is for single-use only.

The safety and effectiveness of the WallFlex Biliary RX Fully Covered Stent System RMV for use in the vascular system has not been established.

The safety and effectiveness of the WallFlex Biliary RX Fully Covered Stent System RMV has not been established in the treatment of benign biliary anastomotic strictures in liver transplant patients and benign biliary post abdominal surgery strictures.

Testing of overlapped stents has not been conducted.

The stent contains nickel, which may cause an allergic reaction in individuals with nickel sensitivity.

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

#### DEVICE DESCRIPTION

The WallFlex Biliary RX Fully Covered Stent System RMV consists of 2 components: the implantable fully covered self-expanding metallic biliary stent (FC-SEMBS) and the Rapid Exchange (RX) delivery device.

The FC-SEMBS is made out of Nitinol monofilament wire with a radiopaque platinum core, braided in a tubular mesh configuration. The stent has proximal and distal flares at each end to aid in preventing migration. The proximal flare also contains the biliary stent retrieval loop. The retrieval loop is used for removal during the initial placement procedure in the event of incorrect placement. The retrieval loop is also used for removal from the bile duct. See Figure 1 for a photograph of the FC-SEMBS.

The biliary stent is covered with a Permalume™ silicone covering along its entire length except for 2 mm on the retrieval loop end.

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Image /page/2/Picture/0 description: The image shows a medical device called an FC SEMS, which stands for Fully Covered Self-Expanding Metal Stent. The device is a cylindrical mesh-like structure with a retrieval loop at one end and proximal and distal flares at either end. The proximal flare is labeled in the image, as is the retrieval loop and distal flare.

Figure 1 - FC-SEMBS

The following models of biliary stent (diameter and length) are part of this system.

| UPN | Description | Delivery<br>System<br>Working<br>Length<br>(cm) | Stent<br>Diameter<br>(mm) | Stent<br>Length<br>(mm) |
|-----------|-------------------------------------------------------|-------------------------------------------------|---------------------------|-------------------------|
| M00570340 | WallFlex Biliary Stent RX<br>Fully Covered System RMV | 194 | 8 | 60 |
| M00570350 | WallFlex Biliary Stent RX<br>Fully Covered System RMV | 194 | 8 | 80 |
| M00570360 | WallFlex Biliary Stent RX<br>Fully Covered System RMV | 194 | 10 | 40 |
| M00570370 | WallFlex Biliary Stent RX<br>Fully Covered System RMV | 194 | 10 | 60 |
| M00670380 | WallFlex Biliary Stent RX<br>Fully Covered System RMV | 194 | 10 | 80 |

The RX delivery device (see Figure 2) is a coaxial tube design. The exterior tube is used to constrain the biliary stent before deployment and re-constrain the biliary stent, if biliary stent repositioning is necessary, after partial deployment. The exterior tube has a clear section so that the constrained stent is visible. A yellow transition zone on the inner tube of the delivery system is visible between the stent and the blue outer sheath. There are four radiopaque (RO) markers to aid in the deployment of the stent while using fluoroscopy.

There are two RO markers on the inner tube of the delivery system identifying the ends of the constrained biliary stent. Between these RO markers is an additional RO marker that indicates at what point re-constrainment is no longer possible. The fourth RO marker at the leading end of the exterior tube indicates how far the biliary stent has been deployed. There is one visual marker on the interior tube between the handles to aid in the deployment of the biliary stent. The visual marker indicates the point at which re-constrainment is no longer

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possible. The interior tube has a single central lumen to accommodate a 0.035 inch (0.86 mm) guidewire.

Image /page/3/Picture/1 description: The image shows a medical device with several labeled components. The device includes a distal handle, a visual marker, and a proximal handle. It also features a delivery system tip, multiple radiopaque marker bands labeled #1, #2, #3, and #4, and a yellow inner member jacket.

Figure 2 – RX Delivery Device

A schematic drawing (Figure 3) of the WallFlex Biliary RX Fully Covered Stent System RMV provides additional details for the primary design features.

Image /page/3/Figure/4 description: This image shows a diagram of a medical device, with several components labeled. The device includes a trailing handle, a leading handle, and a stainless steel tube. There are also several marker bands, including a visual marker band, a leading radiopaque marker band #1, a trailing radiopaque marker band #2, a limit marker band #3, and an exterior tube marker band #4. Other components include a stent, a shipping mandrel, an inner tube, an exterior tube, and a tip.

