# Presentation: 574154

## FDA Summary

**CardioSEAL® Septal Occlusion System with Qwik Load**
**NMT Medical**
**P000049**

**Notes:**
Good afternoon.  Again, my name is Donna Buckley and I’m a mechanical engineer in the Interventional Cardiology Devices Branch of the Office of Device Evaluation and the lead reviewer for the CardioSEAL Septal Occlusion System PMA submission, P000049.
Today, Dr. John Stuhlmuller, the medical officer for this submission, and I will present the FDA summary for the CardioSEAL System.  This device is a transcatheter septal defect occlusion system used in the treatment of high risk ventricular septal defects (VSDs). 
You are being 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 the evaluation of the application.  Finally, you will be asked to vote on the approvability of this device.

## FDA Summary

**FDA Review Team**
**Device Description**
**HDE Approval**
**Nonclinical Evaluation**
**Clinical Evaluation**
**Panel Questions**

**Notes:**
The FDA summary will provide a brief overview of the following:
FDA Review Team
Device Description
Humanitarian Device Exemption or HDE requirements
Nonclinical evaluation
Clinical evaluation and
Panel questions

## FDA Review Team

**ODE****	****-****	****Donna Buckley**
**	****	****	****	****John E. Stuhlmuller**
**OSB****	****-****	****Lakshmi Vishnuvajjala**
**OC****	****-****	****Liliane Brown**

**Notes:**
Members of the FDA review team include:
Donna Buckley and Dr. John Stuhlmuller from the Office of Device Evaluation;
Dr. Lakshmi Vishnuvajjala 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.

## Device Description

**Occluder**
**Double umbrella design**
**Size range: 17 - 33 mm**
**Device size : Stretched defect diameter ratio is 1.7-2.0 : 1**

**Notes:**
The occluder is a double-umbrella design with a nitinol metal frame and attached polyester material.
Four sizes are available ranging from 17 to 33 mm.  
The device size to stretched defect diameter ratio is generally 1.7 to 2.0.
The implant is loaded into the 10F delivery catheter using the Qwik Load device.  It is attached to the delivery system, tracked through the delivery catheter, and deployed across the defect. 

## Device Description

**Delivery Catheter**
**Size: 10F **
**Qwik Load device**
**Used to collapse and load occluder    into the delivery catheter**

**Notes:**
The delivery catheter is 10F in size.
The Qwik Load device is attached to the delivery system.  
It is used to collapse and load the occluder into the delivery catheter. 

## Humanitarian Device Exemption 

**Similar to PMA application**
**Exempt from effectiveness requirements**
**Humanitarian Use Device**
**Device that is intended to benefit patients in the treatment and diagnosis of diseases or conditions that affect fewer than 4,000 individuals in the United States.**

## Humanitarian Device Exemption

**CardioSEAL® device  approved under H990005 in September 1999**
**Same intended use as PMA**

## Nonclinical Evaluation

***In Vitro *****Testing **
**Biocompatibility Testing**
***In Vivo***** (Animal) Testing**

## Clinical Evaluation

** **

**Notes:**
Good afternoon.  
My name is John Stuhlmuller, and 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.

## Clinical Data Sets

**Pivotal Cohort - VSD**
**Non-pivotal**
**Clamshell I F/U - VSD**
**High-Risk Registry - non-VSD**
**Clamshell I F/U - non-VSD**
**Acquired VSD - s/p MI**

**Notes:**
The sponsor has provided information for 5 different clinical data sets.
First is the Pivotal Cohort for VSD closure.
The non-pivotal clinical data sets include the following:
Clamshell I Follow-up for VSD closure
High-Risk Registry for non-VSD closure
Clamshell I Follow-up for non-VSD closure and 
Acquired VSD status-post myocardial infarction
Only the Pivotal Cohort for VSD closure will be reviewed at this time.

