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Summary Basis of Decision Cardiowestt C70 Temporary Total Artificial Heart

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SUMMARY BASIS OF DECISION (SBD)
CARDIOWESTT C70 TEMPORARY TOTAL ARTIFICIAL HEART

SynCardia Systems, Inc.
Application No. 90849
Licence No. 69607

Dated Issued
2006/01/30

Health Products and Food Branch

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Health Products and Food Branch

╔galement disponible en franšais sous le titre: Sommaire des motifs de dÚcision (SMD), CARDIOWESTMC C70 TEMPORARY TOTAL ARTIFICAL HEART, SynCardia Systems, Inc., No de la demande 90849, No de l'homologation 69607

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 reviewer 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 abbrs 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 post-market warnings or advisories as a result of adverse events, 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' 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.

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 Device and Application 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 Control
        • Manufacturing Process
        • Process Validation Studies
        • Quality Plan
        • Quality System Certificate
      • 3.4.4 Preclinical Studies
        • Physical Tests
        • Biocompatibility Tests
        • In Vivo Animal Tests
        • Stability/Shelf-Life Studies
      • 3.4.5 Clinical Effectiveness and Safety
      • 3.4.6 Software Validation Studies
      • 3.4.7 Labelling
    • 3.5 Risk/Benefit Assessment
    • 3.6 Decision
  • 4 Application Milestones

1 DEVICE AND APPLICATION INFORMATION

Device Name
CardioWest™ C70 Temporary Total Artificial Heart
Manufacturer
SynCardia Systems, Inc.
Medical Device Group
Cardiovascular
Biological Material
N/A
Combination Product
Yes [ ] No [ X ]
Drug Material
N/A
Application Type and No.
Application for a new medical device licence, No. 90849
Date License Issued
2005/10/27
Device Catalogue/Model No.
Refer to http://www.mdall.ca/
License No.
No. 69607
Intended Use

The CardioWest™ C70 Temporary Total Artificial Heart is indicated for use as a bridge to transplantation in cardiac transplant candidates at risk of imminent death from non-reversible biventricular failure.

Use of this device is contraindicated in patients who are not cardiac transplant eligible, who do not have sufficient space in the chest area vacated by the natural ventricles, and who cannot be adequately anticoagulated.

2 NOTICE OF DECISION

On October 27, 2005, Health Canada issued a Class IV License with conditions to SynCardia Systems, Inc. for the CardioWest™ C70 Temporary Total Artificial Heart (TAH-t) which requires the manufacturer to submit yearly reports on the marketing experience of this device, including, but not limited to, total units implanted and adverse events.

The CardioWest™ TAH-t is an implantable device intended to replace the ventricles of the human heart. It consists of two artificial ventricles, each with four flexible diaphragms to separate the blood chamber from the air chamber, and Medtronic mechanical valves to control the direction of blood flow. An external console operates and monitors the device.

The CardioWest™ C70 TAH-t is indicated for use as a bridge to transplantation in cardiac transplant candidates at risk of imminent death from non-reversible biventricular failure. Contraindications include use in patients who are not cardiac transplant eligible, who do not have sufficient space in the chest area vacated by the natural ventricles, and who cannot be adequately anticoagulated.

The application included a quality plan, material specifications/manufacturing details, process validation information, sterilization data, biocompatibility studies, bench testing, clinical data, software verification, and packaging and shelf life data.

The market authorization was based on quality, preclinical, and clinical studies. Clinical data was provided from a US FDA study of 31 control patients (best medical treatment) and 81 TAH-t patients. A significantly greater number of TAH-t patients survived to 30-days post-transplant than controls (72% vs 40%) but adverse events in the TAH-t group included infection, bleeding, neurological events, and device malfunction. While some difficulties were identified with the baseline characteristics between control and study groups, the CardioWest™ C70 TAH-t performance was considered to be similar to other bridge to transplant devices. The data submitted demonstrate that the CardioWest™ C70 Temporary Total Artificial Heart can be used safely and effectively when used under the conditions stated in the labelling.

Detailed conditions for the use of the CardioWest™ C70 Temporary Total Artificial Heart are described in the Directions for Use section of the labelling. Based on the Health Canada review of data on quality, safety, and effectiveness, and with the conditions stated in the licence, it is considered that the benefit/risk profile of the CardioWest™ C70 Temporary Total Artificial Heart is acceptable.

