Summary Basis of Decision (SBD) for MEDTRONIC COREVALVE^® SYSTEM

Contact: Medical Devices Bureau

MEDTRONIC COREVALVE^® SYSTEM

Medtronic CoreValve LLC
Application Number: 174668
Licence Number: 089391
Date Issued: 2013/01/13

Foreword

Health Canada's Summary Basis of Decision (SBD) documents outline the scientific and regulatory considerations that factor into Health Canada regulatory decisions related to drugs and medical devices. SBDs are written in technical language for stakeholders interested in product-specific Health Canada decisions, and are a direct reflection of observations detailed within the evaluation reports. As such, SBDs are intended to complement and not duplicate information provided within the Operator's Manual.

Readers are encouraged to consult the 'Reader's Guide to the Summary Basis of Decision - Medical Devices' to assist with interpretation of terms and acronyms referred to herein. In addition, a brief overview of the medical device application review process is provided in the Fact Sheet entitled 'Safe Medical Devices in Canada'. This Fact Sheet describes the factors considered by Health Canada during the review and authorization process of a device licence application. Readers should also consult the 'Summary Basis of Decision Initiative - Frequently Asked Questions' document. These documents are all available on the Health Canada website.

The SBD reflects the information available to Health Canada regulators at the time a decision has been rendered. Subsequent applications reviewed for additional uses will not be captured under Phase I of the SBD implementation strategy. For up-to-date information on a particular product, readers should refer to the most recent Operator's Manual for a product. For information related to Advisories, Warnings and Recalls as a result of adverse events (AE), interested parties are advised to access the Health Canada website.

For further information on a particular product, readers may also access websites of other regulatory jurisdictions. The information received in support of a Canadian device licence application may not be identical to that received by other jurisdictions.

Other Policies and Guidance

Readers should consult the Health Canada website for other medical device policies and guidance documents. In particular, readers may wish to refer to the 'Management of Applications for Medical Device Licences and Investigational Testing Authorizations Policy'.

Table of Contents

1. Product and Submission Information
2. Notice of Decision
3. Scientific and Regulatory Basis for Decision
   • 3.1 Introduction
   • 3.2 Device-Specific Detailed Information
   • 3.3 Devices Containing Biological Material
   • 3.4 Safety and Effectiveness
     • 3.4.1 List of Standards
     • 3.4.2 Method of Sterilization
     • 3.4.3 Manufacturing and Quality Process
     • 3.4.4 Preclinical Studies
     • 3.4.5 Clinical Effectiveness and Safety
     • 3.4.6 Software Validation Studies
     • 3.4.7 Labelling
   • 3.5 Benefit/Risk Assessment
   • 3.6 Recommendation
4. Application Milestones

1 Product and Submission Information

Name of Device:

MEDTRONIC COREVALVE^® SYSTEM

Manufacturer:

Medtronic CoreValve LLC

Medical Device Group:

Cardiovascular

Biological Material:

Porcine pericardium

Combination Product:

No

Drug Material:

Not Applicable

Application Type and Number:

Application for a new medical device licence, Number: 174668

Date Licence Issued:

2012/08/01

Device Catalogue/Model Number:

Refer to MDALL - Your reference tool for licensed medical devices in Canada

Licence Number:

089391

Intended Use:

The Medtronic CoreValve System (MCS) is intended for use in patients with severe symptomatic aortic stenosis and who have an aortic valve annulus diameter ≥20 mm and ≤27 mm by echocardiographic measure. The MCS is intended for use in patients who are determined to have a high mortality risk considered prohibitive for surgery (mortality or serious irreversible morbidity risk of ≥50% at 30 days), based on physician discretion.

2 Notice of Decision

On August 1, 2012, Health Canada issued a Class IV Licence with conditions to Medtronic CoreValve LLC for the Medtronic CoreValve System (MCS). This device was recommended for a Class IV medical device licence with a condition that the manufacturer provides on-going evidence of safety and effectiveness of the device from both clinical studies and marketing history for a period of five years post licensing.

