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Contact: Device Licensing
Edwards Lifesciences LLC
Application Number 176966
Licence Number 86404
Date Issued: 2012/01/03
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, available under 'Related Links Page' on the Health Canada website. The information received in support of a Canadian device licence application may not be identical to that received by other jurisdictions.
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'.
On June 22, 2011, Health Canada issued a Class IV Licence with conditions to Edwards Lifesciences LLC for the Edwards SAPIEN transcatheter heart valve Model 9000TFX (herein known as SAPIEN THV) which requires the manufacturer to provide updates on the PARTNER trial (ongoing trial) and any other clinical data, as well as market history for the SAPIEN THV on an annual basis for a period of five-years post-licensing.
The SAPIEN THV is indicated for use in patients with the following conditions:
The SAPIEN THV is a bioprosthetic heart valve which is placed through a transfemoral approach. The SAPIEN THV is designed to operate in a manner similar to the native aortic valve in preventing backflow from the aorta into the left ventricle during diastole.
The SAPIEN THV is contraindicated in patients with: non-calcified aortic annulus; congenital unicuspid or congenital bicuspid aortic valve; evidence of intracardiac mass; thrombus or vegetation (active infection or endocarditis); or the inability to tolerate anticoagulation/antiplatelet therapy.
The application included a quality plan, material specifications/manufacturing details, process validation information, sterilization data, biocompatibility studies, bench testing, data from pre-clinical studies, data from clinical studies, and packaging and shelf-life data.
The safety and effectiveness of SAPIEN THV was demonstrated primarily on results obtained from the PARTNER clinical trial, Cohort B. The PARTNER trial is an ongoing, controlled trial comprised of two patient Cohorts. Cohort B consists of non-operable patients with severe aortic stenosis randomized to receive either SAPIEN THV treatment via the transfemoral approach versus (vs.) standard care (optimal medical therapy). Study results at the one-year mark demonstrated that patients in Cohort B who received SAPIEN THV treatment via the transfemoral approach showed a 20 percentage point reduction in mortality rate compared to patients who received current standard care [that means (i.e.) 50.7% mortality in the control group versus 30.7% mortality in the SAPIEN THV group]. Study results from Cohort B therefore support the use of SAPIEN THV via the transfemoral approach for the treatment of non-operable patients with severe aortic stenosis compared to standard care. The study results from Cohort A were not included in the submission and remain forthcoming.
Safety and effectiveness of SAPIEN THV were further supported through additional supportive clinical study results, literature, and the submission of A Declaration of Conformity to applicable recognized standards.
The SAPIEN THV 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 SAPIEN THV were described in the labelling and a detailed training program is required for all implanting physicians.
Based on the Health Canada review of data on quality, safety, and effectiveness, Health Canada considers that the benefit/risk profile of the SAPIEN THV is favourable for the indications stated above.
The SAPIEN THV is a bioprosthetic heart valve which is designed to operate in a manner similar to the native aortic valve which prevents backflow from the aorta into the left ventricle during diastole. Placement of the SAPIEN THV has been approved through a transfemoral approach for use in patients with the following conditions:
The SAPIEN THV is commercially available in European Union countries under conditional approval which stipulates the need for yearly submissions of updated clinical data. Other countries including, Israel, South Africa, and Turkey have authorized the sale of the device since 2008.
The SAPIEN THV is available within North America through an ongoing clinical study known as the Placement of Aortic Transcatheter Valve Trial (PARTNER study, protocol version 2.0). Since 2007, 781 SAPIEN THV (Model 9000TFX) have been implanted, with approximately 49% being via the transfemoral approach. The remaining 51% had the SAPIEN THV implanted via a transapical approach, yet study results on the use of this approach remain forthcoming and were not included in the application. As such, the scope of this Summary Basis of Decision shall be limited to summarizing data on the SAPIEN THV via a transfemoral delivery approach only.
As of January 2010, 38 physicians at 11 hospitals have been qualified to implant the SAPIEN THV device under Canada's Special Access Program (SAP). The reported procedural success rate for patients who received the device via a transfemoral approach under the SAP was 90.5%. Subsequent 30-day and 12-month survival rate via transfemoral delivery approach was reported as 90.5% and 75%, respectively.
No recalls have been initiated for the SAPIEN THV device, or the transfemoral delivery system (RetroFlex 3), or accessories.
