1. Amplatzer® Septal Occluder
FDA Summary
Amplatzer® Septal Occluder
AGA Medical
P000039
Good Morning, my name is Donna Buckley and I am a mechanical engineer in the Interventional Cardiology Devices Branch of the Office of Device Evaluation. I am also the lead reviewer for the Amplatzer Atrial Septal Occlusion Device PMA, P
Today, Dr. John Stuhlmuller, the medical officer for this submission, and I will present the FDA summary for the Amplatzer ASO submission. This device is a transcathter septal defect closure device used in the treatment of atrial septal defects and Fenestrated Fontans.
Today you will be asked to discuss and make recommendations on the sponsor’s PMA submission. Your points of discussion of the clinical study results and labeling recommendations will be taken into consideration by FDA in their evaluation of the application. Finally, you will be asked to vote on the approvability of this device.

2. FDA Summary FDA Review Team Device Description Nonclinical Evaluation
Panel Questions
The FDA Summary will provide a brief overview of the following:
FDA Review Team
Device Description
Nonclinical evaluation
Clinical evaluation
and Panel Questions

3. FDA Review Team ODE - Donna Buckley John Stuhlmuller OSB - John Dawson
OC - Liliane Brown
Members of the FDA review team include:
Donna Buckley and Dr. John Stuhlmuller from the Office of Device Evaluation;
Mr. John Dawson from the Office of Surveillance and Biometrics who served as the statistical reviewer; and
Ms. Liliane Brown from the Office of Compliance who coordinated FDA inspection of the investigational sites.

4. Device Description Occluder Double-disc with connecting waist
LA disc size > RA disc size
26 sizes based on connecting waist diameter (range: mm)
Sizing: Connecting waist diameter is matched to the stretched defect diameter
The occluder is a double disk design with a connecting waist. The materials a nitinol wire mesh with polyester material stitched into the disks.
The left atrial disk is larger than the right atrial disk.
26 sizes are available based on the connecting waist diameter. The occluder sizes range from 4 mm to 38 mm in diameter.
The occluder is sized to match the connecting waist diameter to the stretched defect diameter.

5. Device Description Delivery Catheter
6F to 12F depending on device size
Occluder is packaged separately
Manually attached to delivery cable
Loaded into delivery catheter
The delivery catheter is 6F to 12F in size based on occluder size.
The occluder is packaged separately and manually attached to the delivery cable prior to loading into the delivery catheter.

6. Nonclinical Evaluation
In vitro Testing
Biocompatibility Testing
In vivo (Animal) Testing
In vitro or bench testing as outlined in Section 1.4 of the FDA Summary was performed to evaluate the mechanical integrity of the Amplatzer Septal Occluder system
Biocompatibility testing of the device components was conducted in accordance with ISO Standard
Animal studies were conducted in a porcine model on the Amplatzer System.
The results of the in vitro or bench, biocompatibility, and animal testing submitted demonstrate the integrity and functionality of the device for its intended use.
There are no outstanding nonclinical testing issues at this time.

7. Clinical Evaluation Good morning.
My name is John Stuhlmuller. I am a medical officer in the Interventional Cardiology Devices Branch in the Division of Cardiovascular and Respiratory Devices. I am going to provide a brief overview of the clinical information contained in the PMA.

8. Proposed Indications for Use
Closure of:
Secundum atrial septal defects
Fenestrations following Fontan procedure
The sponsor has provided clinical data for two proposed indications for use in the PMA.
The first indication for use is closure of secundum atrial septal defects.
The second indication for use is closure of fenestrations following Fontan procedures.

9. Clinical Data Sets Pivotal Cohort - ASD
Phase IIB patients
Pivotal Cohort - Fenestrated Fontan
51 patients enrolled
Non-pivotal
Phase I, Phase IIA - ASD
Continued Access - ASD
The sponsor has provided information for 5 different clinical data sets as part of the PMA.
Information on the pivotal studies has been provided in the Panel packs.
First is pivotal data set from the Phase IIB registry for atrial septal defect -ASD closure. A total of 459 patients were enrolled in this registry.
Second is the pivotal data set for closure of fenestrations following Fontan procedures. A total of 51 patients were enrolled in the registry.
Non-pivotal data sets not included in the Panel packs include Phase I, Phase IIA and Continued access patients.