The MCS is a transcatheter aortic valve replacement. This device replaces the native aortic valve with a self-expanding, bioprosthetic valve.

The MCS is intended for use in patients with severe symptomatic aortic stenosis and who have an aortic valve annulus diameter ≥20 mm and ≤27 mm by echocardiographic measure. The MCS is intended for use in patients who are determined to have a high mortality risk considered prohibitive for surgery (mortality or serious irreversible morbidity risk of ≥50% at 30 days), based on physician discretion.

The MCS is contraindicated for patients with any of the following conditions:

• known hypersensitivity or contraindication to aspirin, heparin, ticlopidine, clopidogrel, Nitinol, or sensitivity to contrast media that cannot be adequately premedicated;
• sepsis, including active endocarditis;
• recent myocardial infarction (<30 days);
• left ventricular or atrial thrombus by echocardiography;
• uncontrolled atrial fibrillation;
• mitral or tricuspid valvular insufficiency (>Grade II);
• previous aortic valve replacement (mechanical valve or stented bioprosthetic valve);
• evolutive or recent cerebrovascular accident (CVA);
• femoral, iliac, or aortic vascular condition [for example (e.g.), stenosis, tortuosity], that makes impossible insertion and endovascular access to the aortic valve;
• symptomatic carotid or vertebral arterial narrowing (>70%) disease;
• abdominal or thoracic aortic aneurysm in the path of delivery system;
• bleeding diathesis or coagulopathy, or patient refusing blood transfusion;
• evolutive disease with life expectancy <1 year;
• creatinine clearance <20 mL/min;
• active gastritis or peptic ulcer disease;
• pregnancy.

The application included material specifications/manufacturing details, process validation information, sterilization data, biocompatibility studies, physical certification reports, bench testing, and packaging and shelf-life data, and data from pre-clinical and clinical studies.

Effectiveness was demonstrated by clinical study results, literature, and validation testing. In clinical studies, there was substantial data demonstrating similar performance compared to the only licensed percutaneous valve system. The data also indicated that, for the indicated patient population, outcomes were superior to that previously observed for inoperable patients maintained on best medical therapy. Safety was supported by a Declaration of Conformity to applicable recognized standards, biocompatibility testing, bench testing and animal testing. This device has previously been authorized for use through the Special Access Program.

The MCS should be used under the conditions stated in the labelling, taking into consideration the potential risks associated with the use of this device. Detailed conditions for the use of the MCS are described in the labelling.

Based on the Health Canada review of data on quality, safety, and effectiveness, Health Canada considers that the benefit/risk profile of the Medtronic CoreValve System (MCS) is favourable for the indication stated above.

3 Scientific and Regulatory Basis for Decision

3.1 Introduction

The aorta is the main artery that carries blood from the heart to the body. At the junction of the left ventricle and the aorta is the aortic valve, a tricuspid valve that functions to control the flow of blood from the heart to the aorta. Aortic stenosis (AS) is a condition in which the aortic valve narrows preventing the valve from opening fully, thereby decreasing blood flow from the heart. Severe AS affects 4-5% of people over the age of 75 and is often not preventable. Aortic stenosis is thought to possibly be related to age, buildup of calcium deposits on the aortic valve, radiation therapy, medications, or a history of rheumatic fever.

The Medtronic CoreValve System (MCS) was developed to place a prosthetic tissue heart valve in the aortic valve via a catheter. The MCS is intended to replace the native aortic heart valve without open-heart surgery and without surgical removal of the failed native valve. The MCS is placed within the annulus (a fibrous structure that attaches the aorta root to the left ventricle) of the stenotic (narrowed) valve by means of an 18 Fr catheter in patients with severe symptomatic AS, necessitating aortic valve replacement.

As of August 1, 2012, 750 MCS units have been authorized for use at Canadian centres under the Health Canada Special Access Program. Medtronic has created a specific training program that requires sites to conduct a minimum of ten implant procedures under the supervision of a Medtronic proctor before they can be certified as an implanting site.