Figure 3 - Schematic of the WallFlex Biliary RX Fully Covered Stent System RMV

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# SUMMARY OF NONCLINICAL/BENCH STUDIES

As noted below in Table 2, the WallFlex Biliary RX Fully Covered Stent System RMV is identical in billiary stent design and delivery system to the WallFlex Biliary RX Covered stent and delivery system that was previously cleared for marketing (K083627) for a different intended use. Notations of non-clinical information that were relied upon and/or leveraged from prior marketing submissions to support the de novo request are summarized in Table 2.

| Test | Purpose | Methods | Acceptance Criteria | Results | | |
|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|--------------------------------------------------------------------------------------------------------------------------------|----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|------------------------------------------------------------------------------------------------------------|--|
| Sterilization, Cleaning, and Disinfection – Sterilization validation was provided for the WallFlex Biliary RX Partially Covered stent and<br>delivery system that was previously cleared for marketing (K061231). The design and materials of this marketed device are nearly<br>identical to those of the subject device, and therefore it is acceptable to adopt the current device into the sterilization process. | | | | | | |
| Sterilization | Evaluate the sterility<br>level of device<br>components | ANSI/AAMI/ISO<br>11135:1994: Medical<br>Devices - Validation and<br>Routine Control of Ethylene<br>Oxide Sterilization; | The sterility assurance level<br>(SAL) shall be 10-6 | Passed: Sterilization was re-<br>assessed in 2015 to ensure<br>compliance to most recent version<br>of ANSI/AAMI/ISO 10993-7.<br>Testing was conducted on the 10<br>X 120 mm fully covered stent,<br>which was considered worst-case<br>for all the covered WallFlex<br>Biliary stents as it has the largest<br>surface area and greatest amount<br>of silicone covering. | | |
| | Ethylene oxide<br>sterilization residuals | Ensure acceptable<br>level of ethylene<br>oxide (EtOH)<br>residuals | ANSI/AAMI/ISO 10993-7:<br>Biological Evaluation of<br>Medical Devices: Ethylene<br>Oxide Sterilization<br>Residuals | EtOH residual amounts are below<br>the maximum amount allowed:<br>For the stent, the average daily<br>dose of EO to patient shall not<br>exceed 0.1 mg/day. In addition,<br>the maximum EO dose shall not<br>exceed 20 mg in the first 24 hr; 60<br>mg in the first 30 days; 2.5 g in a<br>lifetime. For the delivery catheter,<br>the average daily dose shall not<br>exceed 4 mg. | | |
| | | Biocompatibility: All testing except that for nickel leaching and the toxicological risk assessment was provided for the WallFlex Biliary RX<br>Partially Covered stent and delivery system that was previously cleared for marketing (K061231). This device is identical to the subject<br>device with the exception that the stent has both covered and uncovered portions. This is acceptable as the surrogate stent represents the<br>materials found in the current stent design. | | | | |
| | | | | | | |
| Cytotoxicity | | Determine if polar<br>and non-polar<br>extract of the stent<br>and delivery<br>catheter elicit a<br>cytotoxic response | ISO 10993-5 Biological<br>Evaluation of Medical<br>Devices: Tests for<br>Cytotoxicity: in vitro; MEM<br>Elution method | - | Grade 0 (non-cytotoxic) | |
| Irritation | | Determine if polar<br>and non-polar<br>extracts of the stent<br>and delivery<br>catheter elicit a<br>hypersensitive<br>response | ISO 10993-10: Biological<br>Evaluation of Medical<br>Devices: Tests for Irritation<br>and Sensitization: Rabbit<br>Intracutaneous method | - | Based on histopathologic<br>evaluations, the stent with<br>delivery system is considered a<br>non-irritant | |
| Sensitization | Determine if polar<br>and non-polar<br>extracts of the stent<br>and delivery<br>catheter cause a<br>hypersensitive<br>response | ISO 10993-10: Biological<br>Evaluation of Medical<br>Devices: Tests for Irritation<br>and Delayed Type<br>Hypersensitivity: Guinea Pig<br>Maximization Sensitization<br>method | - | No signs of sensitization from<br>polar and non-polar extracts | | |
| Acute Systemic<br>Toxicity | Determine if polar<br>and non-polar<br>extracts of the stent<br>cause adverse<br>effects | ISO 10993-11: Biological<br>Evaluation of Medical<br>Devices: Tests for Systemic<br>Toxicity: b(4) | - | No evidence of mortality or<br>systemic toxicity from test<br>material extracts | | |
| Genotoxicity | Determine if polar<br>and non-polar<br>extracts of stent are<br>mutagenic | ISO 10993-3: Biological<br>Evaluation of Medical<br>Devices: Tests for<br>Genotoxicity,<br>Carcinogenicity, and<br>Reproductive Toxicity:<br>Bacterial Mutagenicity<br>(Ames Assay) method | - | The stent is considered non-<br>mutagenic in the Ames Bacterial<br>mutagenicity assay | | |
| Implantation | Determine if surgically implanted sections of the stent cause a hypersensitive response | ISO 10993-6: Biological Evaluation of Medical Devices: Tests for Local Effects After Implantation: Rabbit 28-Day Duration Intramuscular Implant method | Based on histopathologic evaluations, the stent with delivery system is considered a non-irritant | | | |
| Subchronic Toxicity | Determine if polar and non-polar extracts of the stent cause prolonged exposure adverse effects | ISO 10993-11: Biological Evaluation of Medical Devices: Tests for Systemic Toxicity: b(4) Study method | There were no signs of systemic toxicity due to leachable components | | | |
| Nickel leaching | Determine if the stent can leach toxic levels of nickel | ASTM F2129: Standard Test Method for Conducting b(4) the Corrosion Susceptibility of Small Implant Devices | Based on the manufacturing methods, acceptable ASTM F2129 results, the available literature on nickel leaching in similar systems, and considering the stent is coated, there is sufficient evidence that the device will exhibit adequate resistance to corrosion and the nickel leach rates will be acceptable | | | |