The PARTNER trial reported a significant difference in its primary endpoint with a 50.7% rate of death from any cause at one year post-intervention in the standard medical therapy arm compared to a 30.7% rate in the SAPIEN arm.
The SAPIEN THV, Model 9000TFX, consists of a pericardium trileaflet valve sutured within a stainless steel expandable mesh frame, with a polyester skirt. The trileaflet valve is fabricated from three equal sections of bovine pericardium tissue. The SAPIEN THV is offered in two sizes, 23 mm and 26 mm. Other components of the SAPIEN THV system include a crimper, RetroFlex Balloon Catheter, and a RetroFlex 3 Delivery System.
The crimper, models 9100CR23 and 9100CR26, is designed for single-use and enables compression of the SAPIEN THV from its expanded size into a collapsed size. Once collapsed, the bioprosthesis can then be easily mounted onto the delivery balloon catheter.
The RetroFlex Balloon Catheter and the RetroFlex 3 Delivery System are used to predilate the stenotic cardiac valves and deploy the bioprosthesis to its proper placement.
The SAPIEN THV consists of three leaflets made of bovine pericardial tissue, sourced from the United States and Australia. Health Canada has assessed the measures taken to mitigate risks associated with animal tissue being used in this device. A sterility assurance level (SAL) of <10-6 (the chance of an organism surviving the sterilization cycle is less than one in a million) has been validated. A risk analysis was conducted for the bovine pericardial tissue component per the following European standards:
The device application also described and provided risk mitigation measures which were found acceptable.
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); British Standard European Norm (BS EN); and European Standard (EN).
|ASTM F138-08||Standard specification for wrought 18 chromium-14 nickel-2.5 molybdenum stainless steel bar and wire for surgical implants (UNS S31673)||2007|
|ISO 105554:1996/Cor.1:2002||Sterile, single-use intravascular catheters - Part 4: Balloon dilatation catheters supplied in the sterile condition, and intended for single use||1996/2002|
|ISO 10993-1||Biological evaluation of medical devices - Part 1: Evaluation and testing||2003|
|ISO 10993-10||Biological evaluation of medical devices - Part 10: Tests for irritation and delayed-type hypersensitivity||2002|
|ISO 10993-11||Biological evaluation of medical devices - Part 11: Tests for systemic toxicity||1993|
|ISO 10993-3||Biological evaluation of medical devices - Part 3: Tests for genotoxicity, carcinogenicity and reproductive toxicity||2003|
|ISO 10993-4||Biological evaluation of medical devices - Part 4: Selection of tests for interactions with blood||2002|
|ISO 10993-5||Biological evaluation of medical devices - Part 5: Tests for in vitro cytotoxicity||1999|
|ISO 10993-6||Biological evaluation of medical devices - Part 6: Tests for local effects after implantation||1994|
|ISO 10993-7 [ANSI/AAMI/ISO 10993-7:1995 (R) 2001]||Biological evaluation of medical devices - Part 7: Ethylene oxide sterilization residuals||1995|
|ISO 11135-1||Sterilization of health care products - Ethylene oxide - Part 1: Requirements for development, validation and routine control of a sterilization process for medical devices||2007|
|ISO 11737-1||Sterilization of medical devices - microbiological methods - Part 1: Estimation of population of microorganisms on products||2006/2007|
|ISO 14155-1||Clinical investigation of medical devices for human subjects - Part 1: General requirements||2003|
|ISO 14155-2||Clinical investigation of medical devices for human subjects - Part 2: Clinical investigation plans||2003|
|ISO 14630||Non-active surgical implants - General requirements||2008|
|ISO 14971||Medical devices - Application of risk management to medical devices||2007|
|ISO 17664||Sterilization of medical devices - Information to be provided by the manufacturer for the processing of resterilizable medical devices||2004|
|ISO 25539-1||Cardiovascular implants - Endovascular devices - Part 1: Endovascular prostheses||2003/2005|
|ISO 5832-1||Implants for Surgery - Metallic materials - Part 1: Wrought stainless steel||2007|
|ISO 5840||Cardiovascular implants - Cardiac valve prostheses||2005|
|ASTM E8||Standard test methods for tension testing of metallic materials||No|
|BS EN 556||Sterilization of medical devices - Requirements for medical devices to be designated||No|
|EN 1041||Information supplied by the manufacturer with medical devices||No|
|EN 980||Graphical symbols for use in the labelling of medical devices 2003||No|
|ISO 14644-1||Clean rooms and associated controlled environments - Part 1: Classification of air cleanliness||No|
|ISO 14644-2||Clean rooms and associated controlled environments - Part 2: Specifications for testing and monitoring to prove continued compliance with ISO 14644-1||No|