Internationally, at the time of the filing of the application, over 11,000 units had been sold. The most common customer complaints received include: the need for implantation of a permanent pacemaker, major arrhythmia, deployment difficulties, and valve dislodgement due to suboptimal positioning of the device with respect to the native annulus at the time of implant.

There has been one Field Corrective Action worldwide in which 286 customers were notified. This included incidents of clicking and sticking during retraction of the sheath on the Delivery Catheter System without the AccuTrak™ Stability Layer during attempts to deploy the valve in accordance with the Information for Use (IFU). Communication occurred by direct contact from Medtronic personnel. There was no removal of product; this field notification involved user training only.

3.2 Device-Specific Detailed Information

The MCS consists of the following components:

• Percutaneous Aortic Valve (PAV) Prosthesis;
• AccuTrak™ Delivery Catheter System (DCS) (to be licensed separately as a Class II device); and
• Compression Loading System (CLS) (to be regulated separately as a Class I device).

The support frame of the PAV is manufactured from Nitinol, a radiopaque metal alloy with self-expanding properties. The PAV is manufactured by suturing valve leaflets and a skirt from a single layer of porcine pericardium into a tri-leaflet configuration. The PAV is available for a range of aortic annulus and ascending aorta diameters; however, in Canada, only the 26 and 29 mm sizes are licensed.

The AccuTrak™ DCS (to be licensed separately as a Class II device) is compatible with a 0.035 in (0.889 mm) guidewire. The distal (deployment) end of the system features an atraumatic, radiopaque tip. A protective sheath covers and maintains the PAV in a crimped position. The handle is located on the proximal end of the catheter and is used to load and deploy the PAV. The handle includes a macro slide knob to open and close the capsule and a micro adjustment knob to facilitate precise placement of the PAV. The micro knob turns clockwise to retract the delivery catheter (for deployment) and counter-clockwise to advance the delivery catheter (for loading). The AccuTrak™ DCS model provides the patented AccuTrak™ stability layer. The AccuTrak™ stability layer is fixed at the handle and extends down the outside of the catheter shaft approximately 91 cm. It provides a barrier between the retractable delivery catheter, introducer sheath, and vessel walls, thus allowing the catheter to retract freely. The outer diameter of the delivery catheter is 15 Fr (AccuTrak™ stability layer) and 12 Fr, and the outer diameter of the valve capsule is 18 Fr.

The CLS compresses the PAV into the catheter and is comprised of the following elements:

• Inflow cone;
• Inflow tube (straight tube);
• Outflow cap;
• Outflow cone; and
• Outflow tube (tube with flared ends).

Each of the components of the MCS (PAV, DCS, and CLS) is packaged separately. The finished components were subjected to packaging validation studies to demonstrate packaging integrity and to confirm preservation of product sterility after handling, distribution, and storage.

The packaging testing performed was based on guidance from International Organization for Standardization (ISO) and American Society for Testing and Materials (ASTM) packaging standards, which outline industry-standard requirements for packaging qualifications and the aging of medical packaging materials.

The packaging configuration for the 26 and 29 mm PAV consists of a primary and a secondary package. The primary package consists of a glass jar with a plastic lid that houses the PAV in a glutaraldehyde sterilant solution. The primary package containing the valve is housed in a foam coffin, which is placed into an outer carton (secondary package). The secondary package (outer carton) also contains a temperature indicator and the IFU. The labels are affixed on the outside of the outer carton. The secondary package is sealed with an end seal label.

3.3 Devices Containing Biological Material

The MCS contains porcine pericardium, sourced from several United States of America-based processing facilities. Health Canada has assessed the measures taken to mitigate risks associated with animal tissue being used in this device.

3.4 Safety and Effectiveness

3.4.1 List of Standards

The following standards were referenced as being used in whole or in part during the design of the system. The following abbreviations contained in the table below are as follows: American Society for Testing and Materials (ASTM); International Organization for Standardization (ISO); and European Standard (EN).