10. Pivotal Cohorts - ASD Device arm Surgical control arm Non-randomized
Multicenter
Surgical control arm
pro- and retrospective patient identification
prospective 1-year follow-up
The device patients were enrolled in a non-randomized open-label, multicenter registry.
The surgical control patients were enrolled also enrolled in a non-randomized open-label, multicenter registry.
Surgical patients were prospectively and retrospectively identified.
All patients completed a prospective 1-year follow-up.

11. Patient Outcome Assessment
Composite Clinical Success at 12 months
Incorporates safety and effectiveness
Patients attempted without major complication, embolization, technical failure, or significant shunt
Secondary safety and effectiveness endpoints
Patient outcome assessment was made using a composite clinical endpoint termed Composite Clinical Success at 12 months.
The composite clinical endpoint incorporates aspects of safety and effectiveness.
The individual clinical endpoints incorporated into assessing Composite Clinical Success include: major complications, embolization, technical failure, and presence of a significant residual shunt.
Additional individual secondary safety and effectiveness endpoints were also evaluated.

12. ASD - Effectiveness Insert table
Technical success defined as device deployment or completion of surgery was seen in 423 of % of device patients and 154 of % of surgical patients.
Procedure success defined as a residual shunt less than 2 mm in patients who were technical successes was seen in 413 of % of device patients and 154 of % of surgical patients.
6 month closure defined as residual shunt  2 mm in patients who were technical successes was seen in 376 of % of device patients and 154 of % of surgical patients.
12 month closure defined as residual shunt  2 mm in patients who were technical successes was seen in 326 of % of device patients and 149 of % of surgical patients.
12 month composite clinical success defined as all patients attempted without major complications, embolization, technical failure, and presence of a significant residual shunt was seen in 311 of % of device patients and 146 of % of surgical patients.

13. ASD - Safety
Major complications were seen in 7 of % of device patients and 8 of % of surgical patients.
Minor complications were seen in 27 of % of device patients and 29 of % of surgical patients.
Overall, 32 of % of device patients experienced a complication and 37 of % of surgical patients experienced a complication.

14. Pivotal Cohort - Fenestrated Fontan
Open-label
Single-arm registry
No control
The pivotal cohort for closure of fenestrations following Fontan procedures were enrolled in a prospective open-label, single-arm registry without a control group.

15. Patient Outcome Assessment
Effectiveness
 2mm shunt at 12 months
Safety
Adverse events
Patient outcome assessment was completed at 12 months.
Effectiveness was defined as successful closure -less than a 2 mm residual shunt at 12 month follow-up.
Safety was evaluated by analysis of potential anticipated and unanticipated adverse events.

16. Fenestrated Fontan - Effectiveness
Devices implanted in 46 of 48 patients attempted
 2mm shunt in 32 of 32 patients at 12 months
Occluders were implanted in 46 of 48 attempted patients.
Successful closure was demonstrated in 32 of 32 patients evaluated at 12 months.

17. Fenestrated Fontan - Safety
Devices implantation attempted in 48 patients
Complications - 4 patients
Major - 2 patients
Minor - 2 patients
Adverse events were evaluated in the 48 patients in which device placement was attempted.
A total of 4 adverse events were seen.
Two major and two minor adverse events were seen.

18. Panel Questions
FDA would like to obtain panel input on the following questions.

19. Question 1 - ASD Indication
1a. Please discuss whether individual endpoints, composite endpoints, or a combination of both should be used to evaluate the safety and effectiveness of the Amplatzer® ASO device?
ASD Indication
To support the ASD indication, the sponsor has submitted data from a prospective, non-randomized concurrently controlled study comparing device closure to surgical closure. The study was designed to assess individual endpoints and composite endpoints. The endpoints evaluated are summarized in the table below (and on pages 5 and 9 of the Panel Package, Section 5.D).
Question 1a. Please discuss whether individual endpoints, composite endpoints, or a combination of both should be used to evaluate the safety and effectiveness of the Amplatzer® ASO device?