# Table 2 – Summary of Nonclinical Studies

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| Toxicological risk | Determine if polar | A toxicological risk | | Exposure to the stent is not likely |
|--------------------|-----------------------------------------------------------------------------|--------------------------------|--------------------------------------------------------------------------------------------------------------------------------------|-------------------------------------|
| assessment | and non-polar | assessment of the fully | | to lead to systemic toxicity. |
| | extracts of the stent | covered stent was conducted | | |
| | pose a chronic | per ISO 10993-18: Biological | | |
| | systemic toxicity | Evaluation of Medical | | |
| | risk | Devices: Chemical | | |
| | | Characterization of Materials, | | |
| | | considering the tolerable | | |
| | | intake of analytically | | |
| | | identified leachables | | |
| | | considering ISO 10993-17: | | |
| | | Biological Evaluation of | | |
| | | Medical Devices: Methods | | |
| | | for the Establishment of | | |
| | | Allowable Limits for | | |
| | | Leachable Substances | | |
| | | | Beach Testing was provided for the WallFlex Biliary RX Covered stent and delivery system that was previously cleared for | |
| | | | marketing (K083627) for a different intended use. This identical to the subject device. This is acceptable as the stent and delivery | |
| | | | system are identical between the K083627 submission and this de novo request. MRI compatibility testing to support the current MRI | |
| | safety labeling was previously reviewed (K112543) for the identical stents. | | | |
| Deployment Testing | The delivery | b(4) | The delivery catheter must safely | Pass: Stent sizes tested represent |
| Stent delivery | catheter should | b(4)<br>stents with the | and accurately deliver the stent to | the smallest and largest sizes |
| accuracy | safely and reliably | delivery system were | the intended anatomic location. | available. Therefore, they can be |
| Trackability<br>● | deliver the stent to | evaluated through simulated | No damage to the stent or | used as surrogates to represent the |
| Guidewire | the intended | use in a worst-case scenario | simulated stricture model should | spectrum of available stent sizes. |
| passage | location without | model | occur. | |
| Deployment and | damage to the stent | | | |
| reconstrainment | or the patient. This | | | |
| force | testing is used to | | | |
| | validate the | | | |
| | accuracy and | | | |
| | repeatability of the | | | |
| | | | | |