List of Standards

Standard	Description
ASTM D 4169-05	Performance Testing of Shipping Containers and Systems
ASTM D 4332-01	Standard Practice for Conditioning Containers
ASTM D 5276-98 (2004)	Standard Test Method for Drop Test Loaded Containers by Free Fall
ASTM D 642-00 (2005)	Standard Test Method for Determining Compressive Resistance of Shipping Containers, Components, and Unit Loads
ASTM 999-01	Standard Methods for Vibration Testing of Shipping Containers
ASTM F 2096-04	Detecting Gross Leaks in Medical Packaging by Internal Pressurization (Bubble Test)
ASTM 88-06	Seal Strength of Flexible Barrier Materials
ASTM F 1980-02	Guide for Accelerated Aging of Sterile Medical Device Packages
ASTM F 2096	Packages, or Packaging Components for Testing
ASTM F 2119-07	Standard Test Method for Evaluation of Medical Resonance (MR) Image Artifacts from Passive Implants
ASTM F 2129-04	Standard Test Method for Conducting Cyclic Potentiodynamic Polarization Measurements to Determine the Corrosion Susceptibility of Small Implant Devices
EN 1041:2008	Information supplied by the manufacturer of medical devices
EN 980:2008	Symbols for use in the labelling of medical devices
EN ISO 10555-1:1996/ A2:2004	Sterile, single-use intravenous catheters. General requirements
EN ISO 11135:2007	Sterilization of health care products - Ethylene Oxide - Part 1: Requirements for development, validation and routine control of a sterilization process for medical devices
EN ISO 11607:2006	Packaging for terminally sterilized medical devices - Part 1: Requirements for materials, sterile barrier systems and packaging systems
EN ISO 11737:2006	Sterilization of medical devices - Microbiological methods - Part 1: Determination of a population of microorganisms on products
EN ISO 14155-1:2003	Clinical investigation of medical devices for human subjects Part 1: General Requirements
EN ISO 14160:1998	Sterilization of single-use medical devices incorporating materials of animal origin - Validation and routine control of sterilization by liquid chemical sterilants
EN ISO 25539-2:2008	Cardiovascular implants - Endovascular devices - Part 2: Vascular stents
EN ISO 5840:2005	Cardiovascular implants - Cardiac valve prostheses
EN ISO 14155-2:2003	Clinical investigation of medical devices for human subjects Part 2: Clinical investigation plan
ISO 10993-1:2003	Biological evaluation of medical devices - Part 1: Evaluation and testing
ISO 10993-5	Biological evaluation of medical devices - Part 5: Tests for in vitro cytotoxicity
ISO 10993-3	Biological evaluation of medical devices - Part 3: Tests for genotoxicity, carcinogenicity, and reproductive toxicity
ISO 10993-9	Biological evaluation of medical devices - Part 9: Framework for identification and quantification of potential degradation products
ISO 10993-10:1994	Biological evaluation of medical devices - Part 10: Tests for irritation and sensitization
ISO 10993-11:1994	Biological evaluation of medical devices - Part 11: Tests for systemic toxicity
ISO 10993-4:1992	Biological evaluation of medical devices - Part 4: Selection of tests for interactions with blood
ISO 10993-6:1994	Biological evaluation of medical devices - Part 6: Tests for local effects after implantation
ISO 13485:2003	Medical devices - Quality management systems - Requirements for regulatory purposes
ISO 14630:1998	General requirements for non-active surgical implants
ISO 14971:2007	Medical Devices - Risk Management - Application of Risk Analysis to Medical Devices
ISO 16429:2004	Implants for surgery - Measures of open circuit potential to assess corrosion behaviour of metallic implantable materials and medical devices over extended time periods
ISO 22442-1:2007	Medical devices utilizing animal tissues and their derivatives - Part 1: Application of risk management
ISO 22442-2:2007	Medical devices utilizing animal tissues and their derivatives - Controls on sourcing, collection and handling.
ISO 22442-3:2007	Medical devices utilizing animal tissues and their derivatives utilized in the manufacture of medical devices - Validation of the elimination and/or inactivation of viruses and transmissible spongiform encephalopathy (TSE) agents
Meddev 2.12.2	Medical Devices: Guidance document

3.4.2 Method of Sterilization

Each of the components of the Medtronic CoreValve System (MCS) has been validated to a Sterility Assurance Level (SAL) of 10^-6. Routine revalidations and monitoring are conducted in accordance with applicable standards for the PAV, DCS, and CLS.

Percutaneous Aortic Valve Prosthesis (PAV)

The PAV is sterilized via a liquid chemical sterilization process. The sterilant solution used and the sterilization process have been used previously by the manufacturer for licensed bioprosthetic devices incorporating materials of animal origin. The PAV is intended for single use and is not intended for re-use or re-sterilization by the user.

Compression Loading System (CLS) and Delivery Catheter System (DCS)

The CLS and DCS are sterilized via Ethylene Oxide (EO). Both components are intended for single use and are not intended for re-use or re-sterilization by the user.

3.4.3 Manufacturing and Quality Process

Manufacturing Process

Material specifications for all parts and components of the system, as well as process flow charts and in-process quality control check points were reviewed and found to be satisfactory.

Process Validation Studies

Process validation was incorporated into the appropriate sections throughout the device application as required.

Quality Plan

Adequate information was provided for the proposed devices' quality plan.

Quality System Certificate

A quality system certificate (ISO standard 13485) that has been issued by Canadian Medical Devices Conformity Assessment System (CMDCAS) recognized registrars has been provided.

3.4.4 Preclinical Studies

Physical Tests

The following tests were conducted:

PAV Frame Testing:

• Finite Element Analysis;
• Frame Specification Conformance;
• Corrosion Resistance of Frame;
• Percent free metal surface area;
• Force on valve commissure;
• Frame retentive force;
• Device Deployment Force.

PAV Valve Testing:

• Device Integrity;
• Hydrodynamic Performance Testing:
  • Steady Forward Flow Test;
  • Steady Backflow Leakage Test;
  • Pulsatile Flow;
  • Flow Visualization.
• Verification of Bernoulli Relationship;
• Structural Performance Testing:
  • 26 mm Round Accelerated Wear Testing;
  • 29 mm Round Accelerated Wear Testing.

Test results demonstrated that the PAV has met the physical and mechanical design specifications.

Biocompatibility Tests

Biocompatibility evaluations were completed on the PAV, DCS, and CLS of the MCS in accordance with ISO 10993-1:2003, Biological Evaluation of Medical Devices Part 1: Evaluation and Testing, and the United States Food and Drug Administration's (FDA) General Program Memorandum No. G95-1, Use of International Standard ISO-l0993, "Biological Evaluation of Medical Devices Part 1: Evaluation and Testing". The required testing for each component was determined based on the nature and duration of body contact in accordance with ISO 10993-1:2003.

Summaries of the biocompatibility testing conducted on each of the components of the MCS were provided. All test results demonstrated that the device was biocompatible and acceptable for its intended use.

In Vivo Animal Tests

An animal study was conducted to evaluate the performance and safety of the MCS. The objectives of the study were to evaluate the hemodynamic performance and to assess the in vivo response to the MCS.

Two chronic survival groups were used:

• Group 1 - four primary animals were enrolled for a 45-day chronic phase; and
• Group 2 - eight animals (six primary and two surviving in-life backups) were enrolled for a 90-day chronic phase.

All animals were implanted with a PAV device. Hemodynamic, fluoroscopic, echocardiographic, and clinical laboratory data were taken at the time of surgical implant. Animals were allowed to recover and were followed for up to 45 or 90 days (depending on group assignment). Echocardiography and clinical laboratory data monitors occurred on Day 7 and 30 for Group 1 and Day 7, 30, and 60 for Group 2. Prior to the termination procedure, hemodynamic, fluoroscopic, echocardiographic, and clinical laboratory data were taken. A necropsy was performed at the conclusion of the study or at the time of early death. Histology was performed, including analysis of the leaflet sections of the PAV.