3 SCIENTIFIC AND REGULATORY BASIS FOR DECISION

3.1 Introduction

The CardioWest™ C70 Temporary Total Artificial Heart (TAH-t) is an implantable device intended to replace the ventricles of the human heart. It is indicated for use as a bridge to transplantation in cardiac transplant candidates at risk of imminent death from non-reversible biventricular failure and is intended for use inside the hospital.

This device has not been previously licensed in Canada and it has not been granted investigational testing status. There have been two special access requests. The CardioWest™ C70 TAH-t was approved by the US FDA in 2004 for marketing with conditions and received a CE mark from the British Standards Institution (BSI) in May 2005. There are no reported incidences within the application or in the MDS database. Fifteen incidents were found in the MAUDE database for this device.

3.2 Device-Specific Detailed Information

The CardioWest™ C70 TAH-t consists of two artificial ventricles, each made of a semi-rigid polyurethane housing. Each ventricle has four flexible polyurethane diaphragms which separate a blood chamber from an air chamber. These diaphragms allow the artificial ventricle to fill and then eject blood when compressed air is injected and removed. Medtronic mechanical valves are mounted in the inflow and outflow ports of each artificial ventricle and control the direction of blood flow. The maximum dynamic stroke volume of each ventricle is 70 mL, which allows for a flow rate of up to 9.5 litres per minute.

The left artificial ventricle is connected via the left atrial inflow connector to the left atrium. The aortic outflow cannula connects the left ventricle to the aorta. The right artificial ventricle is connected via the right atrial inflow connector to the right atrium. The pulmonary artery outflow cannula connects the right ventricle to the pulmonary artery. Each artificial ventricle's driveline conduit is tunneled through the chest wall and exits the patient at the skin exit sites. The right and left driveline conduits are attached to seven-foot pneumatic drivelines that connect to the back of an external console.

The external console operates and monitors the CardioWest™ C70 TAH-t. The console is attached to hospital compressed air and has air regulators and air switches to drive the implanted ventricles. It also includes a monitoring computer with air sensors attached to the venting ports, which are used to provide noninvasive diagnostic and monitoring information on device performance. Device rate, dynamic stroke volumes, and calculated cardiac outputs are displayed on a beat-to-beat basis. Drive pressure and flow waveforms, along with cardiac output trends are provided. Patient-related alarms (e.g., low cardiac output) are also displayed on the computer screen. The console has backup air and backup battery power.

A separate alarm panel on the console provides information on critical drive pressure and backup air and battery status. In addition, an alarm is generated if the computer is not monitoring the patient. All alarms generate audio and visual feedback to the user. A backup air supply (two air tanks) and electrical power (backup power supply and console battery) are automatically activated if the external compressed air and/or AC power are interrupted.

The controller is the major component of the external console, and supplies pulses of pneumatic pressure to the right and left drivelines, which connect into the air chambers of the respective implanted artificial ventricles. These pulses cause the diaphragms to distend and thereby eject blood from the right artificial ventricle into the pulmonary circulation (typically 50-70 mmHg) and from the left artificial ventricle into the systemic circulation (typically 180-200 mmHg). The desired blood pressure will be equivalent to the selected air pressure.

3.3 Devices Containing Biological Material

The outflow conduits of the CardioWestT C70 Temporary Total Artificial Heart need to be pre-clotted with thrombin prior to surgery, however this material is not provided with the device. Purchase of thrombin is at the discretion of the hospital or operating physician.

3.4 Safety and Effectiveness

3.4.1 List of Standards

AAMI TIR26:2000
Ventricular Assist and Heart Replacement Systems
BS EN ISO 15225: 2000
Nomenclature - Specification for a Nomenclature System for Medical Devices for the Purpose of Regulatory Data Exchange
EN738-4: 1998
Pressure Regulators for Use with Medical Gases, Part 4: Low Pressure Regulators Intended for Incorporation into Medical Equipment
EN737-1: 1998
Medical Gas Pipeline Systems, Part 1: Terminal Units for Compressed Medical Gases and Vacuum
EN1441: 1997
Medical Devices - Risk Analysis
EN45502-1: 1998
Active Implantable Medical Devices, Part 1: General Requirements for Safety , Marking and Information to be Provided by the Manufacturer
EN55011: 1991
Group 1 Class A Conducted Emissions
EN55014: 1993
Limits and Methods of Measurement of Radio Interference Characteristics of Household Electrical Appliances, Portable Tools and Similar Electrical Apparatus
EN55022: 1998 AI
Limits and Methods of Measurement of Radio Disturbance Characteristics of Information Technology Equipment
EN60601-1: 1990
Medical Electrical Equipment, Part 1: General Requirements for Safety
EN60601-1-2: 1993
Medical Electrical Equipment, Part 1: General Requirements for Safety, Collateral Standard: Safety Requirements for Medical Electrical Systems
EN60601-1-8: 2004
Medical Electrical Equipment, Part 1: General Requirements for Safety - Collateral Standard: General Requirements for, Tests and Guidance for Alarm Systems in Medical Electrical Equipment and Medical Electrical Systems
EN61000-3-2: 1995
Electromagnetic Compatibility (EMC) - Limits for Harmonic Current Emissions
EN61000-3-3: 1995
Electromagnetic Compatibility - Limitation of Voltage Fluctuations and Flicker in Low Voltage Supply Systems
EN61000-4-6: 1996
AI (2000)
Electromagnetic Compatibility, Basic Immunity Standard, Conducted Radio Frequency Electromagnetic Field, Immunity Test
EN61000-4-8: 1993
A1 (2000)
Electromagnetic Compatibility, Testing and Measurement
Techniques for Power Frequency Magnetic Field, Immunity Test
EN61000-4-ll: 2004
Electromagnetic Compatibility - Testing and Measurement Techniques: Voltage Dips, Short Interruptions and Voltage Variations Immunity Tests
IEC 61000-4-2: 1995
AI (1998), A2 (2000)
Electromagnetic Compatibility for Industrial Process
Measurement and Control Equipment - Electrostatic Discharge Requirements
IEC 61000-4-3: 2002
AI (2002)
Electromagnetic Compatibility, Basic Immunity Standard, Related Radiofrequency Electromagnetic Field, Immunity
IEC 61000-4-4: 1995
AI (2000), A2 (2001)
Electromagnetic Compatibility for Industrial Process
Measurement and Control Equipment Electrical Fast Transit/Burst Requirements
IEC 61000-4-5: 1995
AI (2000)
Electromagnetic Immunity, Power Line Surge Immunity
IEEE Standard 1012-1998
Standard for Software Verification and Validation Plans
ISO 11135: 1994
Medical Devices - Validation and Routine Control of Ethylene Oxide Sterilization
ISO 13485: 2003
Medical Devices - Quality Management Systems - Requirements for Regulatory Purposes
MILSTD 1629A
Procedures for Performing a Failure Mode, Effects and Criticality Analysis

3.4.2 Method of Sterilization

The implantable components of the CardioWest™ C70 Temporary Total Artificial Heart are sterilized using an ethylene oxide (EtO) cycle that has been validated to produce a sterility assurance level of 10-6 as per ISO Ethylene Oxide Sterilization Standard 11135: 1994.

3.4.3 Manufacturing and Quality Control

Manufacturing Process

Material specifications for the implantable components of the CardioWest™ C70 Temporary Total Artificial Heart have been provided and were found to be satisfactory. The manufacturing process was reviewed and found acceptable. There have been no changes in manufacturing since the FDA Investigational Device Exemption (IDE) application.

Process Validation Studies

Information regarding process validation has been provided and found to be satisfactory.

Quality Plan

The application included a quality manual detailing definitions, management responsibilities, design controls, purchasing controls, inspection, measuring and test equipment, product acceptance, and procedures for non-conforming products. The quality manual was reviewed and found to be acceptable.

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

In vitro characterization of the CardioWest™ C70 Temporary Total Artificial Heart on a mock circulatory loop examined the performance of this device. The mock circulation testing setting and parameters were set to simulate hypotensive, normal, and hypertensive blood pressures. The TAH-t provided a range from 2.6-9.5 L/min flow which is sufficient to support total circulation under expected clinical conditions.

Additional bench testing included:

  • Pull tests and torque tests on the ventricle-to-connector joints and drivelines
  • Sterility and packaging tests on implantable components
  • Controller performance of alarms
  • System connections
  • Battery longevity
  • Electrical safety and electromagnetic compatibility
  • Back-up air and power performance
  • Reliability testing (including long-term storage effects)

Test results demonstrated that the CardioWest™ C70 TAH-t has met the physical and mechanical design goals and is safe and acceptable for clinical use.

Biocompatibility Tests

Biocompatibility testing was conducted in accordance with ISO Standard 10993-1 and Good Laboratory Practices. Testing included:

  • Cytotoxicity
  • Acute Systemic Toxicity
  • Subchronic Toxicity
  • Ames Mutagenicity
  • Chromosomal Aberration Assay
  • Mouse Micronucleus Mutagenicity
  • Pyrogen
  • Sensitization
  • Hemocompatibility

All results met acceptance criteria and successfully passed. The CardioWest™ C70 TAH-t is biocompatible and acceptable for the intended use.

In Vivo Animal Tests

No animal studies were provided with the application as in vivo evaluation was performed via previous studies on humans.

Stability/Shelf Life Studies

Combined real-time and accelerated aging study data support the proposed shelf life for the CardioWest™ C70 TAH-t when stored under recommended storage conditions. The sterility of the device was verified using Bacillus subtilus var. niger spores. All devices maintained a sterile barrier.

3.4.5 Clinical Effectiveness and Safety

The CardioWest™ C70 TAH-t was the subject of a US FDA Investigational Device Exemption. The study was a two-arm, non-randomized, multi-center (5) study with 35 control patients (32 retrospective and 3 prospective) and 81 TAH-t patients. The primary efficacy endpoint was treatment success at 30-days post-transplant while secondary efficacy endpoints included survival to transplant and survival to 30-days post transplant. Safety analysis examined adverse events. All patients were in New York Heart Association (NYHA) Class IV at time of enrollment. The control group did not receive the TAH-t but met study inclusion/exclusion criteria. Both groups were on maximal medical therapy and at imminent risk of death before a donor heart could be obtained.

Treatment success was defined as patients who, at 30-days post-transplant, were alive, in NYHA Class I or II, not bedridden, not ventilator dependent, and did not require dialysis. Trial success was achieved in 56 (69%) of the 81 TAH-t patients and in 13 (37%) of the 35 control patients. The difference was highly significant. Statistical significance was also found with respect to survival to transplant and survival to 30-days post-transplant. Of the TAH-t patients, 64 of the 81 (79%) reached transplant after an average of 79 days (range 1-414). Only 16 (46%) of the 35 control patients reached transplant after an average of 9 days (range 1-44). A total of 58 (72%) TAH-t patients and 14 (40%) control patients survived to 30-days post transplant.

The hemodynamic performance of the CardioWest™ C70 TAH-t was assessed through a comparison of pre- and post-implant values of cardiac index, systolic arterial blood pressure, and central venous pressure. Hemodynamic indices were effectively restored to near normal values with TAH-t treatment.

Upon examination of this clinical data, it was concluded that there was an imbalance between control and TAH-t patients in terms of the year in which the heart transplant was made. Most control patients were pre-1996 while most TAH-t patients were post-1994 which could affect outcomes with changes in patient management, medication, etc. There was also an imbalance in multiple baseline characteristics and the two treatment groups were deemed non-comparable. Any direct treatment comparisons on efficacy endpoints were inappropriate and all statistical significance values were un-interpretable. No comparable control groups were found in previous Bridge to Transplant studies, however a set of performance goals was established through a literature search which allowed some analysis of the effectiveness of the CardioWest™ C70 TAH-t. The results for the TAH-t were within the survival to transplant performance goal of 65-70% and were comparable to results from other studies.

