DHHS / FDA / CDRH 1 FDA Summary CardioSEAL® STARFlex™ Septal Occlusion System with Qwik Load NMT Medical P000049/S3

DHHS / FDA / CDRH 2 FDA Summary FDA Review Team Background Device Description Nonclinical Evaluation Clinical Evaluation Panel Questions

DHHS / FDA / CDRH 3 FDA Review Team ODE- Donna Buckley John E. Stuhlmuller, M.D. OSB- Gerry Gray, Ph.D.

DHHS / FDA / CDRH 4 BackgroundBackground STARFlex™ has the same design as the CardioSEAL® device except that a nitinol centering spring has been added CardioSEAL® PMA approved (12/01); closure of high risk VSDs HDE approved (2/00); closure of PFO in patients with recurrent cryptogenic stroke who have failed medical therapy

DHHS / FDA / CDRH 5 STARFlex™ Device Description Occluder Double umbrella design Sizes: 23mm, 28mm, and 33mm Device size : Stretched defect diameter ratio is : 1 Delivery Catheter Size: 10F Qwik Load device - used to collapse and load occluder into the delivery catheter

DHHS / FDA / CDRH 6 Nonclinical Evaluation In Vitro Testing Biocompatibility Testing In Vivo (Animal) Testing

DHHS / FDA / CDRH 7 Clinical Evaluation

DHHS / FDA / CDRH 8 Clinical Data Sets Pivotal Cohort – STARFlex™ PFO Non-pivotal CardioSEAL® (PFO) Clamshell I F/U (PFO) STARFlex™ (non-PFO)

DHHS / FDA / CDRH 9 Pivotal Cohort - PFO Patient subset of High-Risk Registry Open-label, single arm No control group Meets criteria for “Compassionate Use” Primarily single-center study

DHHS / FDA / CDRH 10 Pivotal Cohort - PFO 49 patients Devices placed in 49 of 49 patients attempted

DHHS / FDA / CDRH 11 Patient Outcome Assessment Effectiveness Primary: Complete Defect Closure by Echocardiographic Assessment Secondary: Occurrence of Potential Neurological Events after Device Placement Safety Adverse Events

DHHS / FDA / CDRH 12 PFO - Effectiveness Primary Efficacy determined at 6-month F/U 44 of 49 implanted patients Complete closure reported in 43 of 44 patients evaluated Technical errors were reported in 9 of 49 patients Secondary Efficacy No strokes and 4 transient neurological events were reported

DHHS / FDA / CDRH 13 PFO - Safety Assessment at 1, 6, 12, and 24 months Characterization of adverse events Device related arm fractures Implantation related Catheterization related

DHHS / FDA / CDRH 14 PFO - Safety Serious or moderately serious adverse events in 13 of 49 patients Device-Related - 7 Implantation-Related - 1 Catheterization-Related - 5 Arm fractures in 7 of 49 devices

DHHS / FDA / CDRH 15 Panel Questions

DHHS / FDA / CDRH 16 Question 1 1a. Please discuss the use of “Procedural Success” as the primary efficacy outcome measure for assessment of clinical benefit. 1b. Please discuss the use of the occurrence of potential embolic neurological events after device placement as a secondary efficacy outcome measure for assessment of clinical benefit.

DHHS / FDA / CDRH 17 Question 2 2a. Please discuss the use of “Serious and Moderately Serious Adverse Events” (that were definitely, probably or possibly related to the device, implantation or catheterization procedure) as the primary safety outcome measure for assessment of clinical benefit versus risk. 2b. Please discuss whether the echocardiographic evaluation and clinical evaluation (definitions for occurrence of neurological events) allow adequate assessment of device-related clinical events.

DHHS / FDA / CDRH 18 Question 2 (cont) 2c. Please discuss whether adequate information has been provided to allow assessment of the risk of recurrent cryptogenic stroke versus risk of device- related neurological event. 2d. Please discuss whether adequate information has been provided to characterize the appropriate post-device placement antiplatelet regimen (duration and single versus combination therapy) or anticoagulation regimen (duration and target INR).

DHHS / FDA / CDRH 19 Question 3 3. Please comment on the lack of a pre- specified control group, pre-specified outcome measures, and pre-specified sample size.

DHHS / FDA / CDRH 20 Question 4a and 4b 4a. Please clarify if additional analyses on the current data set could be performed to provide adequate information to support safety and effectiveness. 4b. Please clarify if the collection of additional data using the current patient selection criteria and outcome measures would be adequate to support safety and effectiveness.

DHHS / FDA / CDRH 21 Question 4c 4c. Alternatively, if you believe that a new trial is required, please address the following clinical trial design questions: i. Given our current understanding of the causal relationship of the presence of PFO and stroke (presumed paradoxical embolism), please discuss whether a randomized trial is necessary to evaluate safety and effectiveness. If so, 1. Can a randomized trial be completed at this time? 2. What is an appropriate control group?

DHHS / FDA / CDRH 22 Question 4c (cont) ii. Please discuss whether adequate trials can be designed with historical controls or objective performance criteria. iii. Based on the type of study design proposed, please address the following issues: 1. Please characterize the appropriate patient population for study enrollment. 2. Please discuss the appropriate primary and s secondary outcome measures for evaluation of effectiveness and safety. As part of this discussion, please comment on the use of clinical versus surrogate endpoints.

DHHS / FDA / CDRH 23 Question 4c (cont) 3. Please discuss the appropriate duration of patient follow-up. 4. Please comment on what would be a clinically relevant sample size. 5. Please discuss the criteria for a successful trial. 6. Please comment on whether adjunctive antithrombotic medication regimens should be left to the operator or prospectively outlined in the protocol.

DHHS / FDA / CDRH 24 Question 5 5. Please discuss any improvements that could be made to the training program.

DHHS / FDA / CDRH 25 Question 6 6a.Please comment on the INDICATIONS FOR USE section as to whether it identifies the appropriate patient populations for treatment with this device.

DHHS / FDA / CDRH 26 Question 6 (cont) 6b.Please comment on the CONTRAINDICATIONS section as to whether there are conditions under which the device should not be used because the risk of use clearly outweighs any possible benefit.

DHHS / FDA / CDRH 27 Question 6 (cont) 6c.Please comment on the WARNING/PRECAUTIONS section as to whether it adequately describes how the device should be used to maximize benefits and minimize adverse events.

DHHS / FDA / CDRH 28 Question 6 (cont) 6d. Please comment on the OPERATOR’S INSTRUCTIONS as to whether it adequately describes how the device should be used to maximize benefits and minimize adverse events.

DHHS / FDA / CDRH 29 Question 6 (cont) 6e. Please comment on the remainder of the device labeling as to whether it adequately describe how the device should be used to maximize benefits and minimize adverse events.

DHHS / FDA / CDRH 30 Question 7 7. Based on the clinical data provided in the Panel Package, do you believe that additional follow-up data or post market studies are necessary to evaluate the chronic effects of the implantation of the STARFlex™ device. If so, how long should patients be followed and what endpoints and adverse events should be measured?