UNITED STATES OF AMERICA

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FOOD AND DRUG ADMINISTRATION

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CENTER FOR DEVICES AND RADIOLOGICAL HEALTH

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CIRCULATORY SYSTEM DEVICES PANEL

MEETING

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MONDAY,

SEPTEMBER 10, 2001

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The panel met at 9:00 a.m. in Salon of the Gaithersburg Marriott Washingtonian Center, 9751 Washingtonian Boulevard, Gaithersburg, Maryland, Dr. Cynthia Tracy, Chairperson, presiding.

PRESENT:

CYNTHIA M. TRACY, M.D. Chair

SALIM AZIZ, M.D. Member

MICHAEL D. CRITTENDEN, M.D. Temporary Voting Member

ROBERT DACEY Consumer Representative

RICHARD A. HOPKINS Temporary Voting Member

WARREN K. LASKEY, M.D. Member

NANCY L. McDANIEL, M.D. Temporary Voting Member

MICHAEL MORTON Industry Representative

DAVID J. SKORTON, M.D. Temporary Voting Member

CHRISTOPHER J. WHITE, M.D. Temporary Voting Member

ROBERTA G. WILLIAMS, M.D. Temporary Voting Member

JANET T. WITTES, Ph.D. Member

KENNETH G. ZAHKA, Ph.D. Temporary Voting Member

MEGAN MOYNAHAN Executive Secretary

 

A-G-E-N-D-A

Call to Order, Cynthia Tracy, M.D., Chairperson 4

Open Public Hearing 8

Sponsor Presentation: AGA Medical

P000039, Amplatzer Septal Occluder and Delivery System

Franck Gougeon, Executive Vice President, AGA Medical Corporation 10

John Cheatham, M.D., The Nemours Cardiac Center, Orlando 16

Ziyad Hizazi, M.D., University of Chicago Children's Hospital, Chicago 25

John Moore, M.D., St. Christopher's Children's Hospital, Philadelphia 39

FDA Presentation

Donna Buckley, lead reviewer 51

John E. Stuhlmuller, M.D., clinical reviewer 53

Open Committee Discussion, Recommendations, and Voting

Cynthia Tracy, M.D. 61

Break

Open Public Hearing 195

Adjourn - Break for Lunch

Call to Order, Cynthia Tracy, M.D. 210

Open Public Hearing 210

 Sponsor Presentation: NMT Medical, Inc.

P000049, CardioSEAL Septal Occlusion System with Qwikload

John Ahern, President, CEO and Chairman, NMT Medical, Inc. 210

Carol Ryan, Vice President, Research and Development, NMT Medical 214

John E. Mayer, M.D., Boston Children's Hospital/Harvard Medical School 218

Peter C. Laussen, MBBS, Boston Children's Hospital/Harvard Medical School 224

Kathy J. Jenkins, MD, MPH, Boston Children's Hospital/Harvard Medical School 230

Kimberlee Gauvreau, ScD, Boston Children's Hospital/Harvard Medical School 242

FDA Presentation

Donna Buckley, lead reviewer 258

John E. Stuhlmuller, clinical reviewer 261

Open Committee Discussion, Recommendations,

Cynthia Tracy, M.D. 269

Open Public Hearing 377

Adjourn

  P-R-O-C-E-E-D-I-N-G-S

9:04 a.m.

DR. TRACY: Good morning. I'd like to call to order this meeting of the Circulatory System Device Panel. The topic is discussion of premarket application for AGA Medical Amplatzer Septal Occluder and Delivery System.

MS. MOYNAHAN: I would like to read the conflict of interest statement for this morning, or today rather. The following announcement addresses conflict of interest issues associated with this meeting and is made a part of the record to preclude even the appearance of any impropriety.

To determine if any conflict existed, the agency reviewed the submitted agenda for this meeting and all financial interest reported by the committee participants. The conflict of interest statutes prohibits special government employees from participating in matters that could affect their or their employer's financial interest.

However, the agency has determined that participation of certain members and consultants the need for whose services outweighs the potential conflict of interest involved is in the best interest of the government.

Therefore, a waiver has been granted for Dr. David Skorton for his interest in a firm that could potentially be affected by the panel's recommendations. Copies of this waiver may be obtained from the agency's Freedom of Information Office, Room 12A-15 of the Parklawn Building.

In the event that the discussions involve any other products or firms not already on the agenda in which an FDA participant has a financial interest, the participant should excuse him or herself from such involvement and the exclusion will be noted for the record.

With respect to all other participants we ask in the interest of fairness that all persons making statements or presentations disclose any current or previous financial involvement with any firm whose products they wish to comment upon.

DR. TRACY: Can I ask the panel members to introduce themselves.

MR. MORTON: I'm Michael Morton. I'm the Industry Representative. I'm employed by W. L. Gore.

DR. WHITE: My name is Christopher White. I'm a cardiologist from Ochsner Clinic in New Orleans.

DR. WILLIAMS: Roberta Williams, pediatric cardiologist and Chairman of Pediatrics, University of Southern California.

DR. SKORTON: I'm David Skorton. I'm a cardiologist. I'm the Vice President for Research for the University of Iowa. I want to say for the record that the waiver that was granted, my conflict is institutional, not a personal financial conflict.

DR. ZAHKA: I'm Kenneth Zahka. I'm a pediatric cardiologist at Rainbow Babies and Children's Hospital in Cleveland in Case Western Reserve University.

DR. HOPKINS: Richard Hopkins. I'm a pediatric and adult cardiac surgeon, Chief of Cardiothoracic Surgery at Brown University.

DR. AZIZ: Salim Aziz. I'm an adult cardiac surgeon in Denver, Colorado, University of Colorado.

DR. TRACY: I'm Cindy Tracy. I'm from Georgetown University Hospital, lecture physiologist.

MS. MOYNAHAN: My name is Megan Moynahan. I'm the Executive Secretary of the Circulatory System Devices Panel.

DR. LASKEY: Warren Laskey, interventional cardiologist from the University of Maryland.

DR. McDANIEL: Nancy McDaniel, pediatric cardiologist, University of Virginia.

DR. CRITTENDEN: Mike Crittenden, Cardiac Surgery, Harvard University, West Roxbury, VA.

MR. DACEY: I'm Robert Dacey, Consumer Representative from Boulder County, Colorado.

MR. DILLARD: Jim Dillard. I'm the Director of the Division of Cardiovascular and Respiratory Devices, Anesthesiology. They are also at the Food and Drug Administration.

DR. TRACY: I will at this point open the open public hearing. Oh, I'm sorry. I jumped one step on the script, Megan.

MS. MOYNAHAN: This is the appointment to temporary voting status for today. Pursuant to the authority granted under the Medical Devices Advisory Committee Charter dated October 27, 1990, and as amended August 18, 1999, I appoint the following individuals as voting members of the Circulatory System Devices Panel for this meeting on September 10, 2001.

Michael Crittenden, Nancy McDaniel, Christopher White, Richard Hopkins, David Skorton, Roberta Williams, and Kenneth Zahka.

For the record, these people are special government employees and are consultants to this panel and to the Medical Devices Advisory Committee. They have undergone the customary conflict of interest review and have reviewed the material to be considered at this meeting.

DR. TRACY: Thanks. Okay, now we'll open the open public hearing. At this point there were no specific requests from the public to speak but is there anybody here present who would like to make a statement?

MS. MOYNAHAN: I have a couple of -- if there's no one from the public who wants to speak, I received a couple of letters. Actually, I received eight letters in support of the Septal Occluders that are being discussed today. I don't really have time to read all the letters into the record but what I would like to do is summarize one of them.

The eight letters were actually on behalf of the same patient who received a Septal device last year and she writes in her letter that she had a procedure done and was discharged the very next day. Since that time there has been a big improvement in her endurance and energy and she's has no adverse effects at all.

"These devices not only repaired my defect, saved me the trauma of open-heart surgery along with a lengthy recuperation but also enabled me to return to work within just a few days.

I'm contributing my views in the hope it will have a positive effective on the vote for approval for these devices so they will become available to all those cardiac patients out there who are in need." The other seven letters were in support in a similar fashion.

If there are no other comments, then we'll close the open public hearing and move on to the sponsor's presentation.

DR. TRACY: Before you start, I would just like to remind you to introduce yourselves and state any conflict of interest.

MR. GOUGEON: Members of the panel, members of the FDA, ladies and gentlemen, good morning. My name is Franck Gougeon. I'm the Executive Vice President of AGA Medical Corporation who is the sponsor of this study. I am also one of the founding officers.

It is my pleasure to read out the presentation of the transcatheter closure of secundum atrial septal defect using the Amplatzer Septal Occluder.

We have brought with us three cardiologists who conducted a clinical trial. They include Dr. Ziyad Hijazi of the University of Chicago Children's Hospital in Chicago, Dr. John Cheatham of the Nemours Cardiac Center in Orlando, and Dr. John Moore of St. Christopher's Hospital for Children in Philadelphia.

They will present the study clinical results and be available for your questions.

In addition, there are a number of people here who provide a cross-function representation involved in the clinical trial or the development of the Amplatzer system.

Among them Mr. Ken Lock who managed the study will act as the moderator for questions raised by the panel.

Following my brief introduction, Dr. John Cheatham will provide a study for background evade detorsion. Dr. Hijazi will provide a summary of the study. Dr. Moore will cover the fenestrated Fontan arm of the study. Finally, Dr. Hijazi will conclude with a summary of revised performance in both indications.

We are seeking approval for two indications today. The first covers the transcatheter closure atrial septal defect in secundum position. The second concerned the closure fenestrations post-Fontan operation. And Amplatzer Septal Occluders in sizes ranges from 4 to 38 mm needed to cover both indications.

AGA Medical is a sponsor of this study. This is a privately held operation located in Minneapolis, Minnesota. The company was founded in 1995 and currently employs 55 full-time employees.

The facility consist of 35,000 square feet most of which is dedicated to manufacturing. The last stages of application are done in 10,000 cleaning rooms. Sterilization is assured by a local contractor.

The Amplatzer Septal Occluder is manufactured onsite. The device is a self-expanding, self-centering, double-disc device made from 4,000 to 8,000 nitinol wires.

The two discs are linked together by short-connecting waist corresponding to the thickness of the atrial septal. Sizes range from 4 to 48 mm. These dimensions are based on the center portion of the occluder as the device is designed to stunt the defect.

Polyester patches are sown in both disc and the waist to induce some urgency. In addition, the left atrial disc is slightly angled toward the other disc to provide firm and secure contact between the device and the muscular atrial septum rim. We believe this is an important feature to ensure proper endothelialization of the implant.

For introduction, the prothesis is attached to a stainless steel delivery cable using a microscrew and pulled into a loader. It is then pushed through a six to 12 French introducer sheath and placed across the atrial septal defect.

It relies exclusively on the super elastic properties of the nickel-titanium alloy, a part existing in the tip of the introducer sheath. The left-atrial disc immediately resumes it original shape. The sheath is pulled back to take advantage of the self-center capability of the connecting waist. The implant is pulled gently against the EFD and the right-atrial disc is released to a sandwich effect.

The Amplatzer Septal Occluder study was initiated in May of 1997 as a randomized clinical trial comparing the results of the device with those in open-heart surgery which currently is a gold standard in the United States for repair of atrial septal defects. We refer to this as a Phase IIA of the clinical trial.

However, due to a high fallout rate in the surgical arm of the study, the surgical device panel organized by AGA was held in October 1997 at which time a non randomized prospective clinical trial comparing the device with surgery was deemed clear.

It was also decided that the device patients already enrolled in a trial under the randomized study where a known appropriate to comparison between the two groups.

An investigation plan was modified accordingly and the study resumed in March 1998. We refer to this as Phase IIB of that clinical trial which is the basis for the analysis being presented today. This phase is highlighted in yellow on this slide.

Further modification to the investigational plan, the authorization October 1998 for device centers to capture the prospectively surgical patient as well as device patients and because of slow enrollment in surgical cohort the authorization in January 1999 to capture data retrospectively on patients who underwent surgical repair.

Furthermore, an extension was granted to AGA Medical to continue enrolling patients in the device group was a number of surgical patients needed for the PMA analysis could be reached.

The study was completed in May of 2000 with a total of 459 device patients and a surgical cohort of 155 patients. Although only 110 patients in each group are needed for the analysis, the FDA requested that all device patients be included for comparison between the two groups. We will, therefore, report today on this entire pool of patients.

Finally, I would like to add that from June 2000 to May 2001 an additional 465 patients had been treated with this device and the continued access protocol D96-1. Although we are not reporting on this additional pool of patients today, AGA Medical is not aware of any issues that risk the safety and efficacy of the Amplatzer Septal Occluder.

With that, I would like to introduce Dr. John Cheatham who will give you an overview of the history of ASD closure.

DR. CHEATHAM: Thank you. I'm Dr. John Cheatham, Director of Cardiac Catheterizations and Interventions at the Nemours Cardiac Center located in Arnold Palmer Hospital, Children's Heart Institute in Orlando, Florida. I'm one of the principal investigators. I have no financial interest in AGA Medical. My travel expenses are being reimbursed by the company.

The first clinical question that comes to mind is why close an atrial septal defect. Most patients with a hemodynamically significant ASD are asystematic during the first decade of life. However, by 20 years of age, 50 percent will complain of exertional dyspnea from chronic right intricular volume overload and virtually all, or 90 percent, will have symptoms by 60 years.

If uncorrected until after 50 years of age, a 75 percent mortality can be expected. Another complication of unrepaired atrial septal defect is high rate of atrial flutter and fibrillation with increasing age. However, if correction of the defect at an appropriate age occurs, then congestive heart failure, pulmonary hypertension, thromboembolic events, and atrial arrhythmias may be avoided.

Since the development of cardiopulmonary bypass circuit in the 1950s, surgical repair of atrial septal defect has been possible and is considered the gold standard of therapy. However, this invasive treatment requires a median sternotomy or thoracotomy, exposure to cardiopulmonary bypass, aortic cross-clamp with resulting myocardial ischemia and a right atriotomy.

It also requires a blood transfusion during or after repair of the defect or, at the very least, results in delusional anemia. The repair usually involves either primary suture or patch closure. Surgery is typically performed after two to three years of age, but in selected individuals may be required at an earlier age.

Open-heart surgical correction of ASD usually requires three to five days of hospitalization with a convalescent period of four to six weeks where school and/or work days may be missed.

There are several possible advances of percutaneous transcatheter closure of atrial septal defect compared to conventional surgical repair. Pain and discomfort may be minimized while an incisional scar is eliminated. There's no exposure to cardiopulmonary bypass and the procedure is unlikely to require blood or blood product transfusion or result in delusional anemia.

There should be an expected reduction in hospital stay and rapid return to normal activities including school and work. Finally, this less invasive procedure may result in cost savings.

The history of percutaneous transcatheter closure of atrial septal defect actually began over 25 years ago with King and Mills' first description of success. However, it was a decade later before FDA sponsored clinical trials were initiated in the United States.

Over the ensuing 15 years various device designs, materials, and delivery techniques were tested. However, there were problems associated with some of the early devices. Initially the delivery sheath was as large as 24 French but later was reduced to 11 to 14 French, hardly small by today's standards.

Some of the designs required hooks to secure the device or were configured as a square umbrella which lead to difficult delivery and/or implant. There was a high residual shunt rate associated with some devices which has been linked to poor self-centering capabilities.

Structural flaws resulting in a high percentage of metal frame fatigue fractures or "unbuttoning" of the device also occurred. Finally, virtually all of the early ASD devices were extremely difficult, if not impossible, to reposition and/or to retrieve during implantation.

When defining the characteristics of an ideal device for transcatheter closure of ASD, there are several important features. First, a device and delivery system must be user friendly with simply mechanics. The delivery system should be small in order to treat infants and young children without causing vascular compromise. There must be an effective and high rate of complete closure of the defect which requires self-centering properties.

The occluder should be able to close most atrial septal defects regardless of defect size. The device must be extremely easy to reposition and/or to retrieve to ensure safety and efficacy.

In the rare occurrence of device embolization, preservation of flow and cardiac function must be maintained. The device should be durable while endothelialization occurs and there should be a lack of ongoing morbidity during follow-up.

Finally, the device should be economical. The Amplatzer Septal Occluder and delivery system meet these criteria set forth in the ideal device.

If it's possible, could we dim the lights. I think this is going to be a short movie. This short movie was filmed during a live-case demonstration during one of the recent PIC symposium. The patient and the family has given their permission for this demonstration to the panel today as well as use of their names.

Amplatzer Septal Occluder and the delivery system will be demonstrated. This is an animation of the percutaneous entry into the femoral vein where the sheath is passed into the infera vena cava through the right atrium and the atrial septal defect into the left atrium.

The left atrial disc is deplored on the left side of the atria septum and the entire system brought back toward the atrial septal defect with the middle waist stenting the ASD and the right atrial disc redeployed. The device is then released with the sheath removal.

Over a period of time complete endothelialization occurs. It's very important that the positioned echocardiographer and the operator complete the review of the transesophageal echocardiogram prior to beginning the procedure.

This is an example of a multi-plane transesophageal echocardiogram on a patient with a large isolated secundum ASD demonstrating the septal rims as well as the isolated defect.

It's very important to identify all of these structures at the time of preimplant. Ordagonal views demonstrate an ASD size of 28 to 23 mm in this particular patient.

The AP camera is angled in an LAO cranial position in order to profile the atrial septum leaving plenty of room for the anesthesiologist and the echocardiographer to perform their duties during the procedure.

The operator will typically perform a hemodynamic study initially along with angiography to demonstrate the atrial septal defect. In this particular instance, a right pulmonary vein injection will demonstrate the secundum ASD.

After the angiogram has been performed, an in-hole catheter is then delivered across the atrial septal defect into the left upper pulmonary vein where an exchange guidewire is placed. Over the exchange guidewire a sizing balloon is then placed and positioned across the atrial septal defect.

It's at this point that we determine that the balloon stretch diameter of the defect. The balloon is inflated until there is no further flow across the defect and the diameter of the balloon on transesophageal echocardiogram, as well as on the corresponding fluoroscopic image here are measured.

At this point the appropriate size Amplatzer Septal Occluder is chosen with the middle waist equal to or slighter greater than the balloon stretch diameter. The device is then loaded on the delivery cable using the microscrew technique and then the entire loading system is submerged under saline in order to avoid any introduction of air into the loading sheath.

The short loading sheath is then attached to the long delivery sheath using a lure lock mechanism and the delivery cable advanced. This is the sheath in the left atrium near the left atrial appendage.

One can see under transesophageal echocardiographic guidance the deployment of left atrial disc in this particular patient. One can even see the polyester patch material as well.

The corresponding angiographic appearance or fluoroscopic appearance demonstrates the left atrial deployment of the disc, the middle waist being expanded and the entire system brought into the ASD to stent the ASD with the right atrial disc formed. This is the same process on the transesophageal echocardiogram with release of the device.

One can see the left atrial disc, the right atrial disc, and the middle waist at appropriate position. At this time Doppler flow is also interrogated demonstrating proper function of both AV valves as well as small flow in the device material itself.

A right atrial angiogram is performed and in levo phase typically one may see a little bit of smoke material going through the device while the patient is fully heparinized.

The patient is typically either moved to a separate holding room or, actually more commonly, extubated in the cath lab. With 30 minutes to 60 minutes is fully awake and taking PL fluids and will be discharged usually approximately 24 hours later.

This is a follow-up transesophageal echocardiogram on this particular patient six months later. One can see there is complete closure of the defect. In addition, there is normal flow through mitral and tricuspid valve.

It's also important to demonstrate at this point in time some of the memory characteristics of nitinol. That is, after six months you can see the lower profile pre-implant configuration resumed.

Next I would like to introduce my colleague, Dr. Ziyad Hijazi, to discuss the study data.

DR. HIJAZI: Good morning. My name is Ziyad Hijazi. I am Professor of Pediatrics and Medicine at the University of Chicago and Chief of Section of Pediatric Cardiology. I have no financial interest in AGA Medical. My trip here is being sponsored by AGA Medical.

My task over the next 15 minutes or so is to share with you the results of catheter closure for secundum ASD using the Amplatzer Septal Occluder and comparing those results with open-heart surgery.

Let me give you a little detail about the study organization. We had an independent statistician to analyze the data of the trial. We had an independent echocardiography core lab consisting of two experienced pediatric cardiac echocardiographers to evaluate the results. We had an independent data safety monitoring board to review all complications and adverse events.

Before we proceed, it is important for me to go over certain definitions that are important in this trial. Intent to treat is defined as patient who consented, however a device was not introduced into the patient. Technical success is defined as successful deployment of the device.

Procedural success is technical success with no significant residual shunt. Significant residual shunt is being defined as any residual shunt measuring in diameter more than 2 mm as measured by color Doppler echocardiography.

Primary efficacy success is defined as technical success with no significant residual shunt measured at the 12-month follow-up. Composite success is defined as all attempted patients without a major complication, embolization, technical failure, or significant shunt measuring more than 2 mm.