## Pivotal Cohort - VSD

**Patient subset of High-Risk Registry**
**Open-label, single arm**
**No control group**
**Meets criteria for “Compassionate Use”**
**Primarily single-center study**

**Notes:**
The Pivotal Cohort for VSD closure is a retrospectively derived patient subset of the High-Risk Registry.
“Complex” VSDs eligible for device closure included defects not accessible to closure through an atrial or aortic approach, associated with other cardiac pathology, patients with single or multiple defects, or patients at high surgical risk.
The registry is an open-label single-arm registry without a control group.
Enrollment in the registry is consistent with the compassionate use criteria as outlined in the Expanded Access provisions of the Food and Drug Administration Modernization Act of 1997.
The registry is also primarily a single-center study.

## Pivotal Cohort - VSD

**74 patients**
**Devices placed in 57 of 58 patients attempted**
**Multiple procedures - 6 patients**
**Multiple devices - 26 patients**

**Notes:**
A total of 74 patients were identified for inclusion in the pivotal cohort for VSD closure.
Devices were placed in 57 of 58 patients in which device placement was attempted.
Multiple procedures were completed in 6 patients.
Multiple devices were placed in 26 patients.

## Patient Outcome Assessment

**Effectiveness**
**Clinical Status Scale (CSS)**
**Safety**
**Adverse Events**

**Notes:**
Patient outcome assessment for effectiveness was completed using the Clinical Status Scale.
Patient outcome assessment for safety was by evaluation of potential anticipated and unanticipated adverse events.

## Patient Outcome Assessment

**Clinical Status Scale**
**Developed at Boston Children’s Hospital**
**8 nominal variables each using an ordinal scale**
**Change of 1 on ordinal scale is clinically meaningful change**

**Notes:**
The Clinical Status Scale was developed by the investigators at Boston Children’s Hospital for use in evaluation of patients enrolled in the High-Risk Registry.
The scale consist of 8 nominal variables each using an ordinal scale for patient outcome assessment.
Each ordinal scale was developed so that change of 1 in either direction on the scale represents a clinically meaningful change.

## VSD - Effectiveness

**Effectiveness determined at 6-month F/U **
**44 of 57 implanted patients**
**Anatomical Scale - 14 patients **
**L to R Shunt - 22 patients**
**Different scales - 8  patients**
**Pre - Anatomical & Post - L to R Shunt**

**Notes:**
Effectiveness was determined at 6-month follow-up using the clinical status scale.
44 of 57 implanted patients completed follow-up.
The Anatomical Scale was used pre-procedure and at 6 months in 14 patients.
The L to R Shunt scale was used pre-procedure and at 6 months in 22 patients.
The Anatomical Scale was used pre-procedure and the L to R Shunt Scale was used at 6 months in 8 patients.

## VSD - Effectiveness

**Pre-procedure and 6-month follow-up **
**44 of 57 implanted patients**
**Median change of 2 categories**
**84% of procedures successful at 6 months**

**Notes:**
A median change of 2 categories was demonstrated.
84% of the procedures were considered successful at 6 months.

## VSD - Safety

**Assessment at 1, 6, 12, and 24 months **
**Characterization of adverse events**
**Device related **
**arm fractures**
**Implantation related**
**Catheterization related**

**Notes:**
Patient evaluations were scheduled at 1, 6, 12, and 24 months.
Adverse events by time of event are reported as within 2 days of implant, 2 days to 1 month, 1 month to 6 months, and 6 months to most recent follow-up.
Adverse events were characterized as device related with a separate analysis for device arm fractures, implantation related and catheterization related.

## VSD - Safety

**Adverse events in 57 of 58 patients**
**Total of 222 events**
**Device - 32**
**Implantation - 35**
**Catheterization  - 85**
**Arm fractures in 34 of 107 devices**

**Notes:**
Adverse events were noted in 57 of 58 patients in which device placement was attempted.
A total of 222 adverse events were noted.
32 device related
35 implantation related
85 catheterization related
Device arm fractures were noted in 34 of 107 devices.