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| Expansion/<br>Compression Force<br>Testing | Excessive radial<br>force could injure<br>the surrounding<br>tissue, while a radial<br>force that is too low<br>can result in<br>incomplete<br>apposition of the<br>stent to the lumen.<br>Compression force<br>testing characterizes<br>the ability of the<br>stent to resist<br>collapse under<br>external loads | Expansion and compression<br>forces were measured for<br>b(4) | The radial expansion forces must<br>be at least 85% of b(4) N for 8<br>mm diameter stents compressed<br>to 4 mm.b(4)<br>for 8 mm<br>diameter stents compressed to 6<br>mm, b(4)<br>for 10 mm diameter<br>stents compressed to 6 mm, and<br>b(4)<br>for 10 mm diameter<br>stents compressed to 8 mm.<br>The radial compression forces<br>must be at least 85% of b(4)<br>for 8 mm diameter stents<br>compressed to 4 mm, b(4)<br>for<br>8 mm diameter stents compressed<br>to 6 mm.b(4)<br>for 10 mm<br>diameter stents compressed to 6<br>mm, and b(4)<br>for 10 mm<br>diameter stents compressed to 8<br>mm. | Passed |
|--------------------------------------------|--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|--------|
| Dimensional Testing<br>b | Accurate stent and<br>delivery catheter<br>dimensions help the<br>physician to achieve<br>proper stent sizing<br>and accurate<br>placement in the<br>body. They also<br>affect the functional<br>behavior of the<br>stent. | Dimensions of each stent size<br>and delivery catheter (b(4) 5<br>catheters) were measured<br>using an b(4)<br>and verified to meet the<br>acceptance criteria and that<br>the device complies with its<br>labeled dimensions. Stents<br>also were measured in the<br>unexpanded and expanded<br>states to generate<br>foreshortening information. | All dimensions should be within<br>design tolerance ranges. | Passed |

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| Tensile Strength<br>Testing (bond<br>integrity) | Evaluate if failure of<br>bonds in the<br>delivery catheter<br>could lead to device<br>failure and clinical<br>complications | Bonded joints of the delivery<br>catheters loaded with 0(4)<br>b(4 fully covered stents were<br>tested to failure using a<br>tensile tester P(4) | All bonded components of the<br>delivery catheter should withstand<br>forces that exceed those<br>encountered during clinical use. | Pass |
|-------------------------------------------------|------------------------------------------------------------------------------------------------------------------------------|--------------------------------------------------------------------------------------------------------------------------------------------------|--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| Stent Integrity | Evaluate if stent<br>corrosion can cause<br>or contribute to<br>premature stent<br>failure | Stents were exposed to<br>simulated bile in an<br>accelerated fashion to<br>replicate an aging period of<br>one year:<br>b(4)<br>b(<br>AS | Stents:<br>No crevice or pitting<br>corrosion<br>No more than 2 weld breaks<br>No significant weight loss<br>Meet specification<br>requirements for radial<br>compression and expansion<br>forces<br>Wire must meet specification<br>requirements for tensile<br>properties<br>Stent cover integrity must meet<br>requirements for holes and<br>delamination | Pass: Stents tested represent the<br>worst-case scenario as they span<br>the size range of the stents offered<br>and are not all fully covered<br>which allows potentially more<br>degradation to occur. |