20. Question 1 - ASD Indication
1b. The sponsor is seeking approval for device sizes from 4 mm to 38 mm. Approximately 89% of devices implanted in the pivotal ASD study were between 10 mm and 28 mm. Is there sufficient data to support approval of the entire range of devices (4 mm to 38 mm) or a specific range of device sizes?
Question 1b. The sponsor is seeking approval for device sizes from 4 mm to 38 mm. Approximately 89% of devices implanted in the pivotal ASD study were between 10 mm and 28 mm. Is there sufficient data to support approval of the entire range of devices (4 mm to 38 mm) or a specific range of device sizes?

21. Question 1 - ASD Indication
1c. Based on the data provided on ASD patients and the suggested analysis of the data from question 1a., please discuss whether these data provide reasonable assurance of safety and effectiveness.
Question 1c. Based on the data provided on ASD patients and the suggested analysis of the data from question 1a., please discuss whether these data provide reasonable assurance of safety and effectiveness.

22. Question 2 - Fontan Indication
Based on the data provided on Fenestrated Fontan patients and the suggested analysis of the data from question 1a., please discuss whether these data provide reasonable assurance of safety and effectiveness.
Fenestrated Fontan Indication
To support the Fenestrated Fontan indication, the sponsor has submitted data from a single arm registry with 48 patients.
Question 2: Based on the data provided on Fenestrated Fontan patients and the suggested analysis of the data from question 1a., please discuss whether these data provide reasonable assurance of safety and effectiveness.

23. Question 3 - Training Program
3a. Please discuss any improvements that could be made to the training program.
3b. More than one device was placed in 10 ASD
patients. Please discuss training issues regarding the placement of multiple devices in a single patient.
A summary of the Physician Training Program has been provided in Section 5 of the Panel Package.
Question 3a. Please discuss any improvements that could be
made to the training program.
Question 3b. More than one device was placed in 10 ASD
patients. Please discuss training issues regarding
the placement of multiple devices in a single patient.

24. Question 4 - Product Labeling
4a. Please comment on the
INDICATIONS FOR USE section as to whether it identifies the appropriate patient populations for treatment with this device.
Product Labeling
One aspect of the pre-market evaluation of a new product is the review of its labeling. The labeling must indicate which patients are appropriate for treatment, identify potential adverse events with the use of the device, and explain how the product should be used to maximize benefits and minimize adverse effects. Please address the following questions regarding the product labeling (Section 3).
Question 4a. Please comment on the INDICATIONS FOR USE section as to whether it identifies the appropriate patient populations for treatment with this device.

25. Question 4 - Product Labeling
4b. 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.
Question 4b. 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.

26. Question 4 - Product Labeling
4c. 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.
Question 4c: 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.

27. Question 4 - Product Labeling
4d. 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.
Question 4d: 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.

28. Question 4 - Product Labeling
4e. Please comment on the remainder of the device labeling as to whether it adequately describes how the device should be used to maximize benefits and minimize adverse events.
Question 4e. Please comment on the remainder of the device labeling as to whether it adequately describes how the device should be used to maximize benefits and minimize adverse events.

29. Question 5 - Post Market Evaluation
Based on the clinical data provided in the PMA, do you believe that additional follow-up data or post market studies are necessary to evaluate the chronic effects of the implantation of the Amplatzer® device.
If so, how long should patients be followed and what endpoints and adverse events should be measured?
Post-Market Evaluation
The Panel Package includes the available 1-year data for the Amplatzer® ASO device. Long term adverse effects that may be associated with device implantation include late thrombosis formation, the risk of endocarditis, problems with late operation, and arrhythmias.
Question 5: Based on the clinical data provided in the PMA, do you believe that additional follow-up data or post market studies are necessary to evaluate the chronic effects of the implantation of the Amplatzer® device. If so, how long should patients be followed and what endpoints and adverse events should be measured?