## Panel Questions

**Notes:**
FDA would like to obtain panel input on the following questions.

## Question 1- Safety and Effectiveness

**1a.   Based on the information provided, please discuss the description “complex VSD” as the defining indication for use of the CardioSEAL® for VSD closure. **

**Notes:**
The sponsor has submitted data to support approval of the CardioSEAL® device for closure of ventricular septal defects (VSD) defined as complex.  The data in support of this application has been provided from primarily a single-center, uncontrolled, registry study sponsored by Boston Children's Hospital.  The complexity of VSD in patients entered into this registry  has been defined variously as VSD not accessible to closure through an atrial or aortic approach, associated with other cardiac pathology, patients with single or multiple muscular septal defects, or simply patients at high risk for surgery.
Question 1a:  Based on the information provided, please discuss the description “complex VSD” as the defining indication for use of the CardioSeal® for VSD closure.

## Question 1- Safety and Effectiveness

**1b.   In the absence of a control group, please discuss how to evaluate the safety and effectiveness of the CardioSEAL® device.**

**Notes:**

Question 1b:  In the absence of a control group, please discuss how to evaluate the safety and effectiveness of the CardioSeal® device.

## Question 2 - Safety and Effectiveness

**2.****  ****Does the use of the Clinical Status Scale allow for a clinically meaningful assessment of effectiveness for the device?  **

**Notes:**

A “Clinical Status Scale” was used to evaluate efficacy.  The primary efficacy evaluation includes a comparison of the pre-procedure and 6-month shunt using both the L to R and anatomic scales (Clinical Status by Lesion Measure). 
In order to evaluate safety, adverse events were recorded and categorized as serious, moderately serious, not serious, and unknown seriousness.  Events were also categorized as device related, implantation related, or catheterization related.
Question 2: Does the Clinical Status Scale allow for a clinically meaningful assessment of effectiveness for the device?

## Question 3 - Safety and Effectiveness

**3.  Based on the data provided and your comments regarding questions 1 and 2, please discuss whether these data provide reasonable assurance of safety and effectiveness.**

**Notes:**

Question 3: Based on the data provided and your comments regarding questions 1 and 2, please discuss whether these data provide reasonable assurance of safety and effectiveness.

## Question 4 - Training Program

**4a.  Please discuss any improvements that could be      **
**       ****made to the training program.**
**4b.  Please discuss training issues regarding the      **
**	****  ****placement of multiple devices in a single                                                     ****	****  patient.  **

**Notes:**

A summary of the Physician Training Program has been provided in Section 5 of the Panel Package.
Question 4a:  Please discuss any improvements that could be made to the training program.
Question 4b:  More than one device was placed in 26 patients.  Please discuss training issues regarding the placement of multiple devices in a single patient.

## Question 5 - Product Labeling

**  ****5a.****	****Please comment on the **
**	****INDICATIONS FOR USE section as to ****	****	****whether it identifies the appropriate ****	****	****patient populations for treatment with ****	****this device.**

**Notes:**

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 2). 
Question 5a:	Please comment on the INDICATIONS FOR USE section as to whether it identifies the appropriate patient populations for treatment with this device.

## Question 5 - Product Labeling

**   ****5b.****	****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.****  **
** **

**Notes:**

Question 5b: 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 5 - Product Labeling

**5c.****	****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.**

**Notes:**

Question 5c: 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 5 - Product Labeling

**5d.   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.****   **

**Notes:**

Question 5d:   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 5 - Product Labeling

**5e.    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.**

**Notes:**

Question 5e:    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.

## Question 6 - Post-Market Evaluation

**6.  Do you believe that additional follow-up data or post market studies are necessary to evaluate the chronic effects of the implantation of the CardioSEAL® device?  **
**	****If so, how long should patients be followed and what endpoints and adverse events should be measured?**

**Notes:**

Post-Market Evaluation
The Panel Package includes the available 2-year data for the CardioSEAL® device in the pivotal cohort.  In addition, data were provided from the ClamShell I Follow-Up study (Section 5.D.2) for some patients followed out to 12 years.  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 6:  Do you believe that additional follow-up data or post market studies are necessary to evaluate the chronic effects of the implantation of the CardioSEAL® device?  If so, how long should patients be followed and what endpoints and adverse events should be measured?