November 9, 2015 February 20, 2017 Using real world evidence – industry perspective Pma indication expansion Melissa hasenbank, phd Sr. Clinical Research Manager Jenny andersen Regulatory Affairs Director

Melissa Hasenbank is an employee of Medtronic, plc. disclosures Melissa Hasenbank is an employee of Medtronic, plc. Jenny Andersen is an employee of Medtronic, plc. CRT 2017 | February 20, 2017

Using Real-World Evidence: An industry example Medtronic is providing a recent example for an indication expansion using real- world evidence (RWE) for a Class III drug-coated balloon (DCB) Medtronic relied on recent FDA Guidance to support the proposed indication expansion Balancing Premarket and Postmarket Data Collection for Devices Subject to Premarket Approval (April 13, 2015) Use of Real-World Evidence to Support Regulatory Decision-Making for Medical Devices (July 27, 2016) Factors to Consider Regarding Benefit-Risk in Medical Device Product Availability, Compliance, and Enforcement Decisions (December 27, 2016) The indication expansion utilized data from a Medtronic-sponsored single-arm study in patients treated with DCB and control data from a large national registry The pre-submission process was utilized for discussions and alignment with FDA Ability to leverage existing data in the original PMA (preclinical/clinical) Use of real-world data Development of a prospective analysis plan CRT 2017 | February 20, 2017

In.pact™ admiral™ drug-coated balloon Intended Use To treat peripheral artery disease of the superficial femoral or popliteal arteries Platform Admiral™ Xtreme Percutaneous Transluminal Angioplasty (PTA) Balloon 4-7 mm diameters 20, 40, 60, 80, 120 and 150 mm lengths Drug Paclitaxel Proven anti-proliferative drug 3.5 µg/mm2 Excipient Urea Facilitates drug transfer Naturally occurring, non-toxic CRT 2017 | February 20, 2017

Regulatory History and clinical Programs Medtronic commercialized IN.PACT Admiral DCB in March 2009; the global regulatory status is provided below European Union (CE Mark) CE Mark received in March 2009 Global Commercially available in over 90+ countries United States (FDA) PMA approval in December 2014 Medtronic has developed several clinical programs to evaluate the safety and efficacy of IN.PACT Admiral DCB in the treatment of peripheral artery disease IN.PACT SFA Trial Randomized pivotal trial comparing DCB vs. PTA outcomes IN.PACT Global Study Single-arm study evaluating DCB outcomes in a real-world patient population, including subjects with longer lesions and in-stent restenosis IN.PACT SFA Japan Trial Randomized trial comparing DCB vs. PTA outcomes in a Japanese patient population IN.PACT SFA China Study Single-arm study evaluating DCB outcomes in a Chinese patient population CRT 2017 | February 20, 2017

In-stent restenosis in Peripheral artery disease Unmet Clinical need Presence of a foreign body (stent) stimulates proliferation of smooth muscle cells, resulting in neointimal hyperplasia and re-narrowing of the artery Management of in-stent restenosis (ISR) often requires repeated and complex interventions, which can impact both quality of life and healthcare costs ISR represented a significant unmet clinical need, as the current approved indication for IN.PACT Admiral DCB included native vessel treatment only and existing approved treatments had low effectiveness results Stent with ISR Magnified image showing ISR CRT 2017 | February 20, 2017

Key Regulatory milestones PMA Approval of in-stent restenosis indication Original PMA Approval – December 2014 Interactive Discussions with FDA using Pre-submission Process PMA-S submitted: Request for Indication Expansion – March 2016 FDA Approval of PMA-S – September 2016 CRT 2017 | February 20, 2017

items to consider Use of rWE in indication expansion PMA Supplements Collaboration with FDA is key to successful real-world evidence strategy Frequent interactions with FDA through pre-submission process Ability to leverage existing data (preclinical/clinical) from the original PMA Demonstration of a well designed and conducted clinical evaluation Ability to demonstrate probable benefits outweigh risks Careful consultation of the guidance documents RWE could contribute to valid scientific evidence to support indication expansion Limitations of data should be known and discussed with FDA prior to analysis Analysis methods should be strategically planned to reduce bias concerns IDE requirements and post-market study requirements may still exist CRT 2017 | February 20, 2017

Recent successful Experience using RWE to support a PMA indication expansion An unmet need was identified, as approved treatments for in-stent restenosis in peripheral artery disease patients had unsatisfactory effectiveness outcomes Early clinical evidence suggested that a newly approved device had the potential for promising safety and effectiveness outcomes in this expanded indication Level 1 clinical evidence did not exist for this device in this patient population An approach leveraging FDA guidance documents on the use of real-world clinical evidence was proposed with a prospectively defined analysis PMA approval of this expanded indication helped to address the unmet clinical need of in-stent restenosis in peripheral artery disease in the US CRT 2017 | February 20, 2017

Questions? THANK YOU! CRT 2017 | February 20, 2017