Hemodynamic performance of the MCS was evaluated by echocardiography, diagnostic catheters, and angiography at the time of implant and at post-implant Day 90 at baseline (no pharmacological alteration) and at states of enhanced contractility [that is (i.e.), dobutamine] challenge. Echocardiography was also used on post-implant Day 7, 30, and 60. The MCS met the acceptance criteria.

The in vivo response to the placement of the MCS was evaluated through (1) post-implant characterization by echocardiography, fluoroscopy, and electrocardiography (ECG); (2) analysis of blood samples from baseline and from Day 7, 30, 60, and 90 post-implant; and (3) gross pathology and histopathology. Tests were performed for: cardiac function; ECG, clinical laboratory evaluation; device displacement; erosion/perforation; device integrity; pericardial valve integrity; frame integrity; host response/healing; host tissue deposition (frame-associated); host tissue deposition (pericardial leaflet-associated); host tissue reaction (inflow skirt pericardial tissue); host tissue reaction (peripheral to the frame); endocarditis/infection; and thrombosis/emboli. Based on the results of the study, the MCS met the acceptance criteria.

Stability/Shelf Life Studies

The PAV was evaluated to support labelling with a one-year expiration date. The PAV was subjected to accelerated and real-time aging studies (as applicable) to address material stability, product functionality, and packaging integrity.

3.4.5 Clinical Effectiveness and Safety

The use of transcatheter aortic-valve implantation (TAVI) has in recent years been recognized as a less invasive treatment for patients with AS who are assessed as too high-risk to undergo surgery. In October 2010, the results of a study entitled PARTNER were published in the New England Journal of Medicine. Patients enrolled in this study had severe AS and were deemed inoperable (too high risk for surgical valve replacement). They were randomly assigned to receive current medical management or TAVI. For the TAVI treatment, patients received the Edwards Sapien heart-valve system (herein referred to as the Sapien Valve), which is the only licensed percutaneous valve system. The results of the study demonstrated significantly reduced rates of death from any cause and a significantly lower rate of cardiac symptoms for patients treated with TAVI versus (vs.) current medical management. These benefits were observed despite a higher incidence of major strokes and major vascular events in the TAVI arm.

The key studies that provided clinical effectiveness and safety data in support of the licensure of the MCS were an interim analysis from an ongoing United States Investigational Device Exemption (US IDE) Study, a post-marketing registry study (the ADVANCE Study), an Italian Registry, and a European and Canadian Clinical Evaluation registry started in 2006. Patient demographics and the clinical outcomes were reviewed in support of the licence application. Data from the studies were compared to data obtained from the PARTNER study following a statistical matching process of patient population baseline characteristics, thus ensuring outcomes from similar patient populations were being compared.

The ADVANCE Study is a post-market study that enrolled 1,015 extreme- and high-risk patients at 44 centres in 12 countries within Western Europe, Asia, and South America. The purpose of this study was to provide confirmatory outcome evidence (safety and efficacy evidence) in a real-world patient population. The primary endpoint was 30-day major adverse cardiovascular and cerebrovascular events (MACCE). All patients included in the study suffered from severe AS. The patient population included both high risk (n = 894) and extreme risk (n = 121) patients. The data set was fully monitored, and all adverse events were independently adjudicated by a Clinical Events Committee (CEC) with oversight of the study by an independent Data Safety Monitoring Board (DSMB). This study was completed in 2011.

The Italian Registry is a prospective registry for patients treated with the MCS at 14 centres in Italy. The registry was started in June 2007. Baseline and clinical outcomes data are self-reported by clinicians. This registry is ongoing.

The European and Canadian Clinical Evaluation registry of the 18-Fr CoreValve is a prospective, multicenter, single-arm trial that enrolled 126 patients.  The registry was started in May 2006.

The manufacturer (Medtronic CoreValve LCC) initially submitted clinical evidence from the ADVANCE Study and the Italian Registry to compare the safety and efficacy of the MCS to that of the Sapien Valve results from the PARTNER study; however, the selected subpopulation did not sufficiently match that of the appropriate PARTNER subpopulation (Cohort B population) to allow for a direct comparison to this historic control. Specifically, the patient populations from the ADVANCE Study and the Italian Registry appeared to be markedly healthier for most baseline characteristics when compared to the PARTNER Cohort B patient population. During review, it was concluded that based on the submitted data, a proper comparison to the historical control was not possible given these clinically significant differences, especially considering the primary endpoint of all-cause mortality. Health Canada requested that the manufacturer provide clinical evidence from a sufficiently equivalent patient population to demonstrate that the proposed device was non-inferior to the historic control. The manufacturer submitted further analysis to further stratify the patient populations and to ensure that the MCS subpopulations were comparable to the historical control. The manufacturer analysed the data from the study and provided good comparisons to the historical controls. Based on the retrospective analysis required by Health Canada, comparisons against the historical controls of both the current medical management control arm, and the Sapien Valve-treatment arm were adequately done within the limitations of the historical control comparison.

In addition to the analysis of the results from the three registries, the manufacturer also submitted interim data from the ongoing CoreValve United States Extreme Risk Pivotal Clinical Study [United States Investigational Device Exemption (US IDE) Study]. At the time the data was submitted, the study had enrolled 612 extreme-risk patients with attempted implants at up to 45 hospitals in the United States. The purpose of this study is to evaluate the safety and efficacy of the MCS in the treatment of symptomatic severe AS in patients who have a predicted risk for death or irreversible morbidity of ≥50% at 30 days for aortic valve surgery. Deaths, neurological, vascular, and bleeding events through 30 days have been adjudicated by a CEC and oversight of the study is provided by an independent DSMB. An interim analysis including analysis of baseline patient characteristics and outcomes to 30 days has been performed and was submitted to Health Canada for review. This study is ongoing.

Analysis of Clinical Effectiveness

In general, the patient demographics for all studies were comparable. Enrolled patients were approximately 83 years old and a significant number of patients had previous coronary artery bypass graft (CABG), previous percutaneous coronary intervention (PCI), Peripheral Vascular Disease, chronic obstructive pulmonary disease (COPD), and other concomitant conditions. For most of the studies, patients' Aortic Valve Area was approximately 0.6 cm², Mean Aortic Valve Gradient was approximately 45 mmHg, left ventricular ejection fraction (LVEF) was relatively low (average between 41 and 54%) and moderate or severe mitral regurgitation was approximately 23%. On average, the study patient populations were comparable, with some potential bias towards sicker patients in the US IDE Study.

The totality of the clinical evidence submitted to Health Canada was comparable to data from clinical studies used to support the Sapien Valve. The data also indicated that for the proposed patient population, outcomes were superior to that previously observed for inoperable patients maintained on current medical management. The 30-day all-cause mortality rates were comparable and rates of adverse events demonstrated similar overall outcomes compared to the historic Sapien Valve outcomes, although there were differences in some of the outcome measures. Stroke rates, major bleeding complications, and major vascular complications were lower in patients treated with the MCS compared to those treated with the Sapien Valve. New pacemaker implants were higher in the MCS-treated patients compared to those treated with the Sapien Valve.

At the 12-month time point, all-cause mortality appeared equivalent or lower in the three registries for the MCS compared to the Sapien Valve historical control. All-cause mortality was 30.7% in the PARTNER study at 1-year compared to 32.1%, 21.5% and 21.4% in the extreme risk post-hoc analyses of the registries. Stroke rates and bleeding and vascular complications trended lower with the MCS and new pacemaker implantation rates were higher.

When data is compared to the current medical management control arm of the PARTNER study, the MCS demonstrates superior performance for all-cause mortality, which was 49.7% at 12-months in the PARTNER study for Cohort B.

Although this data is not as rigorous as a head-to-head study, the clinical data presented adequately demonstrate superior performance compared to current medical management. There is also substantial data demonstrating similar performance compared to the only licensed percutaneous valve system, the Sapien Valve. A traditional randomized concurrent control such as current medical management is not possible as the PARTNER study provides strong evidence that the standard of care, including treatment with drugs and/or balloon aortic valvuloplasty, is inferior compared to TAVI. Based on the loss of equipoise due to the results of the PARTNER study, randomization to current medical management is not ethical.

Safety

Safety was supported by A Declaration of Conformity to applicable recognized standards, biocompatibility testing, bench testing, and animal testing. The manufacturer has demonstrated effectiveness by clinical study results, literature, and validation testing.

Contraindications

The MCS is contraindicated for patients with any of the following conditions:

• known hypersensitivity or contraindication to aspirin, heparin, ticlopidine, clopidogrel, Nitinol, or sensitivity to contrast media that cannot be adequately pre-medicated;
• sepsis, including active endocarditis;
• recent myocardial infarction (<30 days);
• left ventricular or atrial thrombus by echocardiography;
• uncontrolled atrial fibrillation;
• mitral or tricuspid valvular insufficiency (>Grade II);
• previous aortic valve replacement (mechanical valve or stented bioprosthetic valve);
• evolutive or recent cerebrovascular accident (CVA);
• femoral, iliac, or aortic vascular condition [for example (e.g.) stenosis, tortuosity], that makes impossible insertion and endovascular access to the aortic valve;
• symptomatic carotid or vertebral arterial narrowing (>70%) disease;
• abdominal or thoracic aortic aneurysm in the path of delivery system;
• bleeding diathesis or coagulopathy, or patient refusing blood transfusion;
• evolutive disease with life expectancy <1 year;
• creatinine clearance <20 mL/min;
• active gastritis or peptic ulcer disease;
• pregnancy.

3.4.6 Software Validation Studies

Software validation is not applicable to the MCS device.

3.4.7 Labelling

The labelling material provided for the MCS device was reviewed and found to meet the requirements of Section 21 of the Medical Devices Regulations.

3.5 Benefit/Risk Assessment

The overall risk of the system was determined to be acceptable. The risk analysis performed was used to assess the existing residual risk associated with the product and to determine if the residual risk is acceptable for clinical use. The Risk Management process is compliant to ISO 14971:2007, Application of Risk Management to Medical Devices.

The risk analysis process includes the following risk management activities:

• Preliminary hazard analysis;
• Design failure modes effects and criticality analysis;
• Process failure modes effects and criticality analysis.

Complete risk management reports were provided and are considered to be acceptable.

The Medtronic CoreValve System meets the acceptance criteria and together with the risk analysis has been deemed safe and effective for its intended use.

Given the valve's indication for use, and based on the valve's demonstrated improved outcomes compared to best medical therapy and comparable outcomes compared to the currently licensed Sapien Valve, a license with conditions is being recommended to provide on-going evidence of safety and effectiveness of the CoreValve from both clinical studies and marketing history. Data from these clinical studies will allow for additional analysis of both the absolute rate of adverse events and differences in adverse event rates compared to other treatment options, as observed in some of the studies, and to investigate any relationship between these adverse events and longer term clinical outcomes. This will include outcomes such as all-cause mortality, strokes, bleeding complications, vascular complications, and the higher rate of pacemaker implants observed following CoreValve delivery. The manufacturer will provide this evidence from both clinical studies and marketing history for a period of five-years post-licensing.

3.6 Recommendation

Based on the Health Canada review of data on quality, safety and effectiveness, Health Canada issued a Class IV Licence with conditions to Medtronic CoreValve LLC for the Medtronic CoreValve System. The one condition is to provide an update on the US IDE Study and any other clinical data as well as a market history for the Medtronic CoreValve System on an annual basis for a period of five years post-licensing. The licence with conditions will allow Health Canada to monitor whether the benefit/risk profile of the Medtronic CoreValve System remains acceptable. Therefore, Health Canada has granted this licence with terms and conditions in accordance with Medical Devices Regulations, Section 36(2).

4 Application Milestones

Submission Milestones: Medtronic CoreValve System

Application Milestone	Date
Request for priority status
Application Received:	2010/11/29
Application Validation:	2010/12/14
Screening Acceptance:	2011/01/20
Review:	2011/03/21
Review of additional information:	2012/06/25
Licence Issued:	2012/08/01