Looking Forward FDA Perspective on New Clinical Trial

Looking Forward: FDA Perspective on New Clinical Trial Designs for LAA Occluders Rachel Neubrander, Ph. D Division of Cardiovascular Devices Office of Device Evaluation Center for Devices and Radiological Health (CDRH) rachel. neubrander@fda. hhs. gov CRT 2017 February 20, 2017

Disclosures • No conflicts of interest to report. www. fda. gov 2

LAA Occlusion to Prevent Ischemic Stroke • WATCHMAN approved March 2015 • LAAO registry launched December 2015 • CMS Coverage with Evidence Development finalized February 2016 Looking forward: • Development of new devices • Address other knowledge gaps www. fda. gov 3

New LAA Occlusion Devices: Framing Benefit – Risk in Pivotal Trials • Is the LAA occlusion procedure associated with an acceptable rate of device and procedurerelated complications? • Does the LAA occlusion device provide adequate protection from ischemic stroke? • In device vs. anticoagulation trials, is the avoidance of long-term AC following LAA occlusion associated with a reduced risk of major bleeding complications? 4

Potential Trial Designs New device: • OAC eligible patients: Randomized controlled trial (RCT) of investigational device vs. approved device or investigational device vs. OAC (particularly NOACs) • OAC unsuitable patients: RCT of investigational device vs. ASA/no treatment Iteration of approved device: • Dependent on the design change(s) • Consider alternative, least-burdensome trial design 5

OAC unsuitable patient population • Individuals with absolute and important relative contraindications to anticoagulation • Randomized trials needed to establish safety and effectiveness and define benefit-risk • Single arm studies using performance goals (PGs) not adequate • Ongoing ASAP-TOO trial adequately powered to address benefit-risk questions in this patient population 6

Safety and Effectiveness of Alternative Medication Regimens Post-LAA Occluder Implantation • Current WATCHMAN US DFU includes: – Warfarin + aspirin for at least 45 days – Aspirin + clopidogrel through 6 months • Alternative post-implantation regimens include: – DAPT alone (no warfarin) – NOACs • Well designed and conducted prospective studies needed 7

Leveraging LAAO registry infrastructure • Potential for more efficient utilization of resources – Post-approval surveillance of safety and effectiveness outcomes – Real world evidence – Meeting data requirements of payers • Embedding IDE studies within a registry – New indications or clinical updates to labels for approved devices – Approval of new devices – Study designs • Single-arm studies with historical controls • Randomized controlled trial 8

Embedding an IDE in an Ongoing Registry The 8 A’s for a High Quality Study • Agreement to participate: Informed consent • Analysis: Study protocol, pre-specified event definitions, statistical analysis plan • Accountability of study subjects: Minimize subject withdrawals and lost to follow-up • Accumulation of data: Minimize missing information • Accuracy of data collection and recording • Adjudication of events • Auditing and monitoring of study data • Access to data by investigators, industry, FDA, CMS 9

Conclusions • High quality data is needed to support marketing of new devices and to address knowledge gaps in field of LAA occlusion • Opportunities to use registry infrastructure for pre- and post-market clinical studies • Early interactions among FDA, sponsors, investigators, and CMS recommended to develop studies to support both marketing and coverage 10