The efficacy endpoint of the trial is to compare the closure rate at 12 months between the two arms of the study, the device closure versus surgical closure. The definition of successful closure is being defined as any patient who underwent the closure, device or surgery, with complete trivial or small residual shunt as assist by color Doppler echocardiography.

A fair disclosure is defined as any patient who underwent a closure, again device or surgery, with more than small residual shunt meaning moderate or large as defined by color Doppler echocardiography. The residual shunt was studied by color Doppler echocardiography and the degree of shunt was graded into trivial, small, moderate, or large according to the width of the color jet at its exit from the atrial septum. This classification was reported in the journal Circulation by Boutin and her colleagues from the Hospital for Sick Children in Toronto in 1993.

So demonstrate that the device success is as good as surgery, we have to show that the primary efficacy success rate of the device must be shown to be within 8 percent of the primary success rate of surgery. Therefore, in simple terms, the acceptable critical difference should be within 8 percent.

To demonstrate safety of the device, we set acceptable rates of untoward aversive and for death and major complications to be less than or equal to 2 percent for death and to be less than or equal to 10 percent for major complications.

Let me go over the included and excluded criteria in our protocol. The inclusion criteria for the device group included any patient with secundum atrial septal defect measuring less than or equal to 38 mm in diameter with significant left-to-right shunt as evidenced by either measurement of Qp/Qs more than or equal to 1.5 to 1, or as evidenced by right intricular volume overload by echocardiography.

Also included patients with a clinical symptom such as paradoxical embolism or atrial dysrhythmia in the presence of a minimal shunt. A distance of more than 5 mm from the margins of the defects to the coronary sinus, AV valves, and the right upper lobe pulmonary vein was also included.

For the surgical group the inclusion criteria were similar to those of the device group with the exception of the size of the ASD being that there is no size limit for ASD, and no size limits for the rims if they're different.

This list, the exclusion criteria for the device patients, you have all of them in the package. There is no need for me to go over them. This slide also list the general exclusion criteria for both groups which are listed there. Again, I will not go over it in detail.

This slide again lists the exclusion criteria for the surgical patients. Again, they are similar to those of device exclusion criteria.

Now, let me go over our patient statement. 459 patients were enrolled in the device arm and 155 in the surgical arm. Of the 459 device patients 17 were enrolled but did not receive a device, what we call they consented but they did not receive a device.

hey were found not to be appropriate for device closure. We will talk about them in the following slide.

One patient consented to undergo surgical closure but was found not to be eligible for open-heart surgery. Therefore, 442 patients underwent an attempt at device closure in the cath lab and 154 patients underwent surgical closure.

Of the 17 patients labeled "intent to treat," six did not meet the inclusion criteria. Eight has an ASD which was too large for the device available at the time and five of them had ordeal conditions the operators felt uncomfortable to attempt device closure.

Let me go back to the eight patients. The eight patients who had an ASD larger than the available device at that time opted to wait for the proper size device to be available. Therefore, three of them underwent a second attempt with successful closure. Again, the third patient was found to have an ASD larger than the available device at that time. That patient opted to undergo open surgical repair.

This slide compares the two groups demographics. Both groups had similar percentage of females. However, as you can see, the surgical group was younger in age. Therefore, any factor associated with age, for example weight and height, was also different in both groups.

Also on this slide some age-related factors were different. For example, failure to thrive and respiratory infections were more common in this surgical group. Since our device group was somewhat older, these patients had more hypertension and stroke.

However, by echocardiography the size of the atrial septal defect in the two groups was similar, a mean of 13.3 mm for the device group and 14.2 mm for the surgical group.

Furthermore, the percentage of patients with right intricular volume overload was similar in both the groups. 94.1 percent of the device group compared to 96.1 percent of the surgical group had right intricular volume overload.

Now, let us talk about technical success for the procedure which is defined as successful deployment of the device or successful completion of the surgical procedure. Out of 442 patients who had an attempt at device deployment, 423 patients had a successful procedure. Therefore, the technical success rate is 95.7 percent, or surgical patients who underwent surgery had technical success.

Now, let us analyze those patients who failed a device procedure which is defined as any patient who had the device inserted but the device was recaptured or embolized and the procedure was aborted. Nineteen of 442 patients had a failed attempt.

Of those 19, 17 patients had medical conditions that the operator did not feel comfortable releasing the device. In one patient, however, the device embolized. In another patient the marker band of the delivery system embolized.

Now, let me talk about the marker band. The delivery sheath initially had a platinum marker band at the tip of the sheath to ease visualization of the sheath by fluoroscopy. This band became dislodged from the sheath and embolized. Therefore, after three incidents the manufacturing company removed this band of the sheath.

Of the 423 patients who had technically successful procedure, 413 had successful procedure. A successful procedure is defined as any patient who received a device or surgical closure with less than or equal to 2 mm residual shunt by color Doppler echocardiography. Therefore, 97.6 percent of device patients had a successful procedure compared to 100 percent of the surgical patients.

Now, let us analyze the efficacy results. Again, the definition of primary efficacy result is that no significant residual shunt measuring more than 2 mm by color Doppler echocardiography at the 12-month follow-up visit. Twelve-month data was available in 331 device patients. 336 of them had successful closure giving a rate of 98.5 percent compared to 100 percent of the surgical patients.

The p-value is .033 with a 90 percent confidence interval of -.052 to +0.017. Therefore, the lower band of the confidence interval is less than 8 percent critical difference agreed upon as mentioned earlier.

This is another way of looking into success. Surgical patients are represented by the blue diamonds and device patients by the red squares. As can be seen over time, the success of device is very close to that of open-heart surgery.

At all points of follow-up the difference was not significant between the two arms. Although we had 100 percent successful closure for the surgical group, I would like to point out that seven surgical patients had residual shunt. However, this residual shunt was less than 2 mm in diameter.

Let me talk about the echo board. This consisted of two independent experienced pediatric echocardiographers from centers that were not involved in the trial. Those two physicians do not have any financial interest in AGA Medical. They only receive consultation fees.

They viewed a subset of the 12-month echocardiograms from both arms for this study. They concurred with the interpretations of the investigators.

Now, let us examine the safety results of the device and compare it to that of open-heart surgery. A data safety monitoring board was formed to assist safety of the procedures. Members were physicians with specialties in echocardiography, electrophysiology, cardio-thoracic surgery, and a statistician.

These members were not participants in the study and had no financial interest in the AGA Medical. They met independently to develop definitions and to adjudicate all adverse events.

These members developed the following definitions for major complications. Events that are life threatening, prolong hospitalization, or have long-term consequences or need for ongoing therapy. These include, but are not limited to, cerebral embolism, endocarditis, pericardial effusion with tamponade, repeat surgery, and death, which were listed in the protocol.

Additionally, cardiac arrhythmias requiring permanent pacemaker placement or long-term anti-arrhythmic medication and device embolization requiring immediate surgical removal, are also included as major complications.

They also developed the following definitions for minor complications. The device embolization with percutaneous retrieval, cardiac arrhythmia with treatment, phrenic nerve injury, hematoma, other vascular access site complications, retroperitoneal hematoma, surgical would complications, and other procedural complications, as listed in the protocol.

Additionally, pericardial effusion requiring medical management evidence of device associated thrombus formation without embolization (with or without treatment) and marker band embolization without known sequelae are included as minor complications.

This slide, compares the rates of major and minor complications between the two groups. 1.6 percent of the device group patients encountered major complications compared to 5.2 percent for the surgical control patients.

At 6.1 percent of the device patients had minor complications compared to 18.8 percent for the surgical group. Therefore, the overall rate of complications was 7.2 percent for the device group compared to 24 percent for the surgical control group. This difference was significant.

This is another way of looking at rate of any complication between the two groups at anytime the difference in the rate of any complication between the two groups was statistically significant favoring less complications for the device group.

This slide sort of describes all major complications encountered in both groups. Again, the total major complication rate was 1.6 percent for the device group compared to 5.2 percent for the surgical group.

This is a busy slide but the slide describes the amount of complications for both groups. Again, the rate for the device group was significantly lower than that of the surgical group.

The FDA required a 12-month composite success which is defined as all attempted patients without a major complication, embolization, technical failure, or significant residual shunt measuring more than 2 mm by color Doppler echocardiography at anytime during this study. Patients could only fail one time and were not allowed to revert to a success over time.

Therefore, this table demonstrates the 12-month composite success of 85.9 percent for the device group. However, if those cases of significant residual shunt encountered immediately after the closure and the shunt disappeared at the 12-month follow-up, which is demonstrated in 20 out of 25 patients, they are allowed to revert. This would result in a 12-month composite success of 91.4 percent which is not significantly different from that of the surgical control group.

Now, let us evaluate the clinical utility of the Amplatzer device. The procedure time and length of hospital stay for the Amplatzer closure were significantly shorter than that of open-heart surgery. Procedure time was measured for the device group from the insertion of the venous sheath to the removal and for the surgical group from the skin incision to skin closure.

Therefore, to summarize our efficacy and safety results, the device successfully at 12 months is 98.5 percent which is equivalent to surgery. This meets the protocol requirement for establishing equivalence since the lower 95 percent confidence-bound is 0.052 which is less than the 8 percent better agreed upon with the FDA.

The device major complication rate of 1.6 percent is lower than the maximum protocol specified rate of 10 percent. The overall complication rate for the device of 7.2 percent is significantly less than for the surgical control of 24 percent. There were no device related deaths and the device group had significantly lower procedure time and shorter hospital stay.

Therefore, ladies and gentleman, I would like to conclude that the Amplatzer Septal Occluder offers a safe, effective and less invasive treatment for closure of secundum atrial septal defects.

Now, it is my pleasure to introduce my colleague Dr. John Moore to share with you the results of the Fontan fenestrations. Thank you.

MR. MOORE: Good morning. My name is John Moore. I'm Director of Cardiology at St. Christopher's Hospital for Children in Philadelphia and Professor of Pediatrics at MCP Heiman University.

I have no financial interest in the device. My expenses have been paid by AGA Medical Corporation.

I'm going to present to you the data regarding Amplatzer Septal Occluder closure fenestrated Fontan procedures.

A little background is in order because this is a little different type of indication. The incidence of all types of single ventricle heart disease, congenital heart disease, is as high as 10 percent. It includes a number of complicated diagnoses such as hypoplastic left heart syndrome which is the most common in that group.

The modified or fenestrated Fontan procedure is a relatively recent introduction in the surgical area which has improved the prognosis of this whole patient group dramatically and has at this point become a standard palliation procedure.

The cartoon on the right demonstrates a patient who has hypoplastic left heart syndrome with essentially absence of left ventricle and one large ventricle which is a right ventricle. This patient has had a modified or fenestrated Fontan procedure, but that is actually the third procedure that was performed.

This third and final operative stage involves completion of a systemic venous baffle here shown in blue which directs "blue" blood into the pulmonary circulation directly without the benefit of a ventricular pump.

The fenestration here shown in purple is a punch opening in the lateral baffle which provides a vent and essentially a right-to-left shunt.

The aims of the fenestrated Fontan procedure are first to separate pulmonary and systemic circulations thereby increasing blood oxygen and reducing cardiac work. The fenestration reduces the Fontan operative risk because vented or shunted blood augments cardiac output and reduces central venous pressure.

However, after the relatively early post-operative period a fenestration may actually become dysfunctional. As I mentioned, there is a right-to-left shunt which may become a significant cause of cyanosis. In addition, there is the ongoing risk of paradoxical embolus through fenestration and stroke.

Therefore, it is often appropriate to perform closure of the fenestration. There are essentially two options for closure, the first being a fourth open-heart surgical procedure.

This procedure would generally follow a diagnostic catheterization demonstrating that it was safe and appropriate to close the fenestration surgically. The operative approach requires, first, a catheterization and then a fourth redo operation. The other procedure available is percutaneous device closure.

Percutaneous device closure may involve the use of general anesthesia and transesophageal echocardiography much as ASD closure does. The hemodynamics performed include a test fenestration in which the fenestration is balloon occluded not to size it specifically but to determine the effect of occlusion on central venous pressure and cardiac output.

Balloon sizing may also be performed in addition or at the same time as test occlusion. In addition, rim assessment is required. Device implant proceeds exactly as described by Dr. Cheatham in the first presentation.

We have a short movie here that demonstrates a Fontan procedure first. This is the baffle and I'll run the movie and show it to you. If you look right here, this is the fenestration shunting blood from the systemic venous circuit into the pulmonary venous circuit directly without passing through the loans.

This is the deployment of the device. First, the pulmonary venous disc is formed, the waist is formed, and the systemic venous disc is formed. The device is released and a follow-up angiogram shows the fenestration to be completely closed.

The study organization for this portion of the study was only slightly different. It was a single arm registry meaning that there was no surgical control group. It was also multi-center. The same independent data safety monitoring board was used to adjudicate adverse events and the same independent statistician provided statistical services for the site.

The efficacy endpoint was identical as described by Dr. Hijazi. A successful closure of the fenestration at 12 months involved less than a 2 mm shunt observed by transesophageal echocardiography at one year. The same grading system was employed.

The safety criteria was also identical. Safety for the device was defined as a death rate less than or equal to 2 percent in a major complication rate less than or equal to 10 percent.

There were a few additional inclusion criteria. Obviously the patient had to have a fenestrated Fontan procedure. The opening in the baffle had to be at least five millimeters from the free atrial wall, essentially a rim requirement.

Finally, the central venous pressure had to be less than 15 mm of mercury during test balloon inclusion in the early hemodynamic evaluation part of the catheterization.

Exclusion criteria included if there was insufficient rim, if there was an ongoing acute infection, or inability to obtain informed consent.

Demographics of this patient group were slightly different than the ASD device patients. These patients were slightly younger, mean age 7.8 years. There was a predominance of male, 60 percent, as opposed to females 40 percent which is just the inverse of the ASD group.

As far as medical history goes, there were a few positives, congestive heart failure one patient, failure to thrive one patient, and stroke. Documented stroke had occurred already in two patients.

The transesophageal echocardiographic fenestration characterization showed that the average fenestration measured 4.2 mm in diameter by transesophageal echo.

This summarizes the patients enrolled in this registry. There were a total of 51 patients enrolled. Three patients were intent to treat patients meaning they were enrolled. They underwent catheterization but no attempt was made to place the device.

Of the 48 attempted patients there were two technical failures and 46 technical successes in which devices were placed. At one-year follow-up 32 patients evaluated showed 100 percent meeting the primary efficacy criteria. There were no failures at that point.

Intention to treat patients, one failed the inclusion criteria with insufficient rim, if you will. Two had anatomical conditions resulting in inability or lack of desire of the operator to place the device. One was multiple small fenestrations. It was not feasible to close these with the Amplatzer device. The other was a patient who had a damaged and malfunctioning prosthetic valve who was definitely going to require surgery and it seemed inappropriate, therefore, to place the device in that patient.

Technical failures were two. Both of these were related to fenestrations which were too small to place the delivery sheet and, therefore, a device could not, and probably should not have been placed.

As I mentioned, the primary efficacy criteria indicated successful closure at one year. Thirty-two patients evaluated at that point met the primary efficacy criteria and were successful.

Safety results are summarized on this slide. In the group there were two major complications or 4.2 percent. One complication was a hemothorax which was related to vascular access site complications in the subclavian vein.

The other complication was damage to a tricuspid valve due to deployment or partial deployment of the device near and within the valve. This patient had to have surgery or tricuspid valve repair.

Two minor complications. One patient had a long hospital stay of one day additional because of nausea and vomiting. The other patient had an atrial arrythmia requiring cardioversion for a total of four complications in this group.

Clinical utility data. The procedure time is fairly long, as you can see, but this is because these patients, as I mentioned, require a fairly extensive hemodynamic evaluation prior to device placement. In addition, many of them undergo additional interventional procedures such as transcatheter stent placement at the time of this catheterization.

In fact, the placement of the device requires a very small percentage of this procedure time and this fluoroscopy time.

More importantly, the hospital stay of these patients is very, very short. You can see they average 1.2 days and we don't have a surgical control group but I think that speaks for itself.

Clinically utility of the Amplatzer device then is that it avoids morbidity and risk of repeat open-heart surgery and that the hospital stay is very short.

Finally, the summary of the safety and efficacy of Amplatzer closure of the fenestrated Fontan. We have a primary efficacy outcome at 12 months of 100 percent. Major complication rate 4.2 percent is within protocol defined limits of less than or equal to 10 percent.

There were no device related deaths. These results are consistent with those obtained for transcatheter closures of secundum ASD by the Amplatzer Septal Occluder device.

In conclusion, the data demonstrates that the Amplatzer Septal Occluder offers a safe, effective, and less invasive treatment for closure of Fontan fenestration.

Finally, I would like to reintroduce Dr. Hijazi who will summarize our presentation.

DR. HIJAZI: Thank you. Good morning again. My name is Ziyad Hijazi. The sponsor of this study has worked with the FDA and the circulatory panel to conduct a sound clinical trial to assist the safety and effectiveness of the Amplatzer Septal Occluder for two indications; secundum ASD closure and Fontan fenestration closure.

The clinical study results meet the endpoints of safety defined in the protocol. Furthermore, in the secundum ASD arm of the trial, the device group had significantly lower complication rates than the surgical control group.

The clinical study results meet the endpoint for efficacy defined in the protocol. The secundum ASD group had the success rate of 98.5 percent in 20 years which is statistically equivalent to the surgical control group. Also, the Fontan fenestrations group had a success rate of 100 percent.

The clinical utility of the device group demonstrated a significantly shorter procedure time and shorter hospital stay than the surgical control group.

It is my pleasure to share with you my own personal experience with the device. To date I have done over 420 closures with the Amplatzer Septal Occluder. About 220 in the United States and the remainder abroad.

In 10 cases I could not implant the device. These patients underwent surgical closure. Four patients had device embolization with successful retrieval in the cath lab in three patients and subsequent device implantation.

The fourth patient required surgical treatment and at the same time the surgeon closed the ASD. Therefore, 409 patients had successful implantation. All but two had successful closure of their defects.

In conclusion, the Amplatzer Septal Occluder is safe and effective for closure of secundum ASD and Fontan fenestrations. Thank you for your attention.

DR. TRACY: Thank you very much. At this point I'll ask the FDA to present their findings.

MS. BUCKLEY: 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 Septal Occlusion, or ASO device submission, PMA No. P000039.

Today Dr. Stuhlmuller, the medical officer of this submission, and I will present the FDA summary for the Amplatzer ASO submission. This device is a transcatheter septal defect closure device used in the treatment of atrial septal defects and fenestrated Fontans.

You'll be asked to discussion 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.

The FDA summary will provide a brief overview of the following: the FDA review team, device description, nonclinical evaluation, clinical evaluation, and questions to the panel.

Members of the FDA review team include myself, 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 a statistical reviewer, and Ms. Liliane Brown from the Office of Compliance who coordinated FDA inspection of the investigational sites.

The ASO Occluder is a double-disc design with a connecting waist. It is made from a nitinol wire mesh with polyester material stitched into the discs. The left atrial disc is larger than the right atrial disc.

There are 26 sizes 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.

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.

In vitro or bench testing is outlined in Section 1.4 of the FDA Summary in your Panel Pack. It was performed to evaluate the mechanical integrity of the ASO system.

Biocompatibility testing of the device components was conducted in accordance with ISO Standard 10993. 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.

Dr. Stuhlmuller will now summarize the clinical evaluation of the device.

DR. STUHMULLER: 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.

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 is for closure of fenestrations following Fontan procedures.

Information has been provided for five different clinical data sets of part of the PMA. Information on the pivotal data sets has been provided in the Panel Packs.

First is the pivotal data set from the Phase IIB registry for atrial septal defect closure. A total of 459 patient 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.

The device patients were enrolled in a non-randomized open-label, multi-center registry. The surgical control patients were also enrolled in a non-randomized open-label, multi-center registry.

Surgical patients were prospectively and retrospectively identified. All patients completed a prospective one-year follow-up.

Patient outcome assessment was made using a composite clinical endpoint termed Composite Clinical Success at 12 months. The intent of this endpoint was to evaluate safety and effectiveness at 12 months. That was residual shunt rate at 12 months. It was not intended to incorporate all residual shunts prior to 12 months.

The individual clinical endpoints incorporated into assessing a 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.

Technical success defined as device deployment or completion of surgery was seen in 423 to 442 device patients and 154 of 154 surgical patients. Procedure success defined as a residual shunt less than 2 mm in patients who were technical successes was seen in 413 of 423 device patients and 154 of 154 surgical patients.

Six-month closure defined as residual shunt of less than or equal to 2 mm in patients who were technical successes was seen in 376 of 387 device patients and 154 of 154 surgical patients.

Twelve-month closure defined as residual shunt less than or equal to 2 mm in patients who were technical successes was seen in 326 of 331 device patients and 149 of 149 surgical patients.

Twelve-month composite success defined as all patients attempted without major complications, embolization, technical failure, and presence of a significant residual shunt was seen in 311 and 362 device patients and 146 of 154 surgical patients.

Major complications were seen in seven of 442 device patients and eight of 154 surgical patients. Minor complications were seen in 27 and 442 device patients and 29 of 154 surgical patients. Overall, 32 of 442 device patients experienced a complication and 37 of 154 surgical patients experienced a complication.

