Evidence Requirements for Magnetic Resonance Imaging (MRI) Labelling of Active Implantable Medical Devices (AIMDs) MTAA Joint Industry Working Group Position Paper June, 2016 Contents 1. Executive Summary ............................................................................................... 3 2. Introduction ............................................................................................................ 4 3. Background ............................................................................................................ 4 4. Risk-based Approach ............................................................................................. 5 4.1 Potential Hazards ................................................................................................... 6 5. Introduction to MRI Modelling ................................................................................. 7 5.1 Major Variables Influencing Lead Electrode Heating .................................................... 8 5.1.1 Lead Design and Lead Length .................................................................................. 8 5.1.2 Lead Path ................................................................................................................. 9 5.1.3 Patient Size, Anatomy and Physiology...................................................................... 9 5.1.4 Patient Position in the Scanner ................................................................................. 9 5.1.5 Scanner Variables .................................................................................................... 9 6. Numerical Modelling of Clinical Risk ...................................................................... 9 6.1 MRI Phase Effects: Sensitivity of heating to complex electric field parameters ..... 10 6.2 Numerical Integration of Modelling Components ................................................... 13 7. Clinical Validation of the MRI Modelling Framework: Consistency of Human clinical study evidence with Modelling Output ......................................................................... 15 8. Industry Perspective on the Role of Modelling ..................................................... 16 9. Demonstrating Compliance with the Essential Principles ..................................... 17 10. Ethical Considerations of Requiring Clinical Trials ............................................... 18 11. Risks of Denying Patients Access to MRI Scans .................................................. 18 12. Post Market Data ................................................................................................. 19 13. Equivalence in the Context of MRI Conditionality ................................................. 19 14. Conclusion ........................................................................................................... 20 15. Recommendations ............................................................................................... 20 16. References .......................................................................................................... 21 MTAA Joint Industry Working Group Position Paper TGA Draft Evidence Requirements for MRI Labelling of Active Implantable Medical Devices (AIMDs) May 2016 Page 2 of 21 1. Executive Summary Magnetic Resonance Imaging (MRI) is recognised as being an indispensable tool for the investigation and diagnosis of conditions that affect soft tissue. Until recent years, MRI scans were contraindicated in patients with Active Implantable Medical Device (AIMD) systems due to the potential for hazardous interactions between the electromagnetic fields generated by the MRI scanner and the implanted medical device system. As the number of patients with implantable cardiac device systems increases concurrently with the increase in use of MRI scans, manufacturers have focussed their attention on validating the conditions under which MRI scans can be safely performed on patients with AIMDs. While this position paper focuses mainly on lead heating, industry acknowledges the other potential hazards identified in the Consultation: Draft clinical evidence guidelines - Medical devices document in Table 4 on Page 99. All potential hazards associated with MRI scanning of implantable cardiac devices are tested in accordance with ISO/TS 10974 and other international standards. As part of product development, manufacturers identify and evaluate potentially hazardous interactions between implanted devices and a multitude of potential risks including MRI scanning. An outcome of the risk management process is the identification of risks that remain after mitigation strategies have been put in place. In these circumstances, a clinical trial may be required to address the significance of any residual risks. There is a range of potential hazards associated with implantable cardiac devices .The effectiveness of risk mitigation measures for safe MRI scanning conditions can be demonstrated by testing according to the internationally recognised ISO/TS 10974:2012 Assessment of the safety of magnetic resonance imaging for patients with an active implantable medical device. Industry has reached a consensus that the most accurate and robust method of determining the MR safety of an implantable pacing or defibrillation system in a human population involves the use of this comprehensive modelling framework. As is stated in Wilkoff et al, “Modelling is a practical and efficient method for exploring thousands of variable combinations of patient anatomy, scanner type, implant location, lead model and lead routing well beyond what is possible through clinical trials. It also allows for analysis of parameter extremes outside the bounds of normal clinical practice, which allows further assessment of safety margins and the sensitivity of influencing variables”. [5] There is currently a large body of collective clinical data across all cardiac device manufacturers demonstrating that a broad range of implantable cardiac device systems perform safely when used under the MR conditions that they have been validated and labelled for. It is industry’s position that the existing clinical evidence in conjunction with modelling and bench testing is the most suitable way to quantify the performance of implantable leads and cardiac devices in an MR environment. Modelling together with bench testing and animal studies is the most effective approach to holistically account for all of the potential hazards associated with MR scanning of patients with implantable cardiac devices. MTAA Joint Industry Working Group Position Paper TGA Draft Evidence Requirements for MRI Labelling of Active Implantable Medical Devices (AIMDs) May 2016 Page 3 of 21 Therefore, the key recommendation of this position paper is that TGA accept modelling using the internationally accepted test method document ISO/TS 10974 in conjunction with bench testing and risk management activities in lieu of clinical evidence for the safety of MR conditional labelling for AIMDs.. Once the modelling has been clinically validated on one system, the model should be applicable to all families of devices without having to provide additional clinical trial data. 2. Introduction The medical devices industry has moved to the use of the internationally recognised standards including ISO/TS 10974:2012 Assessment of the safety of magnetic resonance imaging for patients with an active implantable medical device as primary evidence of safety to support the MR conditional labelling of implantable cardiac systems. A MTAA Joint Industry Working Group comprising representatives from Medtronic, Boston Scientific, BIOTRONIK and St. Jude Medical was formed in September, 2015 to discuss the TGA’s requirement for clinical trial data to support MR conditional labelling. This group includes Australian regulatory affairs professionals and US based MRI subject matter experts who are participating in the development of several MRI related standards including ISO/TS 10974 and AAMI PC76 (which includes acceptance criteria for implantable cardiac systems). This industry Position Paper has been prepared to address the following specific concerns: TGA Requirements: 1. Currently TGA requires clinical evidence resulting from a clinical study or direct clinical evidence from an equivalent product to meet EP14. 2. Computer modelling alone does not meet the TGA criteria for clinical evidence. 3. TGA’s definition of equivalence relates to products with the same technical characteristics (e.g. materials, design, manufacturing process), biological characteristics and clinical use. 4. Modelling data can be used to support the clinical evidence only if the specific modelling approach has been clinically validated for equivalent devices within the same family or system. 3. Background Magnetic Resonance Imaging (MRI) is the ‘gold standard’ scanning modality to investigate or diagnose conditions that affect soft tissue and is therefore an indispensable diagnostic tool. MRI scans have historically been contraindicated for patients with Active Implantable Medical Device (AIMD) systems due to the potential for hazardous interactions between the electromagnetic (EM) fields generated by the MRI scanner and the implanted medical device system. The number of patients with implantable cardiac systems is growing, while at the same time the use of MRI scanning is increasing. Based on these two factors it has been estimated that there is a 50 – 75 % probability that a pacemaker