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| MRI Compatibility<br>• Displacement<br>force<br>• RF induced<br>heating<br>• Artifact testing | Determine the<br>presence of<br>magnetic field<br>interactions,<br>localized tissue<br>heating, and image<br>artifacts in<br>association with the<br>use of an MR<br>system | Testing was conducted in<br>accordance with ASTM<br>F2052-02: Standard Test<br>Method for Measurement of<br>Magnetically Induced<br>Displacement Force on<br>Passive Implants in the<br>Magnetic Resonance<br>Environment, ASTM F2182-<br>02a: Standard Test Method<br>for Measurement of Radio<br>Frequency Induced Heating<br>Near Passive Implants During<br>Magnetic Resonance<br>Imaging, and ASTM F2119-<br>01: Standard Test Method for<br>Evaluation of MR Image<br>Artifacts from Passive<br>Implants | MRI compatibility labeling must<br>be supported by testing. To be<br>considered MRI conditional,<br>displacement forces should not<br>have the potential to damage the<br>tissue where the device is placed<br>and localized temperature<br>increases should not damage<br>tissues when patients are scanned<br>as outlined in the labeling | Evaluated b(4)<br>configurations as<br>worst-case scenario<br>configurations<br>Mean deflection angle of 3°<br>Worst case projected temperature<br>rise of 5.5°C for a whole body<br>average specific absorption rate<br>(SAR) of 4 W/kg<br>Artifacts appeared on the MR<br>images as localized signal voids<br>that extend ~10 mm from the<br>stent wall perimeter and ~2 mm<br>beyond each end of the length of<br>the stent |
|------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------|----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| Shelf Life: Package integrity testing was conducted for the Wallstent Enteral Stent (K000281). The packaging of the Wallstent<br>Enteral Stent is identical to that of the WallFlex Biliary RX Fully Covered Stent System RMV. Functional performance testing to<br>support a 2 year shelf life was conducted on the subject device of this de novo. | | | | |
| Package integrity<br>• heat seal peel test<br>• dye penetration | Evaluate the sterile<br>packaging integrity<br>to ensure that | ISTA 2A Partial Simulation<br>Performance Tests for<br>Packaged Products weighing | Packaging must not be able to be<br>compromised below a minimum<br>pressure threshold. | Pass |
| | devices remain<br>sterile throughout<br>the shelf-life | 150 lbs followed by heat seal<br>peel testing of packaging<br>(Tray/Lid and Pouch) b(4)<br>ISTA 2A Partial Simulation<br>Performance Tests for<br>Packaged Products weighing<br>150 lbs followed by dye<br>penetration testing of<br>packaging b(4) | No channels, pinholes, or other<br>barrier breaches allowed<br>All samples must not have<br>channels visible at 10X<br>magnification | |

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| Deployment Testing<br>• Trackability<br>• Guidewire<br>passage<br>• Deployment and<br>reconstrainment<br>force<br>• System<br>withdrawal | The delivery<br>catheter should<br>safely and reliably<br>deliver the stent to<br>the intended<br>location without<br>damage to the stent<br>or the patient. This<br>testing is used to<br>validate the<br>accuracy and<br>repeatability of the<br>delivery system<br>upon 25 month real<br>time aging | Simulated use in a<br>trackability model consisting<br>of an endoscope working<br>channel configured in a<br>tortuous path b(4) | The delivery catheter must safely<br>and accurately deliver the stent to<br>the intended anatomic location.<br>No damage to the stent or<br>simulated stricture model should<br>occur. The stent should be able to<br>be removed with the delivery<br>catheter if the reconstrainment<br>point has not been exceeded. | Pass: Stent size tested represents<br>the largest size available. This is<br>acceptable for shelf life testing as<br>we do not expect stent size to<br>impact performance after aging. |
|------------------------------------------------------------------------------------------------------------------------------------------|--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|---------------------------------------------------------------------------------------------------------------------------------|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| Expansion/<br>Compression Force<br>Testing | Excessive radial<br>force could injure<br>the surrounding<br>tissue, while a radial<br>force that is too low<br>can result in<br>incomplete<br>apposition of the<br>stent to the lumen.<br>Compression force<br>testing characterizes<br>the ability of the<br>stent to resist<br>collapse under<br>external loads upon<br>25 month real time<br>aging | Expansion and compression<br>forces were measured for<br>b(4)<br>each) | Expansion and compression<br>forces must not be impacted by<br>aging | Passed |

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| Flexural Rigidity | Evaluate rigidity of stents to ensure stent integrity upon 25 month real time aging | Flexural rigidity b(4) | Stents must not become rigid after aging | Pass |
|-------------------------------------------|--------------------------------------------------------------------------------------------------------------------------------|-----------------------------------------------------------------------------------------------------|---------------------------------------------------------------------------------------------------------------------------------------|------|
| Covering Material Integrity | Evaluate covering material for compromised surfaces upon 25 month real time aging | Covering b(4) were evaluated with the unaided eye after deploying and reconstraining the stent b(4) | Maximum of 6 diamonds (openings in the stent mesh) containing compromised coating integrity | Pass |
| Weld Integrity | Evaluate integrity of stent welded wires upon 25 month real time aging | Examined b(4) r broken wire weld joints after stent is deployed and reconstrained b(4) | No more than two broken wire weld joints observed | Pass |
| Tensile Strength Testing (bond integrity) | Evaluate if failure of delivery catheter could lead to device failure and clinical complications upon 25 month real time aging | Bonded joints were tested to failure using a tensile tester for delivery catheters with the b(4) | All bonded components of the delivery catheter should withstand forces that exceed those encountered during clinical use after aging. | Pass |

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## SUMMARY OF CLINICAL INFORMATION

A prospective, nonrandomized clinical study (clinicaltrials.gov Identifier: NCT01014390) was conducted to determine the effectiveness and safety of WallFlex Biliary Fully Covered Stent System in the treatment of benign biliary stricture secondary to chronic pancreatitis (CP), post-liver transplant (OLT), and post-abdominal surgery (CCY).

Only the CP cohort consisting of 127 subjects was evaluated for the de novo request. Neither the de novo request nor the labeling include indications for the OLT and CCY patient populations with the exception of a Warning included within the labeling that states the following:

Warning: The safety and effectiveness of the WallFlex Biliary RX Fully Covered Stent System RMV has not been established in the treatment of benign biliary anastomotic strictures in liver transplant patients and benign biliary post abdominal surgery strictures.

#### Objective of the study

To assess the safety and performance of temporary placement of the WallFlex Biliary RX Fully Covered Stent as a treatment of biliary obstruction resulting from benign bile duct strictures.

#### Methods

The study was a large prospective multinational study utilizing 13 centers in 11 countries outside of the US (OUS). The results of this study were published in the journal Gastroenterology (Deviere, Nageshwar Reddy et al. 2014).

#### Primary Endpoint:

Stent removability, defined as ability to remove the stent endoscopically without serious stent removal related adverse events as assessed from the time of stent removal to 1 month post-stent removal. Per-protocol stent removal occurred at 11 ± 1 month for CP patients.

Secondary Endpoints:

- 1. Stricture resolution during stent indwell, defined by lack of stent-related re-interventions
- 2. Stricture resolution after stent removal, defined by lack of stricture related re-intervention
- 3. Occurrence and severity of adverse events related to the stent and/or the procedure
- 4. Ability to deploy the stent in satisfactory position across the stricture (technical success at placement)
- 5. Length of stent placement procedure, length of stent removal procedure and methods of removal (to include video recording if available)
- 6. Biliary obstructive symptom assessment at all visits
- 7. Liver Function Tests (LFT's) at baseline, at month 1 post-stent placement, at stent removal and at months 6, 12 and 24 post-stent removal

Inclusion Criteria:

- Age 18 or older .

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- . Willing and able to comply with the study procedures and provide written informed consent to participate in the study
- . Chronic pancreatitis or prior liver transplantation or prior other abdominal surgery (to include cholecystectomy )
- Indicated for endoscopic retrograde cholangiopancreatography (ERCP) procedure with stent ● placement for:
- . Symptomatic bile duct stricture (i.e. obstructive jaundice, persistent cholestasis, acute cholangitis) confirmed by cholangiogram and/or
- Bile duct stricture confirmed by cholangiogram and/or
- . Exchange of prior plastic stent(s) for management of benign stricture

## Exclusion Criteria:

- . General:
- Placement of the stent in strictures that cannot be dilated enough to pass the delivery . system
- I Placement of the stent in a perforated duct
- Placement of the stent in very small intrahepatic ducts l
- 트 Patients for whom endoscopic techniques are contraindicated
- I Biliary stricture of malignant etiology
- I Biliary stricture of benign etiology other than chronic pancreatitis or liver transplant anastomosis or other abdominal surgery
- I Stricture within 2 cm of duct bifurcation
- I Symptomatic duodenal stenosis (with gastric stasis)
- 트 Prior biliary self-expanding metal stent
- I Suspected stricture ischemia based on imaging of hepatic artery occlusion or endoscopic evidence of biliary cast syndrome
- 트 Known bile duct fistula
- 트 Known sensitivity to any components of the stent or delivery system
- . Participation in another investigational study within 90 days prior to consent or during the study
- Additional Exclusion Criteria Specific to Chronic Pancreatitis Patients: ●
- . Developing obstructive biliary symptoms associated with an attack of acute pancreatitis
- · Additional Exclusion Criteria Specific to Post-Abdominal Surgery Patients:
- History of hepatectomy
- . History of liver transplant
- · Additional Exclusion Criteria Specific to Liver Transplant Patients:
- Live donor transplantation