With regards to safety, a total of 400 adverse events were observed in the 81 TAH-t patients. The adverse events represent 17.6 device years of experience for an overall event rate of 1.9 events per month while on the device awaiting transplant. By comparison, 89 events occurred in 31 (88.9%) of the control patients during a total of 299 days awaiting transplant, for an overall event rate of 3.6 events per month while waiting for transplant. Infections were the largest contributing category to overall adverse events. The majority of infections (87.2%) did not affect patient outcome. Bleeding incidents were related to the surgical implant and transplant procedures. In some cases, re-operations for bleeding (29.4%) were also required for excessive bleeding around the heart or lungs. Fifty-nine (57.8%) of the 102 bleeding events occurred during the first 3 weeks after implant with another 30 events (29.4%) occurring within 2 days after transplant. Respiratory dysfunction was also surgically related with most events (65.6%) occurring during the first 3 weeks following the implant surgery.

As with the efficacy measures, the statistical significance of the adverse event findings were considered to be un-interpretable. It was deemed difficult to develop a similar performance goals approach for adverse events as that developed for survival to transplant. There were no definitions listed in some studies, with different definitions in other studies. Rates differed among approved devices and rates for the same device changed over time. Clinical judgement was required to establish the safety of the CardioWest™ C70 TAH-t. Adverse event profile trends appeared similar to other devices, but a direct comparison could not be made.

There were 111 driveline kinks that occurred when patients rolled over or sat on their drivelines, and 5 driveline leaks. A design change was implemented to relocate the wire reinforcement within the driveline. There have been no reports of driveline leaks since the change was implemented. One malfunction, a diaphragm tear, was a primary cause of death in one patient. Although extensively investigated, the cause of the failure was never determined and could never be duplicated. There have been two additional instances of diaphragm tears since the incident, one in 2003 and one in 2004; the investigation of these diaphragm tears is ongoing.

Some technical/procedural events were related to a central catheter obstruction of the artificial valve within the TAH-t. Labeling has been modified to include a warning based on these clinical events. The warning advises physicians to not allow any catheter near the left or right inflow valves.

Despite the difficulties identified with the baseline characteristics of the control and study groups, there is sufficient information in support of the CardioWest™ C70 TAH-t, but the manufacturer will be required to submit yearly reports on the marketing experience of this device, including but not limited to, total units implanted and adverse events.

3.4.6 Software Validation Studies

Software verification and validation were performed.

3.4.7 Labelling

Labelling provided includes package labels for both the implant and console, Directions for Use, and a User's Manual for the Circulatory Support System and the supporting software. The labelling material provided was reviewed and found to meet the requirements of Section 21 of the Medical Devices Regulations.

3.5 Risk/Benefit Assessment

A risk management report was included in the application which included a Failure Mode Effects Analysis (FMEA) during product development, in accordance with EN1441. The FMEA looked at possible failure modes for the various components of the system, as well as the potential patient effects and outcomes. Severity, probability of occurrence, and risk levels were examined.

A risk management process was developed for identifying hazards, estimating and evaluating associated risks, controlling these risks, and monitoring the effectiveness of the controls. Residual risks were considered to be acceptable based on 20 years of successful use of the device and were deemed to be as low as reasonably possible.

As part of its approval for marketing in the US, SynCardia Systems, Inc. is also conducting a post-market surveillance clinical study of 50 patients at six implanting institutions. Results of this study will be reviewed as part of the risk assessment process.

Complication rates for this device are relatively high, with 93.8% of CardioWest™ C70 TAH-t patients experiencing one or more adverse events. Use of this device on a patient should be carefully considered and a patient should be made fully aware of the possibility and probability of adverse events.

There is sufficient information in support of the safety and effectiveness of the CardioWest™ C70 Temporary Total Artificial Heart and a Licence with Conditions has been recommended. The manufacturer will be required to submit yearly reports on the marketing experience with this device, including but not limited to, total units implanted and adverse events.

3.6 Decision

Based on the Health Canada review of data on quality, safety and effectiveness, Health Canada considers that post-marketing follow-up data will have to be provided annually on the CardioWest™ C70 Temporary Total Artificial Heart in order to detect possible rare and unforeseen adverse events, and to ensure that the benefit/risk profile of the device 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

Application Milestones
Application Milestone Date
Application Received 2005/03/01
Application Validation 2005/03/08
Screening Acceptance 2005/03/10
Review 2005/04/05
Review of additional information 2005/10/25
Licence Issued 2005/10/27