|ISO 15223||Medical devices - Symbols to be used with medical device labels, labelling and information to be supplied 2004||No|
|EN 12006-1:1999||Non-active surgical implants - Particular requirements for cardiac and vascular implants - Part 1: Heart valve substitutes||No|
|ASTM F2052-00||Standard test method for measurement of a magnetically induced displacement force of passive implants in the magnetic resonance environment||No|
|ASTM F2119-01||Standard test method for evaluation of MRI artifacts from passive implants||No|
|EN 12442-1:2000||Animal tissues and their derivatives utilized in the manufacture of medical devices - Part 1: Analysis and management of risk||No|
|EN 12442-2:2000||Animal tissues and their derivatives utilized in the manufacture of medical devices - Part 2: Controls on sourcing, collection, and handling||No|
|EN 12442-3:2000||Animal tissues and their derivatives utilized in the manufacture of medical devices - Part 3: Validation of the elimination and/or inactivation of virus and transmissible agent||No|
|BS EN ISO 11070:1999||Sterile, single-use intravascular catheter introducers (ISO 11070:1998)||No|
|ISO 14160:1998||Sterilization of single-use medical devices incorporating materials of animal origin - Validation and routine control of sterilization by liquid chemical sterilants||No|
|BS EN ISO 13485:2003||Medical devices - Quality management systems - Requirements for regulatory purposes||No|
|BS EN 20594-1:1994 (incorporating AI:1997)||Conical fittings with a 6% (Luer) taper for syringes, needles and certain other medical equipment - Part 1: General requirements (ISO 594/1:1986)||No|
|ISO 594-1:1998||Conical fittings with a 6% (Luer) taper for syringes, needles and certain other medical equipment - Part 1: General requirements||No|
|ISO 594-2:1998||Conical fittings with a 6% (Luer) taper for syringes, needles and certain other medical equipment - Part 2: Lock fittings - revision of ISO 594-2:1991||No|
|ANSI/AAMI/ISO TlR 19:1998||Guidance for ANSI/AAMI/ISO 10993-7:1995||No|
|AAMI TIR 28:2001||Production adoption and process equivalency for ethylene oxide sterilization||No|
|EN 14299:2004||Non active surgical implants - Particular requirements for cardiac and vascular implants - specific requirements for arterial stents||No|
|ASTM F 720-81(2002)||Standard practice for testing guinea pigs for contact allergens: Guinea pig maximization test||No|
|ASTM F2129-03||Standard test method for conducting cyclic potentiodynamic polarization measurements to determine the corrosion susceptibility of small implant devices||No|
|ASTMG5-99||Standard reference test method for making potentiostatic and potentiodynamic anodic polarization measurements||No|
|ASTM GIS (2003)||Standard terminology relating to corrosion and corrosion testing||No|
The proposed product undergoes terminal liquid sterilization. This sterilization procedure meets the International Organization for Standardization (ISO) 14160-1998 for terminal sterilization, with sterility testing demonstrated at an assurance level of <10-6 over the product shelf-life.
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 was incorporated into the appropriate sections throughout the device application [for example (e.g.) packaging and sterilization].
The quality plan was reviewed and found acceptable.
A quality system certificate (ISO standard 13485) that has been issued by Canadian Medical Devices Conformity Assessment System (CMDCAS) recognized registrars was provided.
Pre-clinical studies validating the hydrodynamic performance and durability of the SAPIEN THV were previously submitted within Investigational Testing Applications files number 98104 (2005); number 112786 (2006); number 125751 (2008); and number 136135 (2008). These previous submissions were deemed acceptable by Health Canada based on the hydrodynamic testing acceptance criteria provided below.
|Steady Back Flow Leakage:||Product Specification: Allowable pressure drop at flow rate of 20 L/min: 14 mm Hg Effective Orifice Area (EOA) >1.5 cm²|
|Steady Forward Flow:||Product Specification: Steady leakage rate at back pressure of 200 mm Hg must not exceed 6 mL/sec|
|Pulsatile Flow Pressure Drop:||Product Specification: Mean pressure difference at flow rate of 6 L/min and beat rate of 70 beats per minute (bpm) must not exceed 25 mm Hg
Minimum performance requirement per ISO 5840:2005 EOA ~ 0.85 cm² for 21 mm valve at nominal pulsatile test conditions
EOA ~ 1.0 cm² for 23 mm valve at nominal pulsatile test conditions
EOA ~ 1.4 cm² for 26 mm valve at nominal pulsatile test conditions
|Pulsatile Flow Regurgitation:||Product Specification: Total leakage at beat rate of 70 bpm and mean aortic pressure of 100 mm Hg must not exceed 9 mL/beat.