The pivotal cohort for closure of fenestrations following Fontan procedures were enrolled in a prospective open-label, single-arm registry without a control group.

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

Occluders were implanted in 46 of 48 attempted patients. Successful closure was demonstrated in 32 of 32 patients evaluated at 12 months.

Adverse events were evaluated in the 48 patients in which device placement was attempted. A total of four adverse events were seen. Two major and two minor adverse events were seen.

Next will be the panel questions presented by Donna Buckley.

MS. BUCKLEY: 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.

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?

Question 1b. The sponsor is seeking approval for device sizes from 4 mm to 38 mm. Approximately 89 percent 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 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.

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.

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.

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

Question 4a. Please comment on the INDICATIONS FOR USE section as to whether it identifies the appropriate patient populations for treatment with this device.

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.

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.

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.

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.

The Panel Package includes the available one-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? Thank you.

DR. TRACY: Thank you very much.

At this point we'll begin the open committee discussion and I'm going to ask Dr. Robert Williams who was the lead reviewer to begin with her questions for the sponsor and then we'll go around the rest of the panel after she's completed.

DR. WILLIAMS: I just have a few questions to start. I was wondering in looking at the patients at the first evaluation after implantation, what do you believe is the sensitivity to thrombi that would be associated with the surface on either the right or the left atrial surface of the device?

MR. LOCK: My name is Ken Lock and I'm the clinical programs manager AGA Medical. I'm an employee of AGA Medical. I will have Dr. Hijazi answer this question.

DR. HIJAZI: I think in our patients, especially being a trial done under the FDA auspices, we have been extremely vigilant looking at any patient's echocardiogram in the post-implantation period and the follow-ups. One of the things that we look very clearly at is the presence of formation of thrombosis.

Clearly we have not seen any reported incidence of thrombosis and that goes with the clinical data that none of our patients had TIAs or strokes. I think echocardiography is pretty sensitive to detect small clots. Maybe less than 1 mm maybe not but I think the important thing is the clinical outcome of these patients.

DR. WILLIAMS: And I saw in one place where TEE was recommended as an aid an another place where it was required. In your current indications is it a required part of the procedure or just recommended?

DR. HIJAZI: This is Ziyad Hijazi again. I think it is required. It's a must. TEE is required for device implantation. The other thing that we may be adding also giving the operator an option is the intracardiac echo if it's available. Either transesophageal echo or intracardiac echo should be required prior to device implantation.

DR. WILLIAMS: Okay. Another question was the indications prohibiting strenuous activity. Is it for one month or six months now?

MR. LOCK: This is Ken Lock. We are recommending one month.

DR. WILLIAMS: One month. And, finally, there was an indication of phrenic nerve injury. I'm sorry. Was that in the device group or in the surgery group?

MR. LOCK: This is Ken Lock. I'll have to check to make sure. I'm pretty sure it was in the device group but I'll check on that.

DR. WILLIAMS: What was the theory about how that might have occurred?

MR. LOCK: I'll have to get details on that and answer it later.

DR. WILLIAMS: It's a minor question. Those are my questions for the moment. I reserve the right to be stimulated by the other members of the panel.

DR. TRACY: Okay. Thank you.

Dr. White.

DR. WHITE: Thank you. My name is Chris White. I'm an adult cardiologist, interventional cardiologist.

I guess my question, No. 1, revolves around the nitinol composition and the nickel. There is nowhere I saw about any concern about nickel allergy. We know that's prevalent among the population. Do you have concerns about what a nickel allergic patient will do with this device?

MR. LOCK: This is Ken Lock. I will have Dr. Hijazi respond to that question.

DR. HIJAZI: Obviously the nitinol, as we all know, is an alloy from nickel and titanium. As Dr. White mentioned, a large percentage of people have nickel allergy.

As a matter of fact, two of the patients in the trial have documented nickel allergy and they came to me and I knew they had nickel allergy. I told them, "Your option is either to take the risk or have open-heart surgery." The opted to take the risk and we implanted the devices in both patients and one of them is now two and a half years follow-up and the other one is one year and no clinical findings at all. I do not think implanting the device inside the vascular system is similar to the contact manifestations of nickel allergy that is prevalent in the general population.

DR. WHITE: I also wanted you to comment on the fact that only three-quarters of your patients have been followed at one year for the primary efficacy. Did I miss that number? 331?

MR. LOCK: That is correct. This is Ken Lock. 331 of the patients available for a one-year visit.

DR. WHITE: Why did you pick a primary efficacy endpoint which was incomplete by the time you present the data? I mean, why would you pick one year's data as being your primary efficacy and then bring us an incomplete data set?

MR. LOCK: This is Ken Lock. The original protocol required analysis to look at 110 patients from each group so in talking with the FDA they requested that we include all patients that we had available to follow up on and that's why we have the 331 patients.

DR. WHITE: Okay. Let me get this straight. You met the number at one year for follow-up of 110 and then you continued to enroll patients so those have not been completely followed yet?

MR. LOCK: That's correct.

DR. WHITE: In the protocol there was concern about implanting the device in presumably older patients who had had heart failure decompensated left ventricular failure, recent MIs. Will that also be part of the contraindication package? How will you deal with an assessment of LV function before the ASD closure?

MR. LOCK: This is Ken Lock. I'll let Dr. Hijazi answer this question.

DR. HIJAZI: Ziyad Hijazi. As we are all clinicians, I do believe that these patients if they are managed well and if they are not dying, I don't think implantation of the device should be a problem in these patients.

As a matter of fact, it may be of more benefit for them rather than to undergo open heart surgery to close an ASD with them. I do believe that if a patient has left ventricular dysfunction and has an ASD with left-to-right shunt that requires a closure.

After the device gets approved I would be able to implant the device in these patients. However, during the protocol and the study period, we try to avoid any patients with such conditions like left ventricular dysfunction.

DR. WHITE: Let me just see if I understand. You did a study for the safety and efficacy of this device and you excluded those patients. Now after approval you want me to implant in those patients?

DR. HIJAZI: If there are patients which are very real, as you know, with ASD and they have significant left ventricular dysfunction and the closure there is beneficial. I do not think that device or closure should be contraindicated for that.

DR. WHITE: Then why did you exclude them from this trial?

DR. HIJAZI: Initially for the study we wanted to do plain straightforward secundum ASD in patients that we encountered on a daily basis.

MR. LOCK: This is Ken Lock. We will include in the labeling that it is a contraindication for patients who have heart failure MIs. That will be in the labeling.

DR. WHITE: Can you tell me also in your contraindication there were patients who were considered to be poor candidates for catheterization. It says, "Any patient whose size or condition would cause the patient to be a poor candidate for cardiac catheterization." Can you give me an example of someone who is a poor candidate for cardiac catheterization? I don't know if I've ever met that person.

DR. HIJAZI: An example of a poor candidate is a patient who, let's say, has significant left ventricular dysfunction and they are dying for somebody to attempt to take these patients to the cath lab to close their ASD I think will be a poor judgement.

DR. WHITE: I guess from the provider's side of this equation, when I read the package labeling I would like specific things. I would like to know what you consider to be a problem. This vague thing about poor candidates, I don't understand really because for different doctors it's different.

I think if there are specific issues that you think are related to this device that would make catheterization a problem, then that ought to be specifically listed in order to help us understand what it is.

Ziyad, can you comment on the difference between -- this application is for ASD but immediately upon the release of this device PFOs are going to get on the horizon. Is there a difference in the treatment of PFO, patent foramen ovale, and ASD?

DR. HIJAZI: This is Ziyad Hijazi again. Technically speaking there is no different. As a matter of fact, a few of the patients in this cohort had PFO with minimal shunt and TIA or dysrhythmia that we close with the Amplatzer Septal Occluder.

DR. WHITE: So in the umbrella of approval for the ASD would also include the PFO patients?

DR. HIJAZI: We're not seeking that for PFO. That would be operator dependent because there is another device, the Amplatzer PFO Occluder specifically designed for the PFO. If this device gets approved and you have a patient with a PFO with left-to-right shunt and you want to close it, it's --

DR. WHITE: Is it a clinical difference?

DR. HIJAZI: No.

DR. WHITE: And I guess my last comment is that I don't -- I understand the difficulty of doing a randomized trial and I wasn't involved in the trial when you came in 1997, but your groups are not comparable. To say that you have a controlled trial here is a little specious. I mean, you've got an adult group for your heavily weighted adult group. Your pediatric group is -- there's no attempt at matching for equivalence.

I'm not sure that's required but I think it kind of -- I think just to set the present and make sure we all understand, these groups are not comparable, I don't think. They are just a different population of patients.

Perhaps you could comment on why they are different, Ziyad. Why did you grab more adults? Why was there not anybody getting operated on in this setting?

MR. LOCK: This is Ken Lock. There are two parts to that. The first part, the difference, we believe, in the populations was attributed to referral patterns of the investigators in the trial.

The surgical control investigators were pediatric cardiologists and they would refer their patients to surgery and they were enrolled into the study.

The adult cardiologists were referred from a broader base of patients of adults seeking a less invasive procedure perhaps or there are adult cardiologists referring them to a site that had the device available. That would account for the difference of the populations and how we got the populations. I'll have Kinley Larntz here speak to the second part of the question.

DR. LARNTZ: Perfect timing. I'm Kinley Larntz. I served as the independent statistician. I'm Professor Emeritus, University of Minnesota. I also work as a consultant to companies and to the FDA occasionally.

You're right. I mean, look, there's a big age difference, right? The key feature of any -- and it wasn't a randomized trial so you are liable to get differences and that's what happened. The key feature statistically that I could figure out was does this age difference make any difference statistically, and so we didn't report.

I apologize that Dr. Hijazi didn't do all the covariate analysis for you on the screen. Maybe you would prefer that he did, but we did a lot of covariate analysis. We used age and also the symptoms that we saw as covariates; failure to thrive, respiratory problems.

It turned out that doing those covariate analysis -- and this is what we would have to do to try to adjust in some way without doing a formal matching. We didn't do a formal matching, I understand, although I did a little bit of that in one example.

Age didn't have an effect on anything. It didn't have an effect on complication rates. It didn't have an effect on closure rates. It didn't have an effect on anything. Every analysis I did with age just turned out to be the same result as if you didn't have age in the equations.

I agree in randomized trials. I'm a statistician. I should agree with that, right? In fact, the best analysis we can do is to try to adjust for what the differences were and in doing that adjustment we found basically -- not basically but exactly the same effects, the same size effects. Everything went through the same way.

DR. WHITE: I'm not criticizing the fact that you didn't randomize these patients. I would not have asked you to do it. I think the reason the complications don't show is because it's a safe procedure with low complications in each group.

But you can't tell me that operating on a range of adult patients for ASDs, which were not done because adults didn't get operated on, wouldn't have shown maybe some difference. You gave surgery every benefit of the doubt in your analysis and that's fine. I think this isn't to compare surgery but it's just not a comparable group and not a good thing to do.

I'm finished.

MR. DILLARD: Dr. Tracy, sorry to interrupt. Jim Dillard. Just a couple comments. I don't usually do this but I think in this case it might be a little bit important for contextual purposes. I think Dr. White brings up some great issues.

A couple of things from the FDA's perspective, the fact about sort of additional patients. I mean, one of the questions that you had is the difference between 110, which I think was really sort of the primary number for the study, versus the continued access number.

One of the things that we do struggle with in designing trials is allowing a sponsor to continue to gather some data over longer periods of time and at what point in time do you bring the data before a panel when you also don't have much experience with a product. Sometimes we at the FDA look to a larger safety database and a longer term, even though the effectiveness numbers may be somewhat different in terms of the statistical calculation.

I think that is certainly the case here where we felt like a larger body of information for safety might certainly be relevant in an area where we really didn't have very much understanding of the technology. I think that is where we see a little bit of a difference here and certainly something that the FDA felt pretty strongly about.

I'm sorry. I'm just going over a couple of notes here. Safety information and really the larger dataset about embolization also. I mean, that was certainly an issue that we looked to and thought that a larger dataset would help us analyze the issue about embolization.

About the control patient population here also. I agree certainly with what the sponsor said at this point. One of the other struggles that we had, and I think even back to 1997 since probably none of the members here were actually at that panel meeting, but one of our concerns when we started looking at some sort of randomized concurrently controlled study which really wasn't feasible at the time.

Then we looked at what other options we had available to us for a control group. One of the considerations was really how contemporary was the data. When we look back the dataset that we might have had available if we didn't do something prospective in terms of a contemporary control group would have been really looking back at older surgical procedures.

I think the tradeoff here was to try to get new surgical data in order to compare the two patient populations. I think, as usual, we all struggle with what the appropriate control group is. In this case we thought the contemporary nature of the data might be important for this particular product. Just a couple of general products. Thank you.

DR. TRACY: Dr. Skorton.

DR. SKORTON: Thank you. I just have a couple questions. One of them has to do with the section on instructions for physicians on using the device. It has to do with the use of imaging methods during the procedure.

In the precaution section, and in the question that was asked by Dr. Williams, you mentioned the importance of using one technique, ultrasound. In the procedural area and in the demonstration that you showed, you showed angiography. That seems needlessly redundant to me.

I would like to ask why you have to do both. If you're going to do echocardiography, why do you need to also do additional angiographic study?

DR. HIJAZI: Ziyad Hijazi again. As an operator in the cath lab, I think any imaging modality will be very helpful for the operator to place the device in the correct position. We do angiography because it gives a road map and a location in more space than echocardiography.

When you do TEE, as you are aware, you just see a confined space. You do not have the entire field in front of you to see where you would open the disc or the waist or something like that. I think most, if not all, operators prefer to have both fluoroscopy as well as echocardiography to guide you during the implantation.

However, there are people in Germany, for example, for small size ASDs the entire procedure is done under TEE alone without fluoroscopy. In my opinion if you try to do this for larger ASD, you will create more problems rather than trying to save two to three minutes fluoroscopy. That's why I think we use fluoroscopy judiciously with TEE during the procedure.

DR. SKORTON: Thank you. Then I have a question for the statistician. Can you go over again how you came up with 8 percent as the predicted difference? I know it was done by a lower limit 95 percent confidence limit, because I agree with Dr. White that this is not a randomized trial. I would like to know statistically how you came up with that 95 percent confidence limit. How you calculated it.

DR. LARNTZ: Oh, how I calculated the 95 percent confidence limit?

DR. SKORTON: Um-hum.

DR. LARNTZ: I used an exact comparison of two binomial proportions using exact test. I gave a lower limit of 5.2 percent. I'm not quite sure. Are you asking where the 8 percent came from?

DR. SKORTON: Yes.

DR. LARNTZ: Okay. That's what I assumed you were asking. Of course, the standard answer from a statistician is that is not a statistical question. The 8 percent is the standard answer we give, but the 8 percent was provided in the protocol in the IDE so that was considered the standard that was to be met for the primary endpoint in the protocol.

That was set up -- I have to admit set up before I got involved and it was deemed, if I might say, and I'll elaborate as best I can nonstatistically, and I apologize for that, but if you're using a less invasive procedure perhaps with some other advantages compared to surgery, you're willing to tolerate a slightly lower final closure rate for the device.

Based on considerations of how much lower, what we wanted to do was prove that it was no worse than 8 percent worse. I hope that explains it as best I can to do that.

DR. SKORTON: Let me tell it back to you to see if I understand. You didn't actually calculate 8 percent. That was an arbitrary figure and it's a little bit more in favor of the device than the actual calculated lower limit would be.

DR. LARNTZ: That's correct. The calculated lower limit is 5.2 percent for the lower bound for equivalence so we met better than 8 percent.

DR. SKORTON: Sure. I agree. I just wanted to point out that it was an arbitrary thing. It wasn't calculated.

DR. LARNTZ: That's correct.

DR. SKORTON: Then the last thing is just a comment. I just want to weigh in agreeing with Dr. White, both sides of Dr. White's remarks. I'm not sure that it would have been important to do a prospective randomized control trial.

I'm not sure that's important. But I don't think we have a comparable control group in this trial. It may not be necessary to have one to make the decision but, just for the record, I don't believe this is a comparable controlled group. It may not have been possible to get one but this isn't one.

DR. TRACY: Dr. Zahka.

DR. ZAHKA: I have a few technical questions about the echocardiographic aspects of the study. It was mentioned that seven out of 155 surgical patients had some residual shunting. Now, what was the comparable number for the device patients?

MR. LOCK: This is Ken Lock. Those seven patients were patients that were reviewed by the Echo Board and they found that they had a trace or less than 2 mm residual shunt in the cohort that was reviewed.

As far as the complete closure of the device group, there was 304 out of 331 patients that had complete closure. The remaining 27 patients had a trace or a trivial residual shunt.

DR. ZAHKA: And that was at one year?

MR. LOCK: That was one year, correct.

DR. ZAHKA: And as the echocardiographers, the independent echocardiographers reviewed the video tapes, were there any measurements actually made on the video tapes that the echocardiographer would then see?

MR. LOCK: This is Ken Lock. I'll have Dr. Kleinman comment on that.

DR. KLEINMAN: Good morning. My name is Dr. Charles Kleinman. I'm a pediatric cardiologist. I'm the Director of Clinical Cardiology at the Nemours Cardiac Center in Orlando at the Arnold Palmer Children's Heart Institute.

I was one of the Echo Review Board members and was compensated on a per diem basis for my time on the Echo Review Board. I do not have any financial interest in AGA Medical and my expenses for today's trip are being borne by AGA.

We did review video tape of the echocardiograms. As you know, it can be a little difficult to do accurate measurements down the line on an echocardiographic view using an analog image of what was originally digital data.

Very few of the echocardiograms that were submitted had digital measurements on the video tape that were done by the individual investigators, although several did.

In the shunts that were seen in the surgical group, it was quite clear that these were rather trivial shunts and they were well visualized and one could see the millimeter or centimeter marks on the analog image. It was quite clear that these were well less than two millimeters in diameter.

In most cases were in the range of less than 1 millimeter in diameter but clearly were visualizable as color flow shunts across the margins of the defect.

I was also wondering whether the echocardiographic reviews looked at the pre-procedure and post-procedure prevalence of aortic regurgitation or mitral regurgitation or, for that matter, tricuspid regurgitation.

MR. LOCK: This is Ken Lock. The only echos that were reviewed by the Echo Board were the primary efficacy echos at one year so they did not see any pre-echos.

DR. ZAHKA: And are there any data available that speak to the issue of whether or not aortic regurgitation or mitral regurgitation or tricuspid regurgitation increases in severity after device placement.

MR. LOCK: This is Ken Lock. There is no data reported in the PMA. I'm wondering if Dr. Hijazi would like to step back up and comment further on that.

DR. HIJAZI: This is Ziyad Hijazi. Obviously when we implant a device in a patient and we do echocardiograms, we just don't look at the residual shunt. We look at the mitral valve as well as the vent because in a couple of instances when we implant a device, the left atrial disc may be close to the mitral valve leaflet and may result in mitral regurgitation. To my knowledge, there have not been cases that reported in this Phase IIB of patients that had mitral regurgitation.

I know of one case abroad where the device was very big and resulted in severe mitral regurgitation that the operator did not deploy the device, just took the device out and sent that patient for surgery.

DR. ZAHKA: Can you comment on aortic regurgitation?

DR. HIJAZI: In all honesty, Dr. Zahka, I do not think there is any case to my knowledge that resulted in aortic regurgitation due to a device implantation.

DR. ZAHKA: Thank you.

DR. TRACY: Dr. Hopkins.

DR. HOPKINS: For the record, I was here in 1997 as a member of this panel. At that time, as I'm sure the investigators remember, I was extremely concerned about the design of the trial. I'm sure a review of the transcripts would show that I felt strongly that a randomized prospective trial could have been done and it was not done.

I have a number of questions and they relate really to the control side as much as to the experimental side. First of all, as was pointed out by earlier panel members, there are really two sets of overall questions here.

One is the safety and the efficacy of this device as compared to arbitrary chosen endpoints, specifically the two percent death rate and the 10 percent major complication rate, which I am going to assume was chosen with discussions with the FDA.

I would point out, and as I recall I pointed out in 1997, that even historical controls for surgical ASD closure for relatively contemporary series, and by that I mean the '90s and late '80s, would have listed a death rate for open-heart surgery at 5 and 10,000, well below 1 percent much less 2 percent. I did have the question and I think you answered it was how were those arbitrary endpoints actually chosen.

The series of questions I have relate a little bit to the surgical arm. Was there a standard surgical protocol that the surgeons participating in this study were to follow that approached the rigor of the technical protocol that you provided your cardiologists who were implanting this device. Or did you simply say do your ASD the way you would normally do it and we'll take your data?

MR. LOCK: This is Ken Lock. That is correct. A protocol was provided to the prospective sites to enroll their prospective patients not looking at the type of surgery that they would perform, the techniques, I should say. Then the retrospective patients we went back and pulled the patient files and didn't really look at the type if it was a modified procedure.

DR. HOPKINS: As I've gone through your nine major surgical complications, there are at least one that I would ask why it was a major instead of a minor which was the wound complication, which I thought was a minor complication by your protocol.

The major complication involving thrombosis of the femoral artery was a complication of femoral artery cannulation which is not standard procedure in today's world of cardiac surgery. The complication of two sternal wires causing pain requiring removal which was listed as a major complication. Most of us today do not use wire. I haven't used wire on a pediatric sternum in 15 years.

A transverse sternotomy broke down on one of the major complications. Once again, it's not standard surgical procedure. I have some concerns about claims that this is equivalent to or better than surgery when, in fact, we don't have a randomized prospective trial.

Now, I've gone through your data multiple times and I get confused as I go through so I'm going to ask your help. It appeared that while there were essentially no residual shunts in the surgical arm as I recall it, there were small and trivial shunts. Did I read your data properly that when these occurred that most of those had actually closed at 12 months?

MR. LOCK: This is Ken Lock. Regarding the device group?

DR. HOPKINS: Yes.

MR. LOCK: Yes. Most have closed over time.

DR. HOPKINS: Okay. And in there surgical patients, and at least in one place, seven surgical patients were noted as having residual shunts. Were those secondary ASDs that were missed or were they margin defects?

MR. LOCK: This is Ken Lock. I do not know the answer to that question.

DR. HOPKINS: It's an important question in the sense that the protocols are different because most ASD patients are not cathed prior to surgery and you are operating based upon pre-operative echo data.

MR. LOCK: We'll have to gather that data. Actually, Dr. Kleinman --

DR. HOPKINS: Do you know the answer to that of those seven?

DR. KLEINMAN: Charles Kleinman. Yes, I do know the answer to that and they appear to be margin defects in all seven cases echocardiographically.

DR. HOPKINS: Were any of the patients who were excluded from the device protocol included in the surgical arm?

MR. LOCK: This is Ken Lock. I believe there were a couple patients.

DR. HOPKINS: -- who failed inclusion criteria for device and were included?

MR. LOCK: That is correct.

DR. HOPKINS: Of the 30 -- I think it was 37 patients who were added retrospectively. Is that correct?

MR. LOCK: Ken Lock. Yes, that's correct.

DR. HOPKINS: How many of the major/minor complications in the overall surgical group were accounted for by this 37?

MR. LOCK: This is Ken Lock. I will have to check on that number for you.

DR. HOPKINS: For the record, I would have to say just grabbing a handful of retrospective patients and throwing them into the surgical arm without listing what proportion of the complications are attributable by that group raises really grave, grave concerns in my mind. As I said, in '97 I don't think it should have been necessary.

In the procedure, you do have 105 minutes of cath time as the analysis. As I recall, this came up in '97. What amo********************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************par DR. HOPKINS: But the total time was on average 15 minutes?A

DR. HIJAZI: Average 15 minutes or less, yes.

DR. HOPKINS: For a statistician did you plot visual plots of the subtypes of complications versus age? What I'm specifically referring to is that in the pediatric population post-pericardiotomy syndrome is extraordinarily common, as high as 40 or 50 percent, particularly over the last couple of years for some reason.

Some of your other minor complications that actually did make it into the major when it created tamponade are a little more common in the adult so when we begin I share the concern about the ages here in that the different ages have different sort of nature of their complications.

The question really for the clinician and the parents is not independent of age. It is very dependent on age because the patient exist at a point in time at a given age. The question is for my three-year-old child what is the complication rate between the two options and what is the mortality rate between the two options?

I'm a little concerned. I can understand statistically when you look at a lump of minor complications versus minor complications, but if you look at the subtypes and plot them versus age, did you note anything?

DR. LARNTZ: This is Kinley Larntz. The answer is that we did not do any analysis on the subtypes and the reason is the numbers were pretty small for the subtypes. The only thing I can say is we looked and divided up the groups into quartiles by age.

I wanted specifically to look at the complication rates for younger versus -- by quartiles in the whole study dataset. That analysis by quartile showed that in each case the surgery group had a larger complication rate than the device for younger patients.

My memory will fail me here but I think the lowest quartile was like less than three years of age or something like that. In each of those quartiles there was a considerable advantage of the same size and magnitude of an advantage with respect to complication rates. But for individual complications I don't think there were enough to do that analysis that you're talking about. I didn't do it anyway.

DR. HOPKINS: On the first part of your answer there in terms of the complication rates between the four quartiles, are you saying that there was a difference in complication rates amongst the four quartiles? In other words, there was more advantage to having the ASD closed younger or older?

DR. LARNTZ: What I should do is find the exact data for you which I can do in just a second. What I think I said, I hope I said, is that each quartile there was an advantage for the device over the surgery group. There was no particular trend in complication rate across time so complication rates were similar across time.

DR. HOPKINS: For all complications?

DR. LARNTZ: For all complications. And I did not break that down by individual complications.

DR. LASKEY: That's on page 49 of the Panel Pack.

DR. LARNTZ: Thank you.

DR. TRACY: Which section?

DR. LASKEY: Table 41.

DR. LARNTZ: Thank you. Right.

DR. LASKEY: Yellow sticky.

DR. HOPKINS: I did see that when I reviewed the data but, once again, the nature of the complications does have some effect on clinical decision making, particularly since I think it's probably the intent of all the pediatric cardiologists in the world that nobody would get to the age of 10 with an ASD still present.

On the fenestrated Fontan why was the size of the residual shunt limit chosen to be the same as in the larger ASDs of 2 mm as an efficacy criteria when surgically we try very hard not to make fenestration larger than 4 mm? In effect, you're saying that a 50 percent reduction in fenestration would be efficacious, which is not the same criteria you're using in normal ASD.

MR. LOCK: This is Ken Lock. I would like Dr. Moore to come forward to address this question.

MR. MOORE: I'm John Moore. The definition was chosen simply because there was no criteria that we could identify in the literature and for consistency with the study data all together.

Clearly there are in the study small ASDs that are not unlike fenestrations in terms of their size which you'll see if you look at the details of the fenestration. Most of them are 4 or 5 mm punch fenestrations. There were certainly some larger than that.

DR. HOPKINS: And do you recall -- I looked for this and I couldn't find it. Are these patients after the device closure of the fenestration routinely anti-coagulated?

MR. MOORE: They have the same anti-coagulation recommendations as the ASD patients. That is, aspirin is recommended for six months.

DR. HOPKINS: Because most of our Fontans are kept on anti-coagulation because they are Fontans, not because of closure. I'm just wondering if the slightly higher persistence of the shunts was actually due to clinical anti-coagulation for being a Fontan.

MR. MOORE: As I indicated, the Coumadin, etc., is not recommended specifically in this protocol, just the aspirin.

DR. HOPKINS: Thank you.

DR. TRACY: At this point I think we'll take a 15-minute break. It's 11:00 by my watch. Let's be back by 11:15.

(Whereupon, at 11:00 a.m. off the record until 11:18 a.m.)

DR. TRACY: All right. We'll resume our questioning. I believe Dr. Hopkins has one more question.

DR. HOPKINS: Sorry. It raises the same questions, you may recall, from four years ago.

There is one question that I had. In the protocols and data and also during the presentations there was reference to proof of complete endothelialization of the device after six months. What is the nature of that proof?

MR. LOCK: This is Ken Lock. What we had done is some animal testing on 12 Yucatan pigs that we looked at at three months and they were completely endothelialized at that time.

DR. HOPKINS: Do we have any human data whatever? Anybody gotten run over by a car or anything?

MR. LOCK: This is Ken Lock. As a matter of fact, we do have one patient that we do have a slide we could show on that.

DR. HOPKINS: You don't have to show me.

MR. LOCK: We do have one patient, yes.

DR. HOPKINS: That does show complete on both sides?

DR. HIJAZI: Endothelialization of the device, yes.

DR. HOPKINS: Thank you.

DR. TRACY: Dr. Aziz.

DR. AZIZ: I've just got a few questions. I enjoyed the presentation. I think it was very lucid and helped me as a surgeon to follow exactly what you folks are doing.

You mentioned, Dr. Hijazi, that there were 12 additional months of data collection and 465 patients and that a number of these patients were from overseas although they were not analyzed in this data analysis. You mentioned there were no adverse events reported. Was the follow-up fairly rigid?

DR. HIJAZI: That's a good question. The patients have been followed-up by their local cardiologist there. To my knowledge nobody has called me to tell me that that patient we have done together has this adverse event or that. But the four embolizations that I reported, those were encountered while I was there so I know that.

If there were other complications, it was not reported to me or to the AGA. As a matter of fact, for the clinical trial internationally all patients that receive the Amplatzer device were reported and we would have known about that.

DR. AZIZ: And the people who were implanting these devices were local physicians or folks from here going out to help them implant them?

DR. HIJAZI: The initial proctoring or training physicians from there contact the company and the company decides on a proctor. Then a proctor goes there and they proctor the physicians three to five cases in each center.

DR. AZIZ: Let me just ask you some theoretical questions. Most of these patients with a device that have been implanted, the mean age is about 18 years old. Looking ahead I'm sure a number of them will probably come for bypass surgery or valve replacements. Do you see any potential problems lifting the heart and surgically manipulating it that might cause either kinking or displacement or problems with the device?

DR. HIJAZI: That's a good question. This is Ziyad Hijazi again. Not to my knowledge. I think once the device endothelializes, which takes anywhere from probably three months to six months for the device to be endothelialized, I do not think that lifting the heart or punching the heart would cause any problem.

Even in the real couple of cases that we had to take to the cath lab to close a residual shunt, going beside the device with a sizing balloon back and forth, that device is completely lodged there. It does not move at all. Actually, I remember with another device about five years ago the residual shunt was large requiring closure in the OR.

I went to the surgery to look and the surgeon had to use three knives to cut around. The device is totally impeded in the tissue so it's very difficult for the device to move during cardiac surgery or during anything else.

DR. AZIZ: I think most surgeons obviously do an ASD closure very well, and apart from I think the marginal echo defects, hopefully we don't see much leakage. If you had a patient who had an ASD repair done surgically and had a significant shunt, could this device be used to obliterate that shunt?

DR. HIJAZI: Dr. Hijazi again. Among the cohort of my patients I have four patients post-surgical closure of their ASD. One of them post-surgical closure twice with 13 mm residual ASD. We like these cases because the margin is very stiff. You just go there, quick sizing, and the procedure is very successful. We had quite a few patients, at least in my personal experience, and I'm sure my other colleagues have encountered other patients.

DR. AZIZ: Also, if you had a patient who had a pacemaker, you would still be able to put this device in?

DR. HIJAZI: Yes. We have patients also that actually have pacemaker implantation, transvenous lines, that they had ASD that we go ahead and implant device closure. It does not really interfere with the packing lead.

DR. AZIZ: Thank you.

DR. TRACY: Thank you. I also enjoyed your presentation. I thought it was very good. I just had a couple of questions that I wanted to raise with you and a comment. The first comment on the packet for the patient would take a Ph.D., I swear, it be able to read through that. I think the language is in much too sophisticated and you might ask Mr. Dacey for some advice on how to rearrange the language on that.

I believe the little angiogram that you showed of the fenestrated Fontan patient had a prosthetic valve in place so I would assume that patient would already be on Coumadin or would be transitioning back to Coumadin.

There is nothing in your labeling that indicates the contingencies for what to do with the patient who is on Coumadin. You do talk about anti-platelet but I would think that some language ought to be incorporated in that.

I also have the same question about re-ops but I think that has been answered satisfactorily. I think I will turn it over to Dr. Laskey.

DR. LASKEY: Thank you. The first thing I want to do is congratulate you for using a MacIntosh for your presentation. I appreciated that very much.

I came away from reading this with the following conclusions. One is that if you are a young adult you'll do well with -- a young adult with an ASD you'll do well with this device. If you are a kid, child, you'll do well with surgery.

I know we beat the age issue up a bit. I do think it's important to dwell as an adult interventionalists I'm likely to see these people. How anxious am I do get involved with the nuances of "ASDs" in adults that are not really addressed in this study but which may comprise a significant fraction of the referral.

The first category there would be you have a fraction 7 or so percent who had bi-directional shunts. Can you tell me a little bit more about them? Did they have pulmonary hypertension or were they just so enormous that they were -- what set these apart from the pure left to right?

DR. HIJAZI: This is Ziyad Hijazi. These patients that had bi-directional shunt they had a smaller ASD/PFO and sustained TIA or paradoxical embolism or dysrhythmia. When you do the contrast echo, often times in many of these patients there was also right-to-left shunt.

DR. LASKEY: Do you think you have enough data here to support not necessarily efficacy but safety for this important subgroup of young adults with PFOs?

Earlier on you said that the device would be used in people with PFOs but you didn't really address that in this study. I beg to differ that a PSO is not an ASD either physiologically or anatomically as you defined ASDs.

MR. LOCK: This is Ken Lock. It would be contraindicated in the labeling that those patients would not be implanted.

DR. LASKEY: In what patient? In a PFO --

MR. LOCK: A PFO.

DR. LASKEY: -- with a cryptogenic stroke?

MR. LOCK: That's correct, a PFO patient.

DR. LASKEY: I see. Okay.

DR. WHITE: But were those included in this trial?

MR. LOCK: This is Ken Lock. There were three patients that did meet that criteria for the study.

DR. LASKEY: Okay. I just have a few other questions. I don't want to steal Janet's thunder and I did have a few statistical questions.

DR. WITTES: You can do it.

DR. LASKEY: No. Just as a prelude. You do report 90 percent confidence intervals for one endpoint and then 95 percent intervals for another endpoint. Can you tell me why the choice of the one for the one and the other for the other and whether that might have made a difference for your lower 8 percent bound?

DR. LARNTZ: This is Kinley Larntz. The intention was to look -- when we use 95 percent bounds we were looking at a lower bound. I think that's what we tried to do consistently. You may find an example where we didn't do that.

When we report 90 percent they are two-sided so we are really concerned about the lower bound on that. It's really a 95 percent lower bound. In fact, I think we were consistent that we were using a 95 percent lower bound and doing that comparison.

I guess the answer is I think we were consistent and it wouldn't make a difference in the lower bound. We actually have, at least with respect to the protocol, a requirement. As was pointed out earlier, we met that with 5.2 percent as opposed to 8 percent which was a requirement.

DR. LASKEY: Thank you. I was just confused and I'll draw your attention to Table 8 in the beginning here, page 12 of the summary of safety and effectiveness data. It's expressed the one way there. Then on Table 27, page 35, in the Panel Pack it's expressed. It's just a little confusing. Then FYI you have a lower bound of -1.052. I'm sure that's a typo. You mean -0.052.

DR. LARNTZ: It's 0.052. I apologize. I saw that typo earlier.

DR. LASKEY: I just wanted to be sure of that.

DR. LARNTZ: I wondered also about the dependence of efficacy of, well, the outcome on size of ASD. While there appears to be no relationship with primary efficacy at 12 months, there does to my eye look like a fall off in the composite endpoint at 12 months with size.

Is there any -- am I missing something here? Is it more difficult to treat these the larger they get? Your numbers do trend down as you go from 6 mm to the 38 mm for the composite endpoint but not for your primary efficacy endpoint at a year.

MR. LOCK: This is Ken Lock. We did notice a trend in the composite analysis. One of the failures for the composite analysis, as we have stated in the presentation, was that the patients weren't allowed to revert to a success so we have more failures, I guess, reported in that.

You are prepped in the primary efficacy that in the end they will become a success. I think I'll have Dr. Hijazi answer the question, "Are larger defects harder to close?" I think he will be able to answer that for us.

DR. HIJAZI: This is Ziyad Hijazi. In terms of the larger defects, Dr. Laskey, there's no question that they seem to pose slightly more challenge to the operator than the small 10 mm straightforward ASD. However, that's why experience, I think, is important when you train people about larger defects.

They do seem to pose a little more challenge but at the end if you look at the results, and we looked at that in terms of the learning curve and everything. There was not really much of a difference between the people who did 10 ASDs or 50 ASDs.

DR. LASKEY: In that vein are you likely to be older if you have a larger ASD or did this not -- I know to the best of your ability you couldn't find a relationship with age here. My brief experience with young college students who come through an adult congenital clinic is that these are gigantic defects usually.

DR. HIJAZI: I agree with you. I think, you know, the older you are the more like that the patient will have a larger ASD. We know that this continued left-to-right shunt through the years does result in a larger ASD as they grow older in age. There's no question when you look at our adult patients they tend to have larger ASDs. I don't know why they were missed all these years.

DR. LASKEY: But they are. Hence, that brings us back to what we're trying not to badger you with but there is an age issue here which is related to the entity itself which it's difficult to make comparisons with the surgical data.

DR. HIJAZI: However, as I mentioned in my presentation, Dr. Laskey, that the mean ASD size for both groups were compatible. 13.3 mm for the device and 14.3 mm for the surgical group. And the same percentage of patients in both groups had significantly large right ventricle. Although they were different in ages, but what we are treating, the ASD itself, they were similar in that aspect.

DR. LARNTZ: If I might follow up just slightly on this. This is Kinley Larntz. It is true that the average age differed, but it is also true that there is a wide range of ages in both groups. In fact, the table you pointed out to me on page 49 indicates the quartile distribution of ages.

Just for reference, if I can, and this again is partly from memory but I think my memory is pretty good on this, the lower quartile is less than about 3.7 or four years. In fact, there were 76 patients in the device group that were less than that.

The second quartile is somewhere -- well, it's obviously greater than whatever I just said, 3.7, up to about six years. There were 102 patients in the device group in that cohort.

Then the next quartile runs from the six up to -- again, it's from memory. I apologize for not looking it up and bringing my notes -- about 18 years. The mean ages, of course -- this is statistics, right? -- heavily influenced by some much older patients that skews the mean. The medians are quite a bit smaller in both groups.

DR. LASKEY: That was my next question. If it's non-Gaussian, then it's not fair to compare the ASD's sizes as means but you need to do it as medians, too. Is the median ASD size in the surgical group larger or smaller than the median ASD in the device group?

DR. LARNTZ: This is Kinley Larntz. I don't know the answer to that.

DR. LASKEY: I would bet they are not the same but it's easy to do.

DR. LARNTZ: It's easy to. I agree.

DR. LASKEY: Thank you.

DR. TRACY: Dr. McDaniel.

DR. McDANIEL: Thank you. I have a few comments on some of the grammar or terminology on some of these things. Maybe suggestions for the contraindication to the device placement where you state, "Any patient with the margins of the defect less than 5 mm to the coronary sinus AV valves and right upper pulmonary vein." Should that be or? I know this is picayune but if you leave it as "and" you're kind of raising your standard as to your contraindication. It's picayune, I admit.

The next question on this, and this is also in the same portion of this information where on page 4 -- don't ask me which section I'm on here -- on alternative practices or procedures. You probably should mention that there is an alternative of doing nothing as opposed to just device closure surgery. Kind of standard medical care is that you always have the option to do nothing, or the patient has that option.

I guess now getting into the patient packet of information, I'm not sure it requires a Ph.D. I have read over this and had a couple of questions on it. One is under the first paragraph of introduction with an ASD. It says usually the hole is in the upper part of the atrial septum. Most pediatric cardiologists would say secundum ASDs are in the mid portion of the atrial septum.

I think, again, that's a minor point but to families reading the literature, or somebody else looking at this you might think sinus stenosis and that's not at all what you're talking about.

Then on page 10 of 23 on the patient information, the second to last paragraph, "Because it is receiving so much extra blood, the left side of the heart does more than its share of work." It's the right side of a heart in an ASD.

Also the sentence says, "Plus the blood is poorly oxygenated." Well, actually, the blood on the right side of the heart is more oxygenated than normal so this is a physiologic error there.

I guess also on the patient information you have four figures which you've used elsewhere from the transesophageal echo, the cartoons. I think that the fourth figure, which is listed here as figure 7 on page 14 of 23, but it's also earlier in your packet, looks very different.

I understand what you're showing, that once the device is released you no longer have retraction of the atrial septum so it moves. Particularly to a non-medical person looking at this picture, it looks very different so I think they might find it confusing because before you've shown part of the tricuspid valve and now you have this other -- you're not showing it in the same way.

I just think it's potentially confusing to the families what you were illustrating. Also, on the patient information as a pediatric cardiologist the patient's parents are confused by this all the time. We're now on page 15 of 23 of the patient information, second sentence, where it says something about an adhesive bandage where an incision was made to insert the catheter.

Patients think incisions have like sutures and those sorts of things. Generally none of these procedures are done with incisions truly. I think it would just be confusing to the families or to the patients themselves if they're adults.

Pardon me. I'm going to look through all my little red stickies here. Looking through the extensive list of individual patient data and those sorts of things, there are a fair number of misspelled drugs and stuff. It doesn't matter but I actually did read it. I wanted to point that out.

I have two additional comments. One is to echo the concerns that surgical practice has changed very much in the last 10 years, particularly related to ASD closure with limited incisions, very short times in the OR.

I can't find the table in here but the length of procedure which you compare the device versus surgery, there was an incredible outlier in the surgical data. Over 300 minutes for an ASD closure for procedure time. That would be very unusual. I just wanted to point out that one patient alone may skew the data a bit.

Then, again, point out that with -- I understand about no literature being out there as far as what is an acceptable fenestration leak in the fenestrated Fontans but, again, I would point out that going from an average of 4.7 mm hole to a 2 mm hole may be successful but its' not the same as enclosure of the ASD.

My second comment on the fenestration is that in one of the tables you referred to secondary fenestrations. My question is are those really baffle leaks that you're closing and is that an important distinction?

MR. LOCK: This is Ken Lock. I'll have Dr. Moore address this question.

MR. MOORE: John Moore. The secondary fenestrations, as far as we know, could have been baffle leaks. As opposed to being intentionally placed punches they probably were baffle leaks.

DR. McDANIEL: That's all.

DR. TRACY: Dr. Wittes.

DR. WITTES: Hi. I'm Janet Wittes. I apologize for being late. It's very hard to get back from Bangor, Maine, on a Monday morning.

I'm a statistician at Statistics Collaborative and I'm a regular member of the panel. I deal with denominators a lot. You're going to have to bear with me about some denominator things and the age.

I also am very worried about the age distribution. Can we start with it? Because I would like to start on tab 1.0, the yellow tab, page 6, where we have the raw data. That, to me, is what really tells us where the people are.

What you'll notice -- maybe you've discussed this in detail before but I'm concerned about statistical adjustment when there's no people in the categories that you're adjusting. If I could just compare children to, say, goldfish and I can adjust them and get an answer.

I'm nervous about comparing two different distributions where there's a blank in a big part of the age distribution. Yes, there's people in all the quartiles but there are people in all the quartiles by definition. There's always going to be people in four quartiles. There's nobody in the surgical group above 40. There's only one person above 30. There's only five people above 20.

It seems to me that the correct analysis -- I mean, again, we recognize this isn't randomized but, nonetheless, it seems to me the only analysis one can make is an analysis that is limited to the 30 years where you don't have a denominator -- or 20 years where you don't have denominators in the surgical group of effectively zero.

So my question is if you look at the data limited to where there are people in both age groups, how would that affect the comparison of your primary efficacy?

The other question is where did the failures occur?

DR. LARNTZ: We have five failures.

DR. WITTES: Yes. Where did they occur?

DR. LARNTZ: I don't know the exact ages of those. This is Kinley Larntz, by the way. We can determine that but I don't have the ages of those patients in front of me.

DR. WITTES: I would like to know because to me it's very different if they occur in the older group where there's no surgical people or in the younger group where you actually have some.

MR. LOCK: This is Ken Lock. It will take me a couple minutes but I will get that for you.

DR. WITTES: Okay. Great.

Question No. 2 has to do with, again, denominators and follow-up. It's actually -- it's going to be a kind of multi-tiered question because it relates also to the difference between the primary efficacy and the composite efficacy and to the question about an apparent decrease in efficacy as the lesion gets bigger. It's one question but intertwined.

It starts really with a question about -- the other piece that's related to is the difference between retrospective identification and prospective. My understanding is there's basically 440 -- well, there's 400 and something or other that started and there's 331 with primary efficacy data. What you say in the text, I think there are 68 who missed their 12-month follow-up and eight more were lost at follow-up.

That's basically 25 percent of the population -- the group. Assure me that there aren't hidden failures in here.

MR. LOCK: This is Ken Lock.

Jodi, if you could put up bar backup slide No. 7, please.

I apologize for the darkness of the slide. We looked at these -- took these very seriously these missed visits. We have extensively worked with the investigators to try to find out exactly what the status of these patients are.

Since the filing of the PMA 28 of those patients have come in for a visit. The shunt status is up there, 27 were closed and one had a small shunt of those 28 leaving 40 patients left to look at. Five patients were seen and data was not available on those patients. We are still collecting that information.

There was the one death that was reported in the PMA that was after the one-year visit but is no longer available for follow-up. Five patients are scheduled now here in the next six weeks. It really leaves 29 patients left out of that 68 that we are still trying to attempt to locate. However, they are not responding to the letters and phone calls.

DR. WITTES: Okay. The worry always is that people who are hard to follow are different from the others. Either they are in such great shape that they just don't want to be bothered, or something bad has happened. Given that you're talking about very small marginal differences between the two groups, I think it's important to find out.

DR. HIJAZI: This is Ziyad Hijazi. On those 29 that have missed their 12-month follow-up, we went back to see when was the last time they were seen, the six month follow-up. Their six-month status is shown there. Twenty-eight of them had complete closure.

Actually, this one that says moderate shunt, Dr. Moore just informed us last night that he saw that patient just last week and he has completely closed the defect. Out of the 29 had complete closure. This is based on their six-month follow-up. We are working aggressively to get the follow-up on all these patients.

DR. WITTES: Okay. The amusing thing, of course, is that by definition with the surgical group you have full follow-up because it's retrospective. Well, basically.

DR. HIJAZI: No, because only 37 patients were retrospective and addressed to the surgical patients who are perspective.

DR. WITTES: So how come you had such good follow-up?

DR. LARNTZ: This is Kinley Larntz. I guess I'll plead guilty to being a little inconsistent. Okay? That's not unusual for me. I'm a statistician and we should all be perfectly consistent. Here is what we did. The surgery group is actually quite hard to follow. That's actually true.

DR. WITTES: That's what I would assume.

DR. LARNTZ: The surgery was quite hard to follow. A decision was made that we would carry forward the surgery results to the 12-month follow-up. Okay? In fact, when it looks like we've got great fault, that's a carry-forward analysis for the surgery.

Once closed we assumed, and I've been assured that surgeons once they think they're closed, they're closed. That was an assumption. It was taken as a worse-case scenario that, in fact, if the surgery group had all closure. We weren't quite consistent. I said that.

If we did the same carry-forward analysis that Dr. Hijazi just mentioned we could do because we did have six-month data on a lot of patients, if we did that we would uncover a total of -- there would be five more cases of non-closure at earlier periods. There were five failures at 12 months and there would be five more which if we were redoing the calculations with that as a carry-forward analysis, which we could do and we did do, we would find that the lower bound that we needed for efficacy, instead of being 5.2 present, it would go to 5.9 percent.

DR. WITTES: But you know I would really fuss at that.

DR. LARNTZ: We didn't put that in the report but we did the calculations just in case someone wanted to bring up the issue. It is an inconsistency. We could have done a carry-forward analysis and I myself would have had some difficulties. I'm not sure I love carry-forward analysis.

In fact, I know I don't love them. Given that we do have information, if you make the same assumption for the device group as the surgery group, we could, in fact, evaluate all the patients and we would wind up with 10 failures out of the whole group. I'll stop at that point.

DR. WITTES: Then again I think one of the things that this is just emphasizing is how different these two groups are. They are different in many ways by the very nature of the way the data are collected.

Okay. Well, given that and the denominators and given the problem with ages and sizes, can we go to yellow section 1.0, page 40. I read these also in a way that sort of says if I look at the 12-month composite endpoint, I'm seeing a decrease in efficacy as device size and, hence, the legion size is getting bigger.

But if I look only at the primary efficacy, I think the naive reading is it stays the same. But if you look a little closer, it seems to me what it's saying, and this is where I need help, is that the denominators have changed so that while the 12-month composite keeps everybody in the denominator.

The primary efficacy looses people. For example, let's go to the 13 mm. Here we've got 15 in the numerator in both the 12-month composite and the primary efficacy, but we have an extra person in the denominator in the 12-month composite.

It seems to me what's happening is that the 12-month composite is keeping as many people as possible and you're seeing that as the device gets bigger, the failure rate gets bigger. The primary efficacy by the way it's defined is losing people in the denominator so that the numerator and the denominator stay the same and you get 100 percent.

Now, what I'm asking is, the question I'm trying to get at is the following. Which is real? All right? Is the decrease in efficacy that we're seeing as a function of size in the composite, is that real? Or is the constancy that we're seeing in the primary efficacy, is that real? It's clear why this is an important question to address.

DR. LARNTZ: This is Kinley Larntz. There's the main aspect of the composite. First of all, the composite, I think, we calculated it assuming that a shunt at anytime was a failure. The agency this morning in their presentation said that we had misunderstood. I apologize for that. And that we should only count shunts at 12 months as failures. There were some procedural shunts that would not be counted as failures if we redefine the endpoint. Those procedural shunts turn out to be related to size. That is, larger ASDs tended to have procedural -- tended to have shunts right after the procedure that were larger than the smaller ASDs. That's part of it.

The second part, and the reason you've got denominator changing partly is that technical failures; that is, failures to place the device were included as failures in the composite, technical failures. The primary endpoint was as a denominator the number of devices that were placed.

DR. WITTES: Okay. So the reading is that it's more difficult to place larger devices?

DR. LARNTZ: There's clearly an effect. That's clearly a statistical effect that larger devices, the technical success rate decreases slightly. It's not a lot but it decreases slightly and that is associated with size. I think the physicians could probably talk about things related to how close you get to the -- how much rim you need and things like that for larger defects.

I don't deny and, in fact, I admit there's a statistical effect that larger defects tend to have lower rates of technical success related to, I think, anatomical conditions related to larger defects.

DR. WHITE: Did you not count some of those failures as just bringing somebody to the cath lab and not yet having a large device available? Weren't they also counted as failures?

DR. LARNTZ: Yes.

DR. WHITE: Is that what you said in here?

DR. LARNTZ: Yes.

DR. WHITE: And then some of those people came back later and got the device when a larger one was available, would they have been counted as composite failures?

MR. LOCK: This is Ken Lock. The intent to treat patients where a device was not placed or even introduced to the body were not included in the composite. However, like you say, a couple of patients came back and had successful procedures.

DR. WHITE: What I'm saying is you would buy us your data against larger devices. If I thought it was a 30 mm device and I had one to close but I got in there and I found out that the balloon actually said 34 so I don't have a big enough device yet, did you count that as a failure or no?

MR. LOCK: We counted that as an intent-to-treat, not as a failure.

DR. WHITE: Not as a failure. So then that wouldn't go to your question of why the bigger ones fail more often.

DR. WITTES: Okay. Then I think I have one more question and then a comment. This actually relates to a question that was brought up earlier that some of the -- I mean, there are not many failures and they went on to surgery. If there were five failures, there couldn't have been more than five of them, right?

DR. LARNTZ: There were five.

DR. WITTES: All five them --

DR. LARNTZ: No. I'm sorry. What happened to those failures?

DR. WITTES: Yeah.

DR. LARNTZ: Oh.

MR. LOCK: Maybe we misunderstood that. There were five failures but none of them have gone on to have their defect closed.

DR. WITTES: Oh, then I misunderstood that. I thought you said -- okay. So they did not go on to surgery so none of the surgery people were people who had been device failures?

MR. LOCK: Correct.

DR. WITTES: I'm sorry. I misunderstood. Okay. My final thing is actually a comment and it has to do with the patient brochure which I thought was really nice. With some corrections it would -- I thought it was -- I really thought that what you were doing was trying to convey to patients and their parents the physiology and what this device was and I thought it was very, very nice and I hope that you will in making the changes, not eliminate the general feeling about it.

DR. TRACY: Dr. Crittenden.

DR. CRITTENDEN: I just have a couple questions and a comment as well. Could someone tell me how many patients need a general versus local anesthesia? Did you have that broken down? Is that something that is fairly common for general anesthesia to be used?

MR. LOCK: This is Ken Lock. In the device group all patients received general because of the use of the TEE.

DR. CRITTENDEN: Okay. Dr. Hijazi, could you discuss your experience with multiple device deployment? That seems to be a little bit more problematic. Could you talk about that a little bit, please?

DR. HIJAZI: Sure. This is Ziyad Hijazi. Multiple defects are present in patients with secundum atrial septal defect, either a second hole or multiple holes. What our, at least my, policy is and the policy of my colleagues is if the holes could be covered with one device, we would use one device to cover everything. That is usually true in the fenestrated type of atrial septum. We have quite a number of these patients in this study.

If the hole is far away from the primary hole, it may require a second device simultaneously. I have actually done over 10 patients myself with two devices simultaneously. We published the paper that came out two years ago describing 22 patients who received two devices.

Their procedural time, fluoroscopy time, success rate and everything is similar to those patients who have a single device. Yet, it is more challenging but I think because of the versatility of the device, it allows you to do these things with great safety.

DR. CRITTENDEN: The next question is does anybody really know what the natural history is of these residual shunts given that there may be more failures of residual shunts given that there may be more failures of residual shunts -- I should say not failures in the larger sizes.

We put more patients at risk for cryptogenic stroke, paradoxical emboli that we're going to create a disease with this? Not create but you understand. We're going to put more people at risk for this.

DR. HIJAZI: Ziyad Hijazi again. Very good question. The natural history has been published in many manuscripts after device closure that the majority of these tiny residual holes that are left in a patient, most of them they go spontaneous closure down the road.

Now, I do not know of manuscripts or reports that came out of patients who have small residual shunt. A few years down the road some of them have the TIA or something like that but I think that is an important question.

DR. CRITTENDEN: Finally, a comment. I was here in 1997 as well and remember it was quite a contentious panel meeting vis-a-vis what kind of comparisons could be made between device closure and surgical closure.

I guess this part of respect represents my bias as a surgeon that I think we could have done better. I'm really disappointed that we didn't have a better study that could have been done in the past four years. Mentally I understand that more patients are going to opt for having a device versus surgery. I mean, that's common sensical but I think we could have worked with surgeons in a more formal way. There's really an unfair comparison and we're basing a lot of conclusions on the comparison I think is highly flawed. That's all I have.

DR. TRACY: Are there any other questions going around again through the panel members? Dr. Williams.

DR. WILLIAMS: Just one follow-up question. I think on page 55 there was a difference in the secondary effectiveness variable among the sites.

I would like to just ask Dr. Hijazi if he has any wisdom about the learning curve for an institution or the operator or the secondary people such as the echocardiography that would advise us in terms of conditions once this device is available more widely that should be included as a condition.

DR. HIJAZI: Yes. This is Ziyad Hijazi. I will answer part of the question and leave the rest to Mr. Ken Lock about the training guidelines that we have.

There is no question that anything in you that you do has a learning curve. There's no question that anything new that you do has a learning curve. I do believe that with such an ideal device like the Amplatzer Septal Occluder with the ability to recapture, reposition the device gives the individual the ability to perform the procedure much better.

Obviously the individual has to be a very good interventional cardiologist but the interventional cardiologist is not the only person involved, although the person is doing the procedure. Echocardiology is extremely important guiding the entire procedure so collaboration between echocardiography and interventional cardiology will result in the least minimal amount of learning curve for that institution.

The other good news is that now most cardiac centers across the country are involved in one or more of the other devices that are undergoing clinical investigation. There's no question that the Amplatzer Septal Occluder has the least difficulty for a person to learn how to implant the device.

Let me put it like that. I think we will do very well with the training of the new physicians who are using current devices once the device gets approved. I'll leave the rest for Mr. Lock to talk about the other guidelines.

MR. LOCK: First of all, I wanted to speak regarding the one site that had a lower success rate. Again, keep in mind that the composite success kept those shunts and that did not reverse to success. That particular center had six procedure failures meaning there was a significant shunt post-procedure. Then eventually those patients all were successes at 24 hours or six months. That's the first part to the question. What I have up on the screen right now is a training program that we would like to implement at AGA.

This would be really three parts to it. It would be the tiered release of the device. Once we would have investigator approval to go ahead and implant, the Tier I would be our current investigators who have experience with the Amplatzer technology.

Then the second tier would be interventional cardiologists with experience with other transcatheter closure devices. The third tier would be just interventional cardiologists that we would proctor and train.

We would also require hospital approval and the hospital will be approved if the following are met. That they have surgical backup and that they have access to transesophageal echocardiography.

And the last slide here talks about the proctoring. We will assign proctors who are experienced clinical investigators and once a site is identified and approved as a site, the proctor will assist in the first three to five cases. We would like the proctor to after three cases assess how the new investigator is doing and then assess if there's more need for the proctoring.

Also the proctors will act as regional technical support so if there are any questions, they can be called upon to assist as needed.

DR. TRACY: Can I just ask what you mean by surgical backup? Does that mean an OR open on standby or what precisely are you asking for?

DR. HIJAZI: Ziyad Hijazi. Surgical backup would mean the presence of a surgeon in the hospital without the need for an open OR at the time. Even the five patients that we had embolization in them, patients were totally asymptomatic from hemodynamic point of view.

As a matter of fact, one of them had embolization over night and was ready to leave the hospital. Of course, we do echocardiogram and chest x-ray prior to their departure and we found the device embolized. We do not require like angioplasty or stent. Even now with angioplasty and stent they change it. Just in the house.

DR. TRACY: Dr. White.

DR. WHITE: I don't want to drag this out but I wanted to ask a couple of specific things. You have not in your exclusions eliminated patients with severe contrast allergies. Is that your intent? Do you not want to warn the operator that if a patient has a known severe contrast allergy, that they should not undergo this procedure?

MR. LOCK: This is Ken Lock. I think that we would include that as a contraindication.

DR. WHITE: And regarding your training of physicians on the section 3A on page 2, I guess --

DR. HIJAZI: Dr. White, your point about the severe contrast allergy, I personally as a physician would implant the device in a patient with allergy doing it without angiography with TEE and fluoroscopy without injecting dye so I don't think that it should be added as a contraindication for device implantation.

DR. WHITE: To contrast. Right.

DR. HIJAZI: Yes.

DR. WHITE: I think you need to handle that just on the labeling issues for the physician who needs to understand that you at least don't think that's a great idea to do that so that he pays attention to that as a plus or minus.

Under 4-1 you talk about the septal occluder system should be only used by those physicians trained in transcatheter defect techniques. My question is do you not want to say trained in the Amplatzer device or are you suggesting that if someone has skilled with any device? Is that what you mean? You mean generically or specifically?

MR. LOCK: I think generically. As I said, in the Tier II those will be our second round of investigators that would be trained in the Amplatzer technology. Our feelings on that were that if they have experience with septal occluders, in general they would understand the concept.

DR. WHITE: So the difference between the devices is not enough? I mean, they are pretty close to being there with a smaller amount of education than somebody who has not done this at all?

MR. LOCK: That's correct.

DR. WHITE: Under 4.2 you mentioned on your slide about backup surgery. I think that I agree with your caveat but I think it ought to also be spelled out that you believe that onsite surgical backup ought to be available. I don't think you need to have an open OR but you don't want to have this procedure being done in places that do not have surgery onsite. I think that's an issue.

Under B under Patient Labeling under Observed Risks you have listed the marker band embolization which is no longer an issue. You should probably delete that since marker bands are on the device. Under Potential Complications under Patient Labeling should you not list the left ventricular heart failure, the decompensation that potentially could occur?

I mean, is it possible that someone could have left ventricular heart failure with closure of this device? Is that a potential complication? You may not have intended it or may not think it's likely but it is a possibility.

DR. HIJAZI: Yes. This Ziyad Hijazi. This is a potential complication and usually in older patients with a stiff left ventricle if you close it.

DR. WHITE: So that ought to be listed for the patient.

Then finally under Appendix B -- I'm sorry, Appendix A at the very end you've listed that your device is tighter and more secure. It says, "The Amplatzer Septal Occluder is relatively new. How do we know it is going to be reliable?" You say its design allows a tighter more secure seal than provided by other devices.

Do you have any evidence for that comparison? If a patient reads this, are they going to pick your device? You want a patient to pick your device over a competitor's device based upon this?

DR. HIJAZI: Ziyad Hijazi. We'll take this out, this comparison, from the note.

DR. TRACY: Dr. Laskey.

DR. LASKEY: I just have a quick question for Dr. Wood. Is there ever a circumstance where you need to close the fenestrations surgically? In other words, mandatory?

MR. MOORE: This is John Moore.

DR. LASKEY: Sorry.

MR. MOORE: The protocol certainly did not require any specific setting to direct the patient to surgery as opposed to device closure. If the patient was going to require surgery anyway for prosthetic valve replacement or whatever, then transcatheter device closure is unnecessary and would not be suggested.

DR. McDANIEL: McDaniel. I'll ask another question along those lines. If the secondary fenestration or baffle leak is very close to the pulmonary artery and anastomosis, do you have any data suggesting the Amplatzer can be put in that position or is that someone you would send to surgery?

MR. MOORE: Well, there is a suggested rim requirement of 5 mm in general as has been alluded to by others. These are small devices and a 5 mm rim essentially is plenty.

DR. TRACY: Do any of the other panel members have any questions?

Dr. Wittes.

DR. WITTES: Yeah. I wonder whether you have the data yet.

DR. LARNTZ: I have not been able to get that. I will get that shortly. It will just take me a minute.

DR. TRACY: Two more in that direction.

DR. ZAHKA: Do you have any sense what the recommended age or weight will be for this procedure assuming that standard practice for atrial septal defect surgery is X? What will this be?

DR. HIJAZI: This is Ziyad Hijazi again. I think we will adopt the same criteria and indications similar to the open heart surgery. In every textbook of cardiac surgery when you read in papers they say that usually it is done before the child goes to school.

So if you have a one-year-old child with ASD, personally I would not send that patient to surgery even if devices are not available at all because that's not the age when we send patients to the OR.

We usually send them three to five years of age. I would do the same thing for devices. My recommendation for children is to undergo the closure just prior to them going to kindergarten.

DR. ZAHKA: Then I have a question about the geometry of the defect. Let's say that a defect is very oval in shape.

DR. HIJAZI: Yes.

DR. ZAHKA: The surgeons obviously change the geometry of the defect dramatically when they take a round defect and make it a slit and close it off. You are, in fact, doing the opposite if you took an oval or slit defect, you make it round and you stent it open. Do you have any sense that there is a subgroup of patients that have more arrhythmias or more this or more that as a result of stenting a defect open that is not circular?

DR. HIJAZI: That is a good question. Ziyad Hijazi. We do not have data on patients who have oval defects whether they had more complications or not. The complication rate of arrthymias in general is low in this cohort of patients. I think follow-up of these patients we'll find out whether changing geometry of the atrial septum will cause a problem or not.

My gut feeling tells me that most likely we will not encounter the problems that these patients are encountering after open-heart surgery on the long run with atrial arrhymias.

DR. ZAHKA: My last question is do you have a sense of what the timeline will be between Tier I, Tier II, and Tier III rollout for training of physicians?

MR. LOCK: This is Ken Lock. If it's approved today and as soon as the device is available, whatever that time frame, we haven't really looked at what the time frame is we will need to roll it out to those sites.

We will be very careful to make sure that we would take our time to get out to the Tier III. So really the Tier II will be the first ones that will be trained in on it over the next few months and then we will be cautious to move forward to the Tier III.

DR. TRACY: Dr. Hopkins.

DR. HOPKINS: I'm glad the training -- I didn't really focus on that the first time around so I'm glad it's come up because I think that's very important in these kinds of devices.

Is it your intent -- and given what Ziyad was talking about in terms of the experience with the larger defects and, with all due respect, not everybody is as talented in the cath lab as Dr. Hijazi. Is it your intent for the Tier III interventionalists that they would also be approved to attack defects larger than 25 mm?

Would there be any commendation at least by eyeball as the other panelists and as you yourself had indicated pose a greater level of difficulty which it appears the break point is around 25 mm that maybe those should be centralized and not fully opened to the total market? What is your intent?

MR. LOCK: I guess in those particularly cases where there are large defects have the size available because when you go into the lab you don't really know until you stretch size the device -- the defect. I'm sorry. We would be willing in those cases where we think that might be a larger defect have proctoring available and technical services available.

DR. HOPKINS: But your intent is in the Tier III that they would have equal access to the larger sizes?

MR. LOCK: Yes.

DR. HOPKINS: Just to comment again, I think I understand exactly what you said about the recommendation for closure. It does go back to the study design. I think all of us feel that ASD should be closed between the age of 3 and 6 and we not even deal with these older patients ever again. The study that is supporting the device is one done in older patients, not effectively to the kinds of numbers in the total device in the younger patient. That's just a comment, not a question.

The one final comment I would ask you to look at is in the patient literature that you give the patient. I would also agree that I thought it was a very good patient manual. Right above where it says, "Alternatives to device and treatment," you talk about the benefits of the procedure. This is on page 20 of 23 where you say many patients have the procedure done in the morning and go home at the end of the day or the following morning.

I would ask that you look seriously at the next sentence which says, "You won't have to endure the lengthy recovery period that would be required after surgery." I think that is a little loaded. Most of our patients go home the next day as well. It just seems a little strong in its language. I don't think you lose much by deleting it.

DR. TRACY: Any other questions from the panel?

Mr. Dacey.

MR. DACEY: I would like to address the patient information. All too often we make some assumptions about our patient populations. The rule of thumb as been for readability 5th grade level. That's been a national criteria. As I look through this, a few things occurred to me.

Clearly there are level and informed consent requirements in preparing patient information/ education literature. There is also this daunting task for physicians that you have this full spectrum. It's wonderful to say, "You should talk to your physician about any questions or concerns you have." That's correct but the community I live in the parent of a child with an ASD, one parent might be an astrophysicist whose been on the website and gathered volumes of information and come into the doctor's office with that and book in three hours of time to talk about it.

Of course, at the other end is the family who may not even speak English and they've got this information put in front of them and they can't even read it. Then I get into it and I look and I see medical jargon and I see illustrations like Figure 1, normal heart blood flow.

Then the next one is generally the same information but it's really a different illustration. It's those little tricks that confuse people. Then when you get into language, I looked at this and it says belly and legs. Now, that's 5th grade level. The higher level, of course, would be abdomen. It cries out to be simplified.

As I further went on -- well, I'll skip that one. The illustrations, the vein access sites are generally good but I would want to make them larger because there's an assumption that people can ready small things. That's not true.

Then you get into this jargonese, "The occluder is compressed into the catheter for delivery." Where are you going to deliver it to? This is a language issue.

Then we get over to Figures 4, 5, 6, 7. The previous illustrations are line illustration and all of a sudden we're looking at diagrams made off of an echo and there's no relationship back and forth. This will further confuse people.

There is really some very good patient communication expertise out there. If I can digress just for a moment, I've put a lot of time in the patient education area and communication with some ASD patients and families.

It turns out that the most remarkable teaching tool has been the model of a heart that the physician can use to point out exactly what's going on, where, and what they are going to do which is complimented by the printed material.

I understand that deals with the practice and not the efficacy and safety but I'm always concerned that patients get the information they need to make the best decision possible which is what everybody here wants also. I guess that summarizes my comments. Yeah, that's it.

DR. TRACY: Thank you.

Mr. Morton, questions or comments?

The sponsor looks like they have one more comment.

DR. LARNTZ: I just wanted to answer the question about age. The ages of the five failures, 3.6, 4.1, 5.2, 10.3. 15.9.

DR. WITTES: Can I do some calculations?

DR. LARNTZ: Sure.

DR. TRACY: Dr. McDaniel.

DR. McDANIEL: While she makes her calculations, one final comment on patient education material. You make the suggestion or statement that animal studies and clinical studies where thousands of patients have proven this reliability. Maybe there are thousands but, you know, it may be an overstatement. I don't know if it needs to be in there.

DR. TRACY: Dr. Crittenden.

DR. CRITTENDEN: I have a question that I'll ask while we're waiting for the electronic abacus to work here.

Dr. Hijazi, how many of the 4 mm and 38 mm devices have you deployed? Do you recall off hand?

DR. HIJAZI: I do not recall the exact number but I can tell you I have put a large number of the larger devices including the 40 mm, which is not being sought for approval here, obviously outside the United States.

Fifty percent of my patients in Chicago are people with very large ASDs about the size of 20 mm. About 45 patients with devices 28 mm to 40 mm. With the smaller most of my Fontan patients are the smaller devices, 4 or 5 mm. I'm sure Dr. Moore the same thing with his Fontan patients.

DR. CRITTENDEN: So for indications for ASD you thionk you need all those sizes?

DR. HIJAZI: Yes. Definitely.

DR. CRITTENDEN: As opposed to Fontan. IN the Fontan obviously you need a smaller one.

DR. HIJAZI: The smaller sizes for the Fontan and the small ASDs. Adult patients with their large ASDs you need the large devices to close their defects.

DR. CRITTENDEN: Thank you.

DR. TRACY: Dr. Wittes, have you finished your calculations?

DR. WITTES: Yes. I can't do any calculations but I'll tell you what my concern is. Now, if the criterion for success is this prespecified 8 percent, what this is saying is that all the failures are occurring in the young age groups where you actually do have surgical controls.

What I worry about is if you look at the data on page 6, it seems to me what it's saying is you have a comparison between kids less than 20 in the two groups. You don't have a real comparison over 20. You say that the five failures are all occurring in that less than 20 group. You are inflating that denominator in the device group by those people where there were no surgeries.

If you were to have made the direct comparison in the age group where you actually had data, I don't you'd hit your criterion. I was trying to calculate but I can't and I don't want to give the wrong number. The point is it seems to me this bears on the message that's coming out is you're almost -- you're equivalent.

You're not inferior if you use the devise. Yet, it seems to me that's an artifact, at least in part, of a very peculiar age distribution where there's no older people in the surgery group. I don't know if I made myself clear.

DR. TRACY: Can I just -- no. I'm confused because isn't it possible in some way just to lop off the older patients and just do a comparison between the Amplatzers versus the surgicals up to the age at which --

DR. WITTES: That's what I was trying to do but my machine didn't want to give me an exact answer.

DR. TRACY: Do you have any information that would answer that question?

DR. LARNTZ: My information is that it's going to be -- with respect to that group if you chose under 20, which I've not done the calculation, but I'm willing to speculate and my speculation is that it will be close to the boundary.

I don't think it's going to be going much below 8 percent because it's at 5.2 and, by my calculation, about 75 percent of the patients in the device group are under age 20 if I just did a rough calculation.

By that we will decrease the denominator by the same number of events. I think it will go down obviously. It will get very close to the 80 percent but I cannot give you an exact number right now. We could do that at some time but it's going to be very close.

DR. TRACY: Dr. Williams.

DR. WILLIAMS: I think if we were going to through the process of recalculating things, we ought to make sure that we retain the most important issues for the patient and remember that there was very conservative accounting for in terms of both -- in terms of efficacy.

I would say that if we were going to truly compare the same age ranges, I wouldn't be concerned about those who had shunts that closed before 12 months because I don't think that's important.

Just remember that there was a lot of very conservative calculation in favor of the surgical arm when this was done. If we evened that all out, I also have the impression not being a statistician that it would come out at least very close, if not still on the favorable side.

DR. TRACY: Okay. Any additional questions? If not, I'll ask the sponsor to step back from the table and we will review the questions posed to us from the FDA. Can we have those questions from the FDA put up?

The first question is, "Based on the information provided, please discuss the description

-- wait. I'm on the wrong thing. Hold on. I'm sorry. Let's try that.

"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." I jumped ahead in anxiety to get through this to this afternoon's questions. That's the real question up there.

Any comments from the panel on this? Please discuss whether individual endpoints, composite endpoints, or a combination of both should be used to evaluate safety and effectiveness.

Is there something -- maybe Dr. Wittes. You looked like you're posed to give us an answer here.

DR. LASKEY: Isn't this the domain of study design? I mean, this is a little late to be discussing this, choice of endpoints.

MR. DILLARD: Jim Dillard. We're in a little bit of a quandary here, I guess, because it is important obviously for study design to sort of prethink about what it is that we're going to use as the analysis tools in order to sort of define the hypotheses going in.

In this case we had some predetermined individual endpoints. We also had some thinking and some input from clinicians saying that perhaps a composite might be an appropriate way to look at this data and interpret it also.

I think at this point what we are really trying to get at is since we have both, it's important to understand what perhaps is going to be the best way -- if you recommend this be approved, the best way to actually portray the data in the labeling, for example, and how to best get this information to patients. I think it's important for analysis and it's also important for later on how we portray the data.

DR. TRACY: My personal observation on differentiating between success of Point A versus Point B is that it's led to confusion here and that the ultimate question is did it work or did it not work? Was the patient better off or not better off having had the procedure done in either way?

I think to that and the final endpoint whether it's a six-month or 12-month endpoint would probably be adequate but I think you have to know early on whether acutely the procedure has been considered successful.

From an analysis standpoint I think it makes it a little bit difficult to deal with these various endpoints. From a procedural standpoint and understanding what's happening to the patient, those points have to be analyzed as you're going along. I think it's the difference between a procedural need to know versus how do you deal with the data. I think deal with the data has a final outcome is probably reasonable.

Dr. Williams.

DR. WILLIAMS: Could I -- my point in saying that the 12-month endpoint is more important is to remember that for the usual indications these are asymptomatic patients. The procedure is done to prevent long-term complications.

The likelihood that a complication will result from a shunt that remains present at six months is negligible with the exception of perhaps cryptogenic stroke or right-to-left embolus.

But for the indications of closure for left-to-right shunt, I think it's meaningless if there is even a moderate shunt at six months that is closed at 12 months. That's why I think the longer term is the only important issue.

DR. TRACY: Does that get to the issues the FDA was raising?

MR. DILLARD: Almost. Maybe I could ask for one clarification for what Dr. Williams just said. Do you think 12 months and presence or absence of shunt would be the most important way to look at, or do you think the fact major complications embolization, technical failure, etc., also is important to include in that analysis?

DR. WILLIAMS: In my mind I think it's important to note both separately because of the issue that many parents or patients would happily take the risk of failure as long as there are no complications and so to keep those two issues separate.

I think, in fact, there are issues relative to the age group problem that are separate for efficacy and for safety. That is, I really do believe that the older population is at higher risk for complications despite the pericardial effusion issue because I think they are also at risk for post-pericardiotomy syndrome.

Whereas it may be true that they are given the anatomic variation in the younger group, they are a little bit more at risk for residual shunt or the decision not to deploy the device once they get into the cath lab because of anatomy that was not expected.

DR. WHITE: Could I just way one thing? I think the best number for me is not given here and that is that the 12-month composite success number is a very good number with the caveat that you allow the successes to occur.

What I'm saying is that they were originally asked to count an immediate failure or shunt as a failure. At 12 months if it closed they weren't allowed to add that as a success. I think if I had to give a family a single number, it would be the composite success with the ability to convert an initial failure to a late success.

DR. TRACY: Which I think, parenthetically speaking, gets to the very critical nature of the patient education that they understand that what you see today is not necessarily what you see in a year.

1b. The sponsor is seeking approval for a

device sizes from 4 mm to 38 mm. Approximately 89 percent 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 from 4 to 48 mm or a specific range of device sizes?

I think my read on the comments that have been made, and perhaps Dr. Crittenden will correct me, is that there have been use of the various sizes of devices from minimum to maximum. Perhaps not in equal numbers but that restricting the size ranges to those where they were more used would unintentionally or adversely restrict to the devices available to a variety of patient populations.

DR. CRITTENDEN: I agree. I think there's enough data from what we've heard from the sponsor's presentation that we probably ought to approve all the sizes that they've asked for in the application.

DR. WHITE: We might consider later on a post-marketing follow-up of those sizes that were less used.

DR. TRACY: Dr. Wittes is grimacing.

DR. WITTES: I'm bothered by this. Maybe I need some help here. This 12-month composite in this gradient that we're seeing with size, you really think that once the data are analyzed correctly with the failures that became successes, once those are back in those numbers will look better?

Because the way it looks to me that is not convincing to me when I look at these data that they shouldn't have surgery if you're going to have to have one of these big devices. That's really what I'm asking.

DR. TRACY: Can you point us to the page that you're on?

DR. WITTES: Yes. It's page 40, the yellow 1.0. I recognize that these are not going to be really the final numbers and that's part of why it's hard to interpret.

DR. WILLIAMS: I think that's part of the territory of having a large device. You have more opportunity for having the media shunt, residual shunt. That is the point of endothelialization. If that really occurs as those margins are secured and also the central part of that device is closed off. Those shunts go away.

That's why I think it is so important to only include the late data because those large devices have to leak more as best as I can understand. I think it's part of the territory of closing the large defects. The important issue is ultimately does it close.

DR. WHITE: But you're saying you think those numbers will get better?

DR. WILLIAMS: Well, they did.

DR. WITTES: How do we know that they did?

DR. WHITE: It think they told us that -- I don't want to speak for the company. I thought they said that at six months they had them all closed.

Do you want to reiterate what you said about the six-month follow-up? You had six-month follow-up on almost all your patients and how many patients at six months did not have a closed shunt. It was a very few number.

DR. WITTES: Well, do you have table 32 with the correct numbers? Maybe that would just do it. Table 32 corrected for the real status at 12 months.

DR. WHITE: You had a slide up of your failures. Can you put that overhead back up?

MR. LOCK: Jodi, can you grab --

DR. WHITE: You're not going to be able to answer that question because they counted those initial composite successes as failures and weren't allowed to convert them. I don't think they know how many to shift.

DR. TRACY: Yes.

DR. LARNTZ: This is Kinley Larntz. We do know that if you do eliminate the procedural shunts the composite success rate goes up to 91.7 percent from 85. About 6 percent of those cases were procedural shunts and those went away.

Now, the main aspect -- I apologize if I'm going over territory I've covered before. The main reason the composite does not have the size effect is that there are technical failures in that group so there is an inability to -- on occasion the device doesn't get placed because of rim or something like that.

That is the primary thing that is going on with respect to age -- excuse me -- with respect to size. There does appear to be -- it is more difficult to make sure that you've got a device placed properly. Some of those were pulled out and not included. Technical failure means the device didn't get placed. There is a higher rate of that and that's where the composite -- that's the association of composite with size.

DR. WILLIAMS: Well, I'm just a country cardiologist but it seems like if there's more rim, there's more opportunity for there to be a leak between the rim and the atrial septum. I guess my question would be of those devices that were placed that continued to have a shunt, at 12 months what were those sizes?

MR. LOCK: Jodi, could you put up slide No. 4, please, on the overhead?

This is Ken Lock. Again, I apologize for the darkness of the slide. You can look over at the primary efficacy column, the third from the right. You can see that the five failures at one year, there was one size 15, one at 16, one at 19, one at 20, and one at 24. Those were the failures.

DR. TRACY: Okay. Thank you.

Dr. Hopkins.

DR. HOPKINS: Yes. In discussion with the other panel members, I'm actually in agreement with both panel members. I think Dr. Williams is exactly right, that the outcome that exist at 12 months or even beyond is really the important outcome. For that reason those so-called early trivial failures really are not failures and shouldn't be so counted.

On the other hand, when you're talking about recommending to adult patients with a large ASD that closure of the ASD should be accomplished to prevent or reduce your risk of bacterial endocarditis and reduce your risk of paradoxical emboli, the absolute closure rate at some point in time does become important. I think you can look at it either way but it's really that sort of 12-month and beyond data. I'm sort of presaging the last question because I think there are questions that have bedeviled this panel now at two complete different sessions having to do with size and also with age that really still are not completely answered. I share your concern about the younger age group in terms of the comparative data.

I also agree with you in terms of the olders that a larger defect is clearly going to have larger residual defects and it's really the issue of whether they are actually completely closed at 12 months. Both the composite and the specific are important and over time.

DR. TRACY: Okay. So I think that gives us lots of comments pertaining to both 1a and 1b. We'll move on to 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.

I will look around the table and see if anybody is wagging their head no. I think that there are data to support the safety and effectiveness of this device and that it's just a little bit difficult analyzing what time should you ask the effectiveness question.

DR. LASKEY: Well, with some qualification because at the extremes here we don't have a lot of data points. I mean, there's a lot clustered in the middle but this is just what we've just been talking about for the last hour really, the extremes of size and age. There's not a lot of information so I don't necessarily agree with that, particularly with the efficacy.

DR. HOPKINS: I would separate the two. I think there is adequate data for safety but I'm still concerned. I would like to see the actual analysis in terms of efficacy for the lower age group and for the larger size group. I haven't seen that analysis here.

DR. TRACY: I think those would be -- the one analysis in terms of the younger age group should be doable from the data that is already available. In terms of the effectiveness, if we are saying that effectiveness at 12 months is more important, then it seems like something that would have to be followed over time so with those additional comments.

Question 2. To support the fenestrated Fontan indication, the sponsor has submitted data from a single-arm registry with 48 patients. 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.

DR. McDANIEL: I was going to say there is safety data there. Efficacy again depends on how you define applications and closing of Fontan. They got the shunts down to 2 mm or less.

DR. HOPKINS: I think this is one where the comparison with surgery does become very critical because the risks of surgery, the difficulty of surgery is not at all the same question as the routine ASD. That's why I think this is a much simpler question.

DR. WILLIAMS: I also think there's so many confounding variables in this population. It would be impossible to ever decide that perfectly.

DR. TRACY: Yes, Mr. Dillard.

MR. DILLARD: Yes. Jim Dillard. Maybe just one clarifying question. This is an issue we struggle with considerably and I think we've been beat up as the agency on both sides fairly well so I would love to get any comments from this panel.

If we have a completed study, a study that hopefully gathers patients over the range that would be appropriate clinically to take a look at a device, and yet we know we will never generally have enough patients no matter how many subgroups you wish to break it up into, one of the things we do as the agency is we will do exploratory analyses certainly on subgroups to look to see if there is anything particularly odd about those subgroups.

Generally as we try to break up those subgroups, and if we want to change an indication based on some of those subgroup analyses or only approve the device for some of the subgroups if we've got an overall successful clinical trial, I think it's problematic from a number of different perspectives, maybe most of which I think we get different comments from the statistician certainly on both sides pro and con.

I think it would be probably an injustice to clinical trials if we started doing the exploratory analyses on a regular basis and then trying to make that the justification or the basis for approval of the subgroups only if we had an overall successful clinical trial.

I would love to get any comments from the panel about if we did some of these exploratory analyses, what is it that you think we ought to look for and what do you think would be important then. I heard certainly size and age but they are going to be awfully small numbers.

DR. LASKEY: Jim, are you talking about both issues or are you just talking about the fenestrated Fontan right now?

MR. DILLARD: Well, I think it's come up in both of them. I know it's been precipitated based on the Fontan question because we're there but I think you certainly had some comments on both of them whether it be the ASD or the Fontan patient population.

DR. WITTES: Well, may I just ask you -- the Fontan I couldn't address because I didn't see what the comparison was. I didn't know how to even read it. It seems to me there is a really big difference between data dredging in the clinical trial and data dredging in a poorly controlled study.

It seems to me in the first you don't want to and in the second you really do because you don't have -- I think there has to be aggressive analysis. You want to make sure that there's nothing in the artifacts of the control group that is making things look better than they should.

It may be in this particular case that because of the way of doing analysis you are, in fact, being very conservative with respect to the surgery. I don't think -- other statisticians may disagree with me but I think one has to do exploratory analysis when one doesn't have randomization.

DR. HOPKINS: I would agree. I don't know if you had arrived when I pointed out I think that some of the negative outcomes of the surgery group are arguable. Yet, I agree with Dr. Williams that the device has been unfairly treated in terms of the 12-month outcome.

I think there are, in fact, confounding variables on both. When we get to the last question I think there are going to be some recommendations from this panel.

MR. DILLARD: Great. Thank you.

DR. TRACY: Question 3. A summary of the physician training program has been provided in Section 5 of the Panel Package. 3a. Please discuss any improvements that could be made to the training program.

Any comments from the panel?

DR. LASKEY: Case selection should be the first 10 items in the training program.

DR. TRACY: Probably case selection and being certain that the operator understands the definition of endpoints and what they are looking for as the outcome of the procedure as well as all the technical aspects.

Any other comments on that?

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.

I would think that would be not the first thing that somebody would take on. That and the larger sizes. You had mentioned that a proctor might be present for something like that. I think those very complex things would be best handled either with a very experienced proctor or in the proctor's hands while the operator is gaining experience.

Other comments?

Moving onto product labeling. Please comment on the INDICATIONS FOR USE section as to whether it identifies the appropriate patient populations per treatment with this device. That is in Section 3 if people want to flip to that.

We did have some comment early in the discussion. That goes to contraindications.

DR. LASKEY: Well, we have some assurance that first paragraph will be modified to eliminate the paradoxical embolus or PFO population.

DR. TRACY: The first paragraph in INDICATIONS FOR USE?

DR. LASKEY: Yes, towards the end of that paragraph. That's refers to that population. So these patients must have hemodynamic evidence of volume overload.

DR. TRACY: Okay. 4b.

DR. HOPKINS: Wait a minute. Can I ask a question? Are you suggesting that a patient who has had a paradoxical embolus through a small defect but does not have RVH would not be a candidate for closure? Did I hear you right or did I mishear you?

DR. LASKEY: No. I didn't say that at all but I would answer your question there's nothing in this Panel Pack that would support anything along those lines either with regards to safety or efficacy.

DR. TRACY: So are you suggesting just a revision in the wording to eliminate paradoxical embolism? What exactly would you suggest there?

DR. LASKEY: Well, I thought we had the assurance of the company that they were going to somehow modify this language so that it becomes clear that the INDICATIONS FOR USE of this device are patients with a secundum ASD with evidence of right ventricular volume overload and/or clinical symptoms.

DR. TRACY: So essentially the patient population as reflected in the patient includes --

DR. LASKEY: Yes. I mean, that's both a question as well as a reiteration of my understanding. I personally think you ought to avoid the paradoxical embolism population.

DR. TRACY: Dr. Williams.

DR. WILLIAMS: I would prefer that we say that the indications in that case have not been established rather than it's contraindication because we don't know it's a contraindication. We just don't have the data in that subset to support it.

DR. LASKEY: Correct.

DR. HOPKINS: I'd agree with that.

DR. TRACY: That could be specifically mentioned that there are no data dealing with that specific group.

DR. SKORTON: Another possibility would just be to cross it off. Just take it of period because the first part of the indication, the first four or five lines, is what the whole PMA is about. The part after "or" there is no data on so I would be in favor os just killing everything after the parenthesis ends.

DR. TRACY: I guess that's one option but then that might leave the physician open to the question should I or shouldn't I and what are the data that support or were any of those patients included in this study.

I think that in the indication I would agree that just lopping it off after the or part would be appropriate but in the specific description of the patient population there should be a statement that no patients were included who specifically had X, Y, Z.

DR. WHITE: I guess, Warren, just to go back to your question, if you would send a patient for surgical correction of an ASD because they had an paradoxical embolus, and if the endpoint that you wished to achieve is closure of the ASD, then I think what the data says in front of us is that the ASD is closed.

The question about whether or not you can stop further paradoxical embolus is what's not addressed. I think we need to be careful about how the clinician who is faced with this choice of closing an ASD how do we help him? How do we help her or guide that person's decision?

I mean, we're not looking at efficacy of paradoxical embolus but it looks to me like this device closes ASDs. So is it not appropriate then to leave it in the language or some in some other way?

DR. TRACY: I think -- my instincts would tell me to take it out since it's not included in the population. Plus there are whole issues of anti-coagulation that are not addressed if somebody has had a paradoxic embolus. We don't have any data that would say what to do with them with a device that may take a year or two to completely close an ASD. We don't know what to do with that patient given any of the data that is here in this application. I think rather than specifically mentioning them here where they were not included in the initial data, I think we should just take it off and then comment.

DR. WHITE: I think there were some patients included enrolled in the trial for this indication. Was there not?

DR. TRACY: Three.

DR. WHITE: A few.

DR. HOPKINS: Why wouldn't you just say indications have not been established for these two specifically because I think it is going to come up.

DR. TRACY: It will. Somehow it has to be addressed either here or following the table. But I don't think we have established this as an indication for this device based on three patients out of the entire study.

DR. HOPKINS: So just say that.

DR. TRACY: It's not a contraindication though either. You can work out where you want to put that.

DR. SKORTON: Could we talk about this a little tiny bit more? I think it's more than just a PFO. The other condition in which a person could have clinical symptoms of paradoxical embolus and the minimal shunt is someone with early Eisenmenger's physiology which also wasn't studied.

Three patients out of this to me doesn't make indication. I know you're not arguing for it to say it is an indication. I think it's more than just PFO. I think the indication that is strongly supported is for the common garden variety secundum ASD with a big shunt. I don't have any qualms about that whatsoever.

PFOs and early Eisenmengers, I just don't know what to make of it. I mean, you could say indications haven't been established. That's fine with me. I just wouldn't want to see that part left in the indication section. That's my only point.

DR. TRACY: I think that's a good point. I think that is pretty clear. It should be removed from the indication.

Okay. 4b. Please comment on the contraindication 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.

I think we were struggling to get a slightly tighter definition of any patient whose condition would cause the patient to be a poor candidate for cardiac catheterization. Maybe something slightly more specific. Size is obviously important and that is in your statement there. What other conditions make the patient a poor candidate?

DR. SKORTON: I'm sorry if I missed it but I thought in the discussion with the clinicians it was suggested that transesophageal echo was a very important part of this so there might be a contraindication if the person is not a candidate for transesophageal echo because of esophageal disease.

DR. WHITE: But if you can do intracardiac echo I think you can compensate for that.

DR. TRACY: That's right. ICE might take the place of TEE. Would you still feel that way if you could gain the same data by ICE?

DR. SKORTON: I guess I would personally feel okay about it but we're talking about labeling now and not how I feel. I think that intracardiac echo is not a universally applied technique. This is going to be universally marketable if we take a certain action.

I'm okay with that if we put some words in to that effect. Relative contraindication if you can't do TEE. If ICE is available, one could consider that. That means if there is a medical center where they don't do ICE, which I'm betting is most med centers, and the patient is not a candidate for transesophageal echo, it might be a contraindication or relative contraindication.

DR. LASKEY: Is Doppler a part of ICE now?

DR. HIJAZI: Yes.

DR. WILLIAMS: But it would make sense for those patients who have esophageal abnormalities be done in a high resource center that had the availability of ICE.

DR. TRACY: Okay. So adding some wordage in there about the use of TEE and relative or absolute contraindications that might exist for that. And some other plan would have to be in place to deal with those patients.

Does anybody want to raise the nickel allergy again? I don't know that that is a contraindication or whether that should be somewhere mentioned maybe as a warning or something, but I think it should be raised since nitinol may not mean anything to other people and the patient has to understand that there is nickel in there.

4c. then. 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.

DR. WHITE: I think that under 4.2 we need the specific wording about onsite surgery needs to be listed.

DR. TRACY: 4.2 is physicians must be prepared to deal with urgent situations which require removal of embolus devices that result in critical hemodynamic compromise. Yes, that should have some wordage about having surgical backup available.

Any other comments on warnings/precautions? I think there should be some wording in there about this does not supplant the need for Coumadin if there is another contraindication. That should be in there. Or another indication for the use of Coumadin. That should be in there somewhere.

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.

DR. WHITE: Well, I read through these as an operator who does these and they are tedious. I can't criticize them. You do need the proctor with you. These do not supplant the need for someone with experience with the device. You can't open a package and do this. I wouldn't criticize what they've written. I think they've done about as well as you can do but that just doesn't suffice alone.

DR. TRACY: This very clearly is a procedure that needs proctoring.

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.

If we are including the patient package, I think there are some issues there. The principle is good but the language needs tightening up and there's some actual physiologic things that were incorrectly stated in there.

Any other comments?

DR. WITTES: Can I add something? I would still like to add something to Table 5 because the person who reads this is going to only notice the age difference in one demographic table and this is going to be hidden away. It seems to me that one could take another panel of Table 5, just mimic it, and stick the less than 20 or some age group that you really have reasonable comparisons to.

DR. TRACY: That may come up again here in our next question.

Post-market evaluation. The Panel Package includes the available one-year data for the Amplatzer device. Long-term adverse effects that may be associated with device implantation include late thrombosis, etc., and arrhythmias.

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?

I think there are a number of comments. Maybe, Dr. Wittes, you can restate what you just said in terms of looking --

DR. WITTES: But what I had to say was actually different from this. This is more how should you follow individual patients and what's happening in long term.

Mine was just for Table 5 which shows the overall results including the group. I'm still worried about the group that doesn't have an age comparison. All I want is to make sure that the comparison is there.

DR. TRACY: Okay. Would it be worthwhile asking for follow-up on -- I guess we can't ask for more surgical data on older population. Is there anything we can do to improve the patient population that we're looking at here? Increase the population? Do we need to?

DR. HOPKINS: I think this is an important part of the panel's recommendations. I think that safety and relative efficacy has been shown here. I think the concern is that at the two ends of the spectrum we're still not absolutely sure about efficacy.

Therefore, I think the panel should recommend that there be designed at least a registry type of approach. If not looking at every patient who receives one of these devices, at least looking at those subgroup of patients who fall into those two areas, the large defect and the younger patients and the long-term residual shunt patients, as to what the long-term efficacy of this device is because that's fundamentally the question here.

The fact is it has been shown they are safe, that you can stick these things in and not hurt a lot of people. The question is really should this be the procedure of choice.

Unfortunately it is a long-term question but it is a question that has not been answered yet. I would recommend to the panel that we seriously consider requiring at the minimum a registry type of approach to asking that question over the relative long term about those two groups.

DR. TRACY: I guess the question is how long is long?

DR. HOPKINS: Well, when the ASD is completely closed at age three, the patient has a normal heart. It's being proposed that closing the ASD returns the patient to a normal life expectancy. You could argue they should be followed for life. I'm not necessarily proposing that, but I am proposing that I think that the large defects that are residual, that probably somewhere in the range of five years for the younger patients and somewhere in the range of five to 10 years, that a registry data and follow-up should be required so we can answer that question.

Dr. Williams.

DR. WILLIAMS: I agree with what Dr. Hopkins has said in terms of efficacy. I also maybe raise the question reacted to by my other colleagues in terms of safety for the largest devices which is a rather inflexible structure.

There have been some very sparse and non-peer reviewed abstracts that have suggested for very large atrial devices there have been some interference with shortening of the long axis of the ventricle in systole which may have some affects on ventricular function.

You would also wonder because if its location the very largest defects whether there could be some distortion of either the AV valve embolism and the function in that area.

Or perhaps some distortion of the aortic root with aortic insufficiency and if there shouldn't be some post-market surveillance with the very largest defects for both AV valve and posterior semilunar valve insufficiency as well as ventricular function. I really don't know how long. Maybe 10 years or so. Maybe Dr. Zahka has an idea about this.

DR. ZAHKA: I've actually struggled a bit eve this morning back and forth about what I think should be the long-term follow-up for these devices. Ideally it would be wonderful to have a 10-year follow-up, five-year follow-up where we had some kind of control group as well.

Since I think there are going to be a proportion of surgical patients who have ASD closure who are going to have arrhythmias, I don't know what I would do as a panel member 10 years from now, hopefully in my retirement, where we sat here and said, "Oh, my God. There are arrthymias 10 years out," because we don't have the control group.

Yet, I would wonder if we're going to start seeing aortic regurgitation or AV valve regurgitation. My sense is we're going to see that by a year. Are we, in fact, accomplishing anything by the five or 10-year follow-up? I assume there is going to be some kind of like a pacemaker registry at the company of these patients.

If the case reports and the medical literature do begin to suggest that there is something going on, I would hope that we would then be able to in a very systematic say recall patients for a prospective evaluation at that time when we know what we're looking for and be able to collect the data in a very logical and effective way.

DR. WILLIAMS: I'm persuaded by the arguments of my colleague but because of the stockmarket I will probably still be working.

DR. SKORTON: I have a compromise to suggest. I'm still a little bit uncomfortable with some of the subgroups, and yet I think 10 years is a very long time. A lot of things change in 10 years. I better be retired in 10 years.

Also, we need to help the FDA and the sponsor by giving some discrete endpoints and things to look at. Just as a strawman, I'm going to suggest that we recommend a five-year post-market surveillance of the groups implanted with devices larger than 28, smaller than 10, those with residual shunts, and those implanted under age 10 years.

And at the endpoints we look for our just thrombi and endocarditis and general cardiac function on echo, that we don't do the arrhythmias because they are very hard to interpret.

Those might not be the exact right ones but something like that where we give them a discrete number of things to look for and those will be the things based on which the FDA would call us back to talk about them later.

DR. WHITE: As an adult cardiologist could I suggest that we might include the paradoxical emboli patients and follow them as a post-marketing surveillance. This is a small population of patients that are not likely to be prospectively studied. IT's not likely that we are going to see data on ASDs with paradoxical emboli to above.

This is an opportunity to collect that data in a post-market environment which would be fairly disciplined. The device is performed in a small population of these patients.

I understand the difficulty in feeling comfortable about the prevention of the paradoxical emboli but I'm not uncomfortable about the ability to close the ASD. That's why I feel like the glass is more half empty than half full about this.

DR. TRACY: That would suggest that the structure or the registry would include data for the clinical indication and that would be one of the questions that would be asked.

Mr. Morton.

MR. MORTON: Could I make a couple of comments? The agency recently sponsored a workshop on post-market studies and surveillance and it concerns me that we're using the term registry because registry I know from experience with other devices they are awkward.

They are difficult to deal with. You get a lot of information that is not necessarily the information that you want. It's not necessarily information that is going to answer the questions that you're asking here. I would suggest that really you're not looking at a registry. In your recommendation is was not a registry. It was not.

I would also ask that we ask the sponsor actually is there information in both their cohort and in their continued access study. That seemed to be quite a few patients. Could there be data there that is going to answer these questions without moving into a true post-market study which would be extremely difficult to manage?

DR. TRACY: Those are very good points.

DR. HOPKINS: I stand corrected on the registry. I actually think, Dr. Skorton, your recommendation is very close to being on point. At the five-year you might identify one or two issues that need to be followed another five years.

I think we have evidence that certainly with valve patients we've significantly altered their national history and they really need to be followed for a long time before we really sort out what the best options are. I think the case is going to be similar here. I think it's a good on-point.

DR. TRACY: Dr. Zahka.

DR. ZAHKA: I was just wondering if there was a one in a thousand or one in 500 risk of a late thrombus and/or endocarditis, would that change our recommendations today if we knew that information today? Or one in a hundred with endocarditis or late thrombus.

DR. SKORTON: That's really a tough question to answer but I think the answer is it's not just a matter of what we would do. It's a matter of what the materials in the device might change. The way it's put in might change. The anti-coagulation you give might change. There are so many moving parts.

Plus the companies aren't going to stand still while this is going on. They are going to develop better materials, different wires, different polyester. I think it's a moving target.

I think that your point is well taken about not having a widely open registry. I think a tightly focused series of studies and follow-up will make us feel better and will help move the field along.

It won't be too intrusive on the company's time or on the clinical investigators. I think we make our best guess now as to the things we want to follow and hopefully we don't find anything.

DR. TRACY: That covers the written questions by the FDA. Does the FDA have any additional questions or comments at this time?

MR. DILLARD: No. That's it from FDA. Thank you.

DR. TRACY: Okay. Does the sponsor have any additional comments? Okay. Then at this point I would like to give time for an open public hearing. Is there anyone in the audience who wishes to address the panel on this topic before we take our vote? Okay. Then we will close the open public hearing.

MS. MOYNAHAN: I'd like to read through the options for the vote.

The Medical Device Amendments to the Federal Food, Drug, and Cosmetic Act as amended by the Safe Medical Devices Act of 1990 allows the FDA to obtain a recommendation from an expert advisory panel on designated medical device premarket approval applications that are filed with the agency.

The PMA must stand on its own merits and your recommendation must be supported by the safety and effectiveness data in the application or by applicable publicly available information.

Safety is defined in the Act as reasonable assurance based on valid scientific evidence that the probable benefits to health under conditions on intended use outweigh any probable risks.

Effectiveness is defined as reasonable assurance that in a significant portion of the population the use of the device for its intended use as conditions of use when labeled will provide clinically significant results.

Your recommendation options for the vote are as follows:

(1) Approval if there are no conditions attached.

(2) Approvable with conditions. The panel may recommend that the PMA be found approvable subject to specified conditions such as physician or patient education, labeling changes, or further analysis of existing data. Prior to voting all of the conditions should be discussed by the panel.

(3) Not approvable. The panel may recommend that the PMA is not approvable if the data do not provide a reasonable assurance that the device is safe or if a reasonable assurance has not been given that the device is effective under the conditions of use prescribed, recommended, or suggested in the proposed labeling.

Following the voting the chair will ask each panel member to present a brief statement outlining the reasons for their vote.

DR. TRACY: I'd like to ask for a motion at this time regarding the approvability of this device. Dr. Williams, as the lead reviewer, you are certainly welcome to make that motion.

DR. WILLIAMS: I move approval of the use of the Amplatzer Septal Occluder device in patients with ASD in the secundum position and patients requiring closure of the fenestration following a fenestrated Fontan procedure.

DR. TRACY: Are there any conditions you would like to place on the approval? Does any panel member feel that any conditions should be placed on this?

DR. LASKEY: I do. I think we've discussed that. I think the conditions to be applied pertain to post-marketing surveillance of some high risks of groups which I guess we can discuss openly here.

She recommended approval without conditions. There is no second part so the first thing is do we have a motion.

MS. MOYNAHAN: Is that what you were suggesting as approval without any conditions attached?

DR. WILLIAMS: No. Actually I had thought we could then say if there was an amendment with conditions. I move for approval with conditions of post-market surveillance.

DR. TRACY: Then if we could delineate what those conditions are, we'll discuss and vote on each of the conditions before we vote on the approval. So we have one condition is that there must be some type of surveillance put in place to look at the patients at the extremes, the large size and the younger ages, and following those devices over time the exact mechanism of that surveillance is not determined. There may be data available within that total population which can give some of that information but there likely will need to be some ongoing surveillance of the device. Does that state what the panel intends?

MS. MOYNAHAN: I think we should vote on each one separately, each condition.

DR. TRACY: Okay. All those in favor --

DR. HOPKINS: Point of process. How specific do you want us to be on these conditions?

MS. MOYNAHAN: You can refer to your earlier discussion and say as we discussed earlier. For example, with labeling or the post-market surveillance.

DR. HOPKINS: Then I would like your motion really, or the amendment to your motion, that it be really to suggest Dr. Skorton's recommendation for the post-market surveillance studies.

MR. DILLARD: Jim Dillard. Just a real quick recap of process. I think you've got a motion on the table for approvable with conditions that was seconded by Dr. Skorton. Now we're at condition No. 1 which is a post-market surveillance effort.

I think you can have any discussion that you want associated with that particular condition and then you can go ahead and vote on each particular condition and then at the end on the entire motion if that helps.

DR. TRACY: So the condition -- the condition is that we have post-market surveillance. Referring back to the earlier conversations, Dr. Skorton laid out some pretty, I think, reasonable and specific points to follow. For that condition, can I take a vote for all in favor of condition No. 1.

MS. MOYNAHAN: Nine in favor.

DR. TRACY: Opposed? Okay. So condition 1 is approved.

Any additional conditions?

DR. WHITE: Can we discuss the follow-up of the paradoxical embolus indication? Add that as well as a post-marketing tool.

DR. TRACY: I think that might have been included in the prior discussion regarding the surveillance. I don't think we need a separate motion on that. That is included in the discussion that we had.

DR. WHITE: Then also can we discuss as a condition then that we adopt the labeling recommendations that we made, the changes to the labeling>

DR. TRACY: Yes. That's fine. Labeling changes. To summarize, the labeling changes that we are proposing. Help.

DR. SKORTON: They were in the indications and contraindications and precautions and warnings.

DR. WITTES: Table 5.

MR. DILLARD: Yes, in Dr. Wittes' Table 5. I didn't hear this specifically but just a question, I think, for the committee. In terms of taking a look at some of the subgroup analyses, which I don't know if Dr. Wittes is going to bring up again, but if we look at some of the extremes, how would be handle that in the labeling and would you have any additional suggestions based on how we would look at the data? That's the only thing I didn't hear specifically about a labeling change.

DR. TRACY: Maybe Dr. Wittes can if she's had a chance to do some more calculations on that, but I think that the thing that we don't have data on should be stated what we do and what we don't have data on.

That can then leave some discretion in terms of the operator how they want to handle that lack of data without specifically contraindicating the procedure for that type of clinical situation. Any other --

DR. WITTES: But, again, I think it's a little more subtle than that. It's that there are data but they are not directly comparable. I think that is the subgroup issue here.

I don't know how to answer the question and I don't know what I think. What I feel is that what is presented currently is not sufficient and doesn't reflect what the data show.

One of the problems is we don't really know what the data show because we haven't seen the analysis that would say, "Ah ha, this is what the data are showing relevant to specific questions."

I guess one of the things I don't understand is if you see a patient, do you say, "This is a five-year-old. Should I make this choice or that choice?"

"This is a 10-year-old. Should I make this choice or that choice?" "This is an 18-year-old."

I mean, do you as clinicians think about the age of the kid or the adult and make a decision that is pertinent to that age, in which case I think it's very important, the age and the size.

DR. WHITE: I think that's a different issue than this committee should decide, though. I think we're asked to look at the reasonableness or the probable efficacy and safety. I think we've seen nothing that suggest that it's not reasonable to think that's going to be safe.

I think that a clinician might well make those judgements and individual patient interaction. I have seen nothing about the extremes of the device that make me nervous that it's not going to work.

DR. WITTES: No, I'm not saying that. But it seems to me we haven't seen the data analyzed in a way that addressed those issues at all. In a clinical trial you really wouldn't worry so much about it.

In a situation like this I think the data should be presented. The presentation may just make everybody feel great. This is fine. But in the absence of a good control, I do think that there needs to be more on the label that describes analysis.

DR. TRACY: Let me see if I can put this together. One condition is that we would recommend some changes in the labeling that would indicate who has and who has not been studied in this protocol more clearly, the few little changes which you can refer back to the previous discussion regarding the nickel and the anti-coagulation issues, etc. That would be one condition.

I do think there is another condition that we will be asking the company to provide additional analysis of their data to the FDA that would take out those upper age ranges that were not really included in the surgical group. I think that is an additional condition that we might come up with. However, I would like to take a vote, if that's all right, on the condition regarding the labeling as we have discussed.

DR. SKORTON: I just have one question. I do share some of your concerns but I don't think they should affect the labeling. I don't think they are discrete enough to affect the labeling. I haven't heard you say anything.

I'm not convinced, for example, labeling should say this device is not proven to work in younger people or older people. When I'm going to vote on labeling, I'm talking about the precautions, warnings, indications, contraindications. The only indication one that I thought we agreed on changing was the one having to do with the PFO.

DR. TRACY: Correct.

DR. SKORTON: But we weren't going to have a disclaimer in the indications about the extremes of age. I thought that was the point of doing a post-market study.

DR. WITTES: I fully agree with that. All I'm saying is that when the data are presented as a summary, that summary should be expanded, but not to say don't include it.

MS. MOYNAHAN: Can we take a vote on the labeling?

DR. TRACY: Yes, on the labeling. All those in favor of the condition dealing with labeling that we've just discussed, please indicate so.

MS. MOYNAHAN: All right. That's 10 in favor. We do have 10 voting people here. I only counted nine in the last one. Was there anyone that abstained or voted against it that I missed or was everyone's hand up for the surveillance issue? Okay. That was 10 in favor then.

DR. TRACY: Okay. All right. Then there is nobody that's opposed to that condition. Any additional conditions? Do we want to try to turn the request for additional analysis into a condition? No. That's just simply going to happen. Okay. Any additional conditions? Okay.

At this point we need to vote on whether the device is approvable with the conditions as we have already voted on or not. All in favor of approval with the conditions as stated.

MS. MOYNAHAN: That's ten in favor. Then we can also go around and each person can state their vote and the reason for it.

DR. WHITE: I'm Chris White and I vote for the motion with limitations because I'm convinced that the data that's been presented today is reasonably safe and effective.

DR. WILLIAMS: Roberta Williams. I vote yes because I do believe it passes the reasonableness test.

DR. SKORTON: I'm David Skorton and I vote yes because I believe it shows reasonable evidence of safety and efficacy.

DR. ZAHKA: I'm Kenneth Zahka and I voted yes because I think this will help a number of children and young adults with atrial septal defects.

DR. HOPKINS: Dr. Richard Hopkins. I voted yes because I think it does meet safety and efficacy against the arbitrary standard. While the discussion well reflects our concerns about the relative efficacy with other options, that is going to be addressed by the conditions imposed and by clinician judgement.

DR. AZIZ: Salim Aziz. I voted yes because I think it does demonstrate safety and efficacy.

DR. TRACY: Dr. Laskey.

DR. LASKEY: Yes. Warren Laskey. I voted for approval with the conditions much as my colleagues have. I would like to also personally acknowledge the efforts of Dr. Amplatz who is standing in the corner there who made a major, major contribution to interventional cardiology.

DR. McDANIEL: Nancy McDaniel. I voted in favor of approval with the condition stated having met the safety and efficacy. Again, it's going to be a great contribution to the care of these patients.

DR. WITTES: I votes yes for much the same reason as everybody else did.

DR. CRITTENDEN: I voted for approval with conditions for similar reasons. It was safe and relatively effective.

DR. TRACY: Any additional comments, Mr. Dacey or Mr. Morton?

If not, we will end this portion of today's meeting and break for lunch. We have a vote to come back at 2:15.

(Whereupon, at 1:34 p.m. off the record for lunch to reconvene at 2:15 p.m.)

 

 

 

 

 

 

 

 

A-F-T-E-R-N-O-O-N S-E-S-S-I-O-N

2:17 p.m.

DR. TRACY: I'd like to call to order this meeting of the Circulatory System Device Panel. The topic for discussion this afternoon is a premarket application for NMT Medical CardioSEAL Septal Occlusion System with Qwikload.

At this point I would like to hold an open public hearing. There were no requests ahead of time but is there anybody here who would care to make a presentation on this or other topics?

Okay. If not, then we will close the open public hearing and move on to the sponsor's presentation.

MR. AHERN Good afternoon. My name is John Ahern. I'm the President and CEO and Chairman of the Board at NMT Medical, a public company and I am a stockholder in that company.

Madam Chairperson, panel members, and FDA representatives, we are pleased to have an opportunity to present data in support of the safety and efficacy of the CardioSEAL Septal Occlusion System device in the treatment of complex ventricular septal defects. More common forms of congenital VSDs, which can be readily identified and repaired using standard surgical procedure, are not a subject of this PMA.

Clinical data used in support of this PMA were obtained from a ongoing clinical trial sponsored by Children's Hospital, Boston, and provided to us under a licensing agreement.

Following my brief introductory remarks our presentation will proceed as follows:

We'll have a device description presented by Carol Ryan who is the Vice President of Research and Development of NMT Medical. Followed by discussion of indications by Dr. John Mayer. Dr. Mayer is a Senior Associate in Cardiovascular Surgery at Children's Hospital in Boston, Professor of Surgery, Harvard Medical School.

We will then have a discussion of the procedure by Dr. Peter Laussen. Dr. Laussen is Co-Director, Senior Associate in Anesthesia, Children's Hospital, Boston, and Associate Professor of Anesthesia, Harvard Medical School.

Following that we'll have the clinical trial overview by Dr. Kathy Jenkins. Dr. Jenkins is Associate in Cardiology, Children's Hospital, Boston, Assistant Professor Pediatrics, Harvard Medical School.

Then we'll lead on to trial results and analysis by Dr. Kimberlee Gauvreau. She is an Associate in Cardiology, Children's Hospital, Boston, Assistant Professor Pediatrics, Harvard Medical School. Also Dr. Gauvreau is the Assistant Professor of Biostatistics at Harvard School of Public Health.

Then we'll follow with conclusions by Dr. Jenkins.

We've also invited a number of experts who are familiar with either the VSD device in clinical trial or the statistical data, the clinical data involved with that.

I would like to introduce Ms. Amy Britt who is the Research Manager of Children's Hospital in Boston, Dr. Mark Boucek who is Medical Director of Pediatric Heart Transplantation, Children's Hospital in Denver, and Professor of Pediatrics at University of Colorado, Hill Sciences.

Also Dr. Mark Hoyer. Dr. Hoyer is the Director of Interventional Cardiology, Riley Hospital for Children, Indianapolis, and Clinical Associate Professor of Pediatrics, Indiana University.

Finally, Dr. James Lock, Cardiologist-in-Chief, Children's Hospital in Boston, Professor of Pediatrics, Harvard Medical School.

They are here today and available to answer any questions as needed.

Just a brief marketing history of the CardioSEAL device. The FDA has already approved the device based on its safety data and it's commercially available in the United States under the Humanitarian Device Exemption Regulations for three different HDE approvals, one of which is the same indication proposed by the PMA which was approved by the FDA almost two years ago.

The other two HDE indications were for a PFO closure in patients failing medical therapy and also the fenestrated Fontan procedure. The device is also commercially available in the European community, Canada, Latin America, and the Pacific Rim. Approximately 10,000 CardioSEAL devices have been implanted since 1996.

I would like to introduce Carol Ryan who will provide data on the device.

MS. RYAN: Good afternoon. Again, my name is Carol Ryan. I'm an employee of NMT Medical and a shareholder.

The CardioSEAL Septal Occluder is a second generation device which has been designed for percutaneous closure of intracardiac defects. The CardioSEAL implant is comprised of a structural framework and a tissue scaffold.

The structural framework is fabricated primarily from MP35n, an alloy which has excellent corrosion resistance and is inherently non-ferromagnetic. MP35n has been used in a variety of implants including pacemaker leads, stents, aneurysm clips, and orthopedic applications.

The tissue scaffold is knitted polyester fabric similar to those commonly used for vascular grafts and cardiac patches.

The implant is available in four sizes ranging from 17 mm to 33 mm. The design is similar to a double umbrella with each umbrella comprised of four MP35n springarms or eight per device.

Each springarm has three functional coils per arm. The center coil, which is called the shoulder coil, the elbow joint and the wrist joint. These coils are put there to control functional stresses within the springarm and provide adequate fixation within the heart.

A pin is centrally located on the proximal side of the device for attachment to the delivery system. Platinum springs are soldered to the end of each springarm for enhanced radiopacity. The tissue scaffold, a knitted polyester fabric, is attached to the framework using polyester suture.

The implant is packaged attached by suture to a disposable loading system called the Qwik Loader. The Qwik Loader is utilized to collapse the umbrella and introduce it into the delivery sheath. The CardioSEAL delivery system is designed to facilitate attachment, loading, delivery, and deployment of the CardioSEAL through a commercially available 10-French sheath.

One-size delivery system is compatible with the entire family of CardioSEAL implants. This particular version of the delivery system is a third-generation design with improvements and ease of use over prior generations.

The system is comprised of a control handle, a catheter shaft of pushing the implant through the sheath, a spring guide with a sleeve on the distal end for capturing the implant pin wire and the delivery system pin wire.

This video depicts the attachment and loading of the CardioSEAL implant. First the pin wire of the delivery system is advanced from the sleeve at the distal end of the spring guide. The implant pin is now placed within that sleeve and the two pins are locked in place.

The implant is then collapsed within the Qwik Loader. The occluder disc, which is a packaging aid, is disposed of. You can see the implant being pulled into the clear part of the Qwik Loader.

The catheter shaft is advanced to be adjacent to the implant. A Touhy-Borst is attached which will be used for flushing the system to remove air bubbles. Several of the loader components are now disposed of.

The suture is being removed there. The system is thorough flushed to remove air bubbles. This is easily visualized through the clear tube. Then the Qwik Loader is placed into a 10-French sheath in place across the defect.

Critical design features of the CardioSEAL implant include a design focused on long-term biocompatability including a well-characterized tissue scaffold which promotes fast and thorough encapsulation. This photo of a sheep explant at 90 days demonstrates the complete endothelial coverage of the implant.

The spring arms are where the laser is pointing. This is the edges of the device. There is complete endothelial coverage of both the fabric and the spring arms including the device septum interface. The metallic framework has excellent corrosion resistance and a low medal surface area to minimize leeching and it is MRI compatable.

The double-umbrella design gives the implant the ability to conform to variable anatomy and a low profile in the septum following implantation to minimize hemodynamic disturbances.

Now, I would like to introduce the next speaker, Dr. John Mayer of Boston Children's Hospital and Harvard Medical School. Dr. Mayer will speak on the INDICATIONS FOR USE of the CardioSEAL.

DR. MAYER: I have no interest in this company and have only been paid for travel and an honorarium. I am here to speak with you for, if you will, the surgeon's perspective about this device and its utilization. Hopefully I go in the right direction on the slides. And I didn't.

I apologize to my pediatric cardiology and cardiac surgery colleagues who are on the panel, but for the other members I would like to review a little bit about what the anatomy is that we're talking about.

Defects in the ventricular septum can occur in a variety of locations, the most common one being here in what we call conoventricular or perimembranous area, but they can exist in any point in the right ventricle. This view is as though the interior wall of the right ventricle has been removed and one is then looking at the septum.

The defects in particular that we are talking about as applications for this device are those down here in the apical muscular area where there is a lot*of trabeculation in the right ventricle that can cover the right ventricular side of the defect and primarily those also in the anterior muscular area. We'll go into that in more detail.

This slide is simply to just give you an idea about the occurrence of these various sorts of defects in these locations. This is based on a review of a large number of cases over a 15-year period at children's hospital in Boston.

You can see the perimembranous VSDs are, in fact, far and away the most common defects, but there are a significant number of patients who have both muscular and multiple ventricular septal defects.

This is actually from a series from the University of Alabama in Birmingham and the only reason for showing all of this data is to point out that, in particular, if one looks at risk factors for mortality after surgical ventricular septal defect closure, the presence of multiple ventricular septal defects, particularly when they are in that trabeculated area of the ventricular septum, are the ones that are associated with the highest mortality, at least in that series.

And this is just an angiogram demonstrating the types of defects that we're talking about. You can see, in fact, here there are multiple holes, one in the perimembranous area but two down here in this more heavily trabeculated area of the right ventricle. These are, in fact, the defects that we're proposing and have gained experience with for device closure.

So one of the questions that clearly is germane to this issue is what would be a high-risk or complex VSD and I will provide you with my own viewpoint of that. There are two major criteria.

One is that the typical surgical approaches would compromise ventricular function and, in particular, the use of left ventriculotomy. I'll show you some pictures of how that works from the surgical perspective.

Or a very extensive right ventriculotomy which might be necessary to close multiple holes. Or that there is a high probability of there being a significant hemodynamically significant residual ventricular septal defect.

Some cases in which that can occur are in patients who have failed a previous VSD closure, in those patients who have multiple apical or anterior muscular VSDs. A terminology has been used sometimes that this is a so-called Swiss cheese septum, multiple holes. And certain isolated posterior apical ventricular septal defects which are covered by the trabeculations as we showed in the previous slides.

I think certainly when I came to Boston a left ventricular approach was a standard approach to defects in this heavily trabeculated part of the septum. This is just an artist depiction of how this operation is performed so that one actually makes an incision in the left ventricle.

The reason for doing this is because in many cases these defects are single and actually relatively easily identified from a left ventricular aspect, but from the right ventricular aspect they are much more difficult because of all of the crossing trabeculations. One can simply through this left ventriculotomy sew a patch in to occlude the defect.

When we looked, however, in the late 1980s at a group of patients who had undergone an apical left ventriculotomy for defects in this area, what we found is that fully half of the patients who had undergone that approach had a significant residua as a consequence of this approach.

Despite the fact that many times this seemed as though it was easy to close, there were a significant number of patients who had residual ventricular septal defects.

We had three patients or three episodes where an aneurysm formed at the site of the left ventriculotomy. A significant number of the patients had clinically significant left ventricular dysfunction after this approach. Actually two of the patients either went on to die or had to be transplanted.

Now, as I think was already alluded to, this device is not being proposed to be used to close every hole in the ventricular septum. Certainly we have evolved as an institution to take the following approaches, and that is that defects that are close to the atrial ventricular valve leaflets or the chordae or defects that are close to the semilunar valves are ones that we have not employed this device to use clinically.

To remind you again, we are not talking about defects that are easily accessible from a surgical perspective, those in this so-called subpulmonary area, the perimembranous area, because of their proximities to the either semilunar or atrial ventricular valves.

Defects in what we would call the inlet septum or AV canal type of defect are not ones that we would propose to use the device for. We are really talking about defects down here in this heavily trabeculated part of the septum.

So, in summary, we would use conventional surgery for the conoventricular VSDs so that includes perimembranous VSDs now align the defects as occur in tetralogy. Inlet VSDs, we have used surgical approach for single large high anterior muscular VSDs and certainly those for the outlet VSDs.

Our current approach is, however, to use a transcatheter approach for multiple apical and anterior VSDs and posterior apical VSDs covered by trabeculations. We have utilized the device in certain post-repair residual VSDs.

Thank you. I'm going to introduce to you Dr. Peter Laussen from our cardiac anesthia group who is going to describe the procedure.

DR. LAUSSEN: Good afternoon, ladies and gentlemen. My name is Peter Laussen. I'm Co-Director of the Cardiac Anesthesia Service at Children's Hospital and Associate Director of the Cardiac Intensive Care Unit.

I have no financial relationship with NMT Medical. They are covering my expenses for this presentation, however.

My presentation goals are to describe the technique initially with an animated video and some angiographic still frames. But as way of introduction, I think it's important to emphasize that in contrast to our experience with ASD and PDA device deployment, there may be hemodynamic events that occur during the placement of a VSD device across a complex VSD.

However, with appropriate anticipation and collaboration between our staff and the catheterization laboratory, patients are safety managed during this intervention.

Let me first start with the video produced by NMT.

(Whereupon, there was a video presentation.)

DR. LAUSSEN: Next I would like to show a number of still antiographic frames that highlight aspects of this procedure because it's germane to discussion about adverse hemodynamic events.

In this particular still frame a petal catheter has been placed within the left ventricle and on left ventricular angiography the muscular VSD is demonstrated.

As also shown in the video, this still frame demonstrates the antegrade passage (trans-atrial septal) of an end hole balloon tip catheter from the left ventricle across the VSD into the right ventricle. It is generally easier to cross the VSD from within the left ventricle because of the trabeculations on the right ventricular septal surface.

This slide demonstrates the transvenous-transcardiac guidewire pathway. In this circumstance wire has been delivered through the femoral vein infera vena cava transeptally across the mitral valve to the left ventricle across the VSD into the right side of the circulation where it is being snipped and removed from an alternavenous access site which, in this case, is the internal jugular vein.

The importance of this is that undue pressure applied to this wire may directly injure the myocardium and cause acute atrial ventricular vulvar regurgitation. It is the passage of this wire and subsequent large sheaths that may result in homonymic adverse events during the procedure.

It is easier rather than to leave a large 11-French sheath within the atrial system in the femoral artery and across the aortic valve, generally the VSD is crossed from the right ventricular side with a large 11-French sheath which in this circumstance has been passed from the internal jugular vein down across the VSD crossing from the right ventricle to the left ventricle.

The CardioSEAL delivery system is delivered through the sheath. The distal arms are open within the left ventricle and the device is then removed back against the left ventricular side of the septum and then across the septum for deployment of the proximal arms. Also the transesophageal echo probe which is used to assist with deployment of the VSD device across the septum.

Following deployment of the device, the device is detached from the delivery system and an LV angiogram is performed to demonstrate appropriate position.

The reason for going through these angiographic slides is to highlight the transvenous-transcardiac pathway of the guidewires and sheaths because the hemodynamic adverse events that may occur during this procedure are primarily related to the technique.

Early in our experience we evaluated patients undergoing this procedure, the hemodynamic and potential cardiac complications during this procedure and determined that the complications and adverse events were independent of the patient's diagnosis or indication for device deployment independent of the pre-catheterization clinical status as assessed by ASA classification and independent of patient size.

However, acute resuscitation may be necessary during the procedure despite the events are readily treatable and reversible. Hemodynamic instability, therefore, may relate to hypovolemia which primarily relates to frequent catheter changes through large sheaths because of arrhythmias which may be ventricular, super ventricular, and cardiac output which commonly reflects acute vulvar insufficiency during the procedure and, in rare circumstances, cardiac arrest may occur.

However, with appropriate treatment with blood volume replacement, the use if inotropