1. Looking Forward: FDA Perspective on New Clinical Trial Designs for LAA Occluders
Rachel Neubrander, PhD
Division of Cardiovascular Devices
Office of Device Evaluation
Center for Devices and Radiological Health (CDRH)
CRT 2017
February 20, 2017

2. Disclosures
No conflicts of interest to report.

3. 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

4. New LAA Occlusion Devices: Framing Benefit – Risk in Pivotal Trials
Is the LAA occlusion procedure associated with an acceptable rate of device and procedure-related 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?

5. 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

6. 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

7. Current WATCHMAN US DFU includes:
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

8. 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

9. 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

10. 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