Minimum performance requirement per ISO 5840:2005
Regurgitant fraction ≤10% for 21 mm valve at nominal pulsatile test conditions
Regurgitant fraction ≤10% for 23 mm valve at nominal pulsatile test conditions
Regurgitant fraction ≤15% for 27 mm valve at nominal pulsatile test conditions
In addition, the Sponsor also provided current information regarding the following tests:
Specific testing of the stresses influenced by the activity of crimping (and over expansion) along with testing of the valves for durability and performance after crimping onto the device was also provided. Test results demonstrated that the SAPIEN THV met all physical and mechanical design goals and is safe and acceptable for clinical use.
Summaries describing the biocompatibility testing conducted on the SAPIEN THV, Retroflex 3 Delivery System, Retroflex Balloon Catheter and Crimper were provided. All test results demonstrated that the bioprosthetic heart valve was biocompatible and acceptable for its intended use.
No animal studies were provided with this application. In a previous application for a similar device [that is (i.e.) Cribier-Edwards Percutaneous Aortic Heart Valve] in vivo animal studies were provided and accordingly referenced within the device application. Based on these animal studies, the SAPIEN THV was demonstrated to be safe for clinical use.
Real-time stability study data submitted support a 24-year shelf life for the SAPIEN THV when stored under recommended storage conditions.
The efficacy and safety of SAPIEN THV device has been evaluated primarily through the ongoing PARTNER study, in addition to previous provision of other supportive clinical studies and literature. The PARTNER study is a prospective, randomized-controlled, multicentre pivotal study which evaluates the efficacy and safety of SAPIEN THV in a stratified population of high risk and non-operable patients with aortic stenosis.
The PARTNER study began evaluating placement of the SAPIEN THV within two independent Cohorts. Cohort A randomized high risk operative patients to either open surgical aortic valve replacement or transfemoral or transapical placement of the SAPIEN THV device. Cohort B randomized non-operable patients to either standard therapy or transfemoral placement of the SAPIEN THV device. Of the patients randomized to the standard therapy, a variety of treatment options were made available to them.
While the study results from Cohort A are published in the June 2011 edition of the New England Journal of Medicine, these results have yet to be submitted to Health Canada and therefore were not considered. As a result, the scope of this clinical summary focuses on study results obtained from Cohort B only.
A total of 358 non-operable patients were enrolled in Cohort B, with 179 patients randomized to receive implantation of the SAPIEN THV device and 179 patients randomized to receive standard therapy. The overall objective for Cohort B was to demonstrate superiority of the SAPIEN THV device compared to standard therapy. The primary endpoint of this study was the rate of death from any cause (i.e. all-cause mortality). The co-primary endpoint was a composite of death from any cause or repeat hospitalization. The time frame of the study commenced during the patient's hospitalization. The patients were then followed at 30 days, 6 months, and 1 year, and yearly thereafter.
At the one-year mark, study results obtained from Cohort B showed the composite endpoint of all-cause mortality and repeat hospitalization at one year to be significantly lower in patients who received implantation of the SAPIEN THV device (42.5%) compared to the patients who received standard therapy (71.6%). Similarly, all-cause mortality at one year was significantly lower in the SAPIEN THV device arm (30.7%) compared to the standard therapy arm (50.7%). As such, study results from Cohort B support a clear benefit of implantation of the SAPIEN THV device (delivered via transfemoral approach) in treating non-operable patients with severe aortic stenosis compared to standard therapy. However, study results on the long-term mortality benefit of the SAPIEN THV from the PARTNER study are currently limited. As such, long-term follow-up is warranted through the provision of yearly updates on the ongoing PARTNER study and any other clinical data obtained for a period of five-years post-licensing.