#### Results

#### Chronic Pancreatitis Study Cohort Information

#### Patients:

One hundred and twenty-seven (127) patients with a benign biliary stricture secondary to chronic pancreatitis with either ongoing biliary obstructive symptoms or being managed for biliary obstructive symptoms were enrolled.

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## Demographics:

The mean age was 52.5 years (sd 10.3 years) and 104 (82%) of the 127 enrolled were male. The median time since CP diagnosis was 28 months. At baseline median total bilirubin level was 0.6 mg/dl (range 0.1-22.0 mg/dl) and median alkaline phosphatase level was 201 IU/1 (range 27-2371 IU/I).

The benign biliary stricture location was mostly distal, notably 115 (90.6%) were in the distal common bile duct (CBD), 2 (1.6%) in the mid CBD, 8 (6.3%) in the proximal CBD, and 2 (1.6%) were papillary. The majority of patients had received a prior sphincterotomy (124; 97.6%) and had previously received endotherapy using plastic biliary stents (105; 82.7%). The gallbladder was in situ in 101 (79.5%) of patients.

## Patient Disposition:

The intent-to-treat (ITT) patient cohort includes all 127 enrolled patients. The per-protocol (PP) patient cohort has 118 patients. Nine (9) patients were excluded from the PP cohort due to death due to unrelated causes (7), transition to palliative care in setting of pancreatic cancer (1) and withdrawal of consent (1).

Stent removability, stricture resolution and rates of SAEs were assessed for the ITT cohort (127) and PP cohort (118).

Stricture recurrence after stent removal or complete distal migration was assessed on 94 patients who reached stricture resolution.

Clinical indwell performance and removal success were assessed as post-hoc analyses in the ITT and PP cohorts.

#### Stent Placement:

Five WallFlex stent sizes (diameter x length) were available and stent selection was as follows: 8 x 60 mm (4; 3.1%), 8 x 80 mm (0; 0%), 10 x 40 mm (78; 61.4%), 10 x 60 mm (43; 33.9%), and 10 x 80 mm (2; 1.6%). The stent was successfully placed in 100% (127/127) of patients. Mean procedure duration was 26.6 min (sd 21.0 min).

#### Stent Migration

Stent migration in the course of the study was reported in 19 of 127 patients. The migration was proximal - in the direction of the liver - in 7 cases (37%), was partial distal - in the direction of the duodenum but still inside of the common bile duct - in 7 cases (37%), and was complete distal - completely out of the common bile duct - in 5 cases (26%). The 19 migrations were observed a median of 318 days (range 60-1140 days) after stent placement.

#### Stent Removability

Stent removability is defined as the ability to remove the stent endoscopically without serious stent removal related adverse events as assessed from the time of stent removal to one (1) month post-stent removal. Stent removability was successful in 72.4% (92/127) ITT patients and 78.0% (92/118) PP patients. A summary of the subjects classified as failures is given below:

- . Seven (7) deaths due to unrelated causes (ITT only)

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- One (1) transition to palliative care in setting of pancreatic cancer (ITT only)
- One (1) withdrew consent (ITT only)
- Thirteen (13) early endoscopic removal ●
- Four (4) loss to follow-up
- One (1) surgery for progression of CP
- Three (3) stent removal related SAEs
- Three (3) spontaneous stent migration without restenting
- Two (2) spontaneous stent passage with immediate restenting ●

## Removal Success

Removal success is defined as either scheduled endoscopic stent removal with no removalrelated serious adverse events (SAEs), or spontaneous stent passage without the need for immediate restenting. Removal success was achieved in 84.3% (107/127) ITT patients and 90.7% (107/118) PP patients after stent indwell ranging from 8 to 613 days. Forceps/graspers and/or a snare were used in all but one case in which a stent-in-stent technique was used for endoscopic removal of the WallFlex stents.

A summary of the subjects classified as failures is given below:

- Four (4) patients experienced removal-related serious adverse events including three (3) . cases of cholangitis and one (1) case of abdominal pain.
- Stent removal was not indicated in nine patients (9) due to death (7), transition to palliative care in setting of pancreatic cancer (1) and withdrawal of consent (1) (ITT only).
- . Attempts were not made in five (5) patients due to loss to follow up (4) and surgery for CP progression (1).
- . Two (2) patients experienced complete distal stent migration that required immediate restenting.

NOTE: Stent-in-Stent removal as a technique for removal of biliary self-expanding metal stents was described in peer-reviewed publications (Tan, Lillemoe et al. 2012, Menon 2013, Tringali, Blero et al. 2014). In total, the three references report on 7 cases. The authors concluded that the stent-in-stent technique is effective when difficulties are encountered during self-expanding metal stent removal due to stent migration or hyperplastic stent ingrowth or overgrowth.

## Stent Functionalitv During Stent Indwell

Stent functionality during stent indwell is defined as lack of required reintervention during intended indwell or spontaneous stent passage without the need for immediate restenting within 6 days. Stent functionality during stent indwell was obtained in 77.2% (98/127) ITT patients and in 83.1% (98/118) PP patients.

A summary of the subjects classified as failures is given below:

- Seven (7) deaths due to unrelated causes (ITT only) ●
- One (1) transition to palliative care in setting of pancreatic cancer (ITT only) .
- One (1) withdrew consent (ITT only) ●
- . Thirteen (13) early endoscopic removal
- Four (4) loss to follow-up ●

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- . Two (2) spontaneous stent passage with immediate restenting
- One (1) surgery for progression of CP .

## Stricture Resolution

Stricture resolution is defined by the lack of stricture-related re-intervention. At the end of indwell, stricture resolution without the need for restenting was achieved in 74.0% (94/127) ITT patients and in 79.7% (94/118) PP patients.

A summary of the subjects classified as failures is given below:

- . Nine (9) not indicated for removal due to death (7), transition to palliative care in setting of pancreatic cancer (1) and withdrawal of consent (1) (ITT only)
- Nine (9) immediate restenting after scheduled removal ●
- Eight (8) immediate restenting after early removal ●
- Four (4) loss to follow-up ●
- Two (2) spontaneous stent passage with immediate restenting ●
- One (1) surgery for progression of CP ●

## Stricture Recurrence

Stricture recurrence is defined by the need for stricture related re-intervention post-stent removal. Over a median follow-up period of 19.0 months (range 0.9-29.7 months) after stent removal, 85.1% (80/94) ITT patients and 85.1% (80/94) PP patients with stricture resolution at time of removal did not experience stricture recurrence.

A summary of the subjects classified as failures is given below:

- Ten (10) patients had strictures re-occur ●
- . Four (4) patients were lost to follow-up

## Liver Function Tests

Bilirubin levels and alkaline phosphate levels were measured at visits from baseline to 24 months post-removal. Reported are the mean ± standard deviation (number of patients) bilirubin level in mg/dL and alkaline phosphatase level in U/L.

Bilirubin: Baseline: 1.6 ± 3.1 (126), Indwell month 1: 0.6 ± 0.4 (109), Stent removal: 0.8 ± 1.3 (106), Post-removal month 6: 0.8 ± 1.2 (66), Post-removal month 12: 0.6 ± 0.3 (57), Postremoval month 24: 1.0 ± 2.1 (24)

Alkaline phosphatase: Baseline: 332 ± 363 (125), Indwell month 1: 166 ± 130 (113), Stent removal: 166 ± 198 (105), Post-removal month 6: 142 ± 151 (67), Post-removal month 12: 127 ± 139 (59), Post-removal month 24: 136 ± 115 (25)

## Biliary Obstructive Symptoms

Biliary obstructive symptoms were right upper quadrant pain, fever, jaundice, itching, dark urine, pale stool, and nausea. The number of patients with any symptom was normalized by the number of patients for which visit data were available.

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Baseline: 51.2% (65/127), Indwell month 1: 16.3% (20/123), Indwell month 3: 8.6% (10/116), Indwell month 6: 6.…