Incident reports were summarized, both from the PARTNER Cohort B clinical trial and from other marketing experience, and these did not alter the assessment of the safety and effectiveness of the SAPIEN valve. The labelling of the device also includes a listing of anticipated possible adverse events.
Adverse events and complaints are reported to Edwards using three systems:
The sponsor has provided detailed information from the three systems above.
Failure Mode and Effects Analyses (FMEAs) were also conducted on the SAPIEN THV Model 9000TFX and the RetroFlex 3 delivery system and accessories. These FMEAs were prepared according to Edwards Standard Operating Procedures which are compliant with ISO 14971:2000 (+A1:2003), Application of Risk Management to Medical Devices. The summary report of each FMEA concludes that for each residual risk, there are no hazards currently identified that have a risk level of "intolerable" (i.e. in recognition of the criticality of the patient population). During conduct of the FMEAs, one event was identified for a potential paravalvular leakage caused by an inadequate seal between the bioprosthesis and the native annulus. An inadequate seal may be due to poor sizing and/or low placement in the native annulus, allowing for flow through the bioprosthesis frame and skirt. The effects of this event can however be mitigated through careful placement of the valve and adjusting for any alterations in the patient's haemodynamic blood flow.
Further risk mitigation measures were taken that are known to influence patient treatment outcomes, but are not related to the manufacture of design of the device, including: physician training; patient screening; and hospital selection.
Physicians offering treatment with the SAPIEN THV device must first demonstrate their knowledge and experience with the device as identified within the manufacturers' Standard Operating Practice (SOP) Training Manuals. As part of the training program, physicians must attend a continuing education program. The continuing education is offered in several ways through presentations at public symposia, case study review, sharing of best demonstrated practices, direct guidance by Edwards Lifesciences THV specialists, and teleconferences.
Clinical experience with the SAPIEN THV indicates that patient outcomes are affected by patient selection, assessment awareness and management of co-morbidities and conditions that may influence procedural risks. As such, a SOP on patient screening has also been developed and is part of the physician training program.
Hospitals selected for use of the SAPIEN THV need to qualify based on several influencing factors as follows:
Software validation is not applicable to the SAPIEN THV medical device.
The labelling material provided for the SAPIEN THV medical device was reviewed and found to meet the requirements of Section 21 of the Medical Devices Regulations.
A risk analysis was conducted in accordance with ISO 14971:2000. It was determined that the risks identified with the SAPIEN THV device along with non-device risks (e.g., physician training, patient screening, and hospital selection) were mitigated to acceptable levels. There were no unacceptable risks associated with the use of SAPIEN THV. In addition, study results obtained from the ongoing PARTNER study for Cohort B demonstrated a clear benefit of use of the SAPIEN THV device (via transfemoral approach) in treating non-operable patients with severe aortic stenosis compared to standard therapy. However, study results on the long-term mortality benefit of the SAPIEN THV from the PARTNER study are currently limited. As such, long-term follow-up is warranted through the provision of yearly updates on the ongoing PARTNER study and any other clinical data obtained for a period of five-years post-licensing.
Included in the assessment was the potential for animal/human material composition issues, biocompatibility, contamination, mechanical damage, and the potential for deterioration of the device through prolonged use. In addition, FMEAs on the SAPIEN THV device and RetroFlex 3 delivery system were conducted and determined to be acceptable for each potential failure mode identified.
It is therefore reasonable to conclude that the SAPIEN THV device has met the acceptance criteria and together with the risk analysis has been deemed safe and effective for its intended use. However, as a condition of licensing, the manufacturer is required to submit yearly updates on the PARTNER study and any other clinical data obtained for a period of five-years post-licensing.
Based on the review of quality, safety and effectiveness data, Health Canada issued a Class IV Licence with conditions to Edwards Lifesciences LLC for the Edwards SAPIEN THV which requires the manufacturer to provide updates on the PARTNER study (ongoing trial) and any other clinical data, as well as market history for the SAPIEN THV device on an annual basis for a period of five-years post-licensing. This conditional licensing shall allow for detection of possible rare and unforeseen adverse events, and to ensure that the benefit/risk profile of SAPIEN THV remains acceptable. Health Canada has granted this licence with terms and conditions in accordance with Medical Devices Regulations, Section 36(2).
|Request for priority status|
Rejection/approval issued by Director, Medical Devices Bureau (MDB):
|Review of additional information:||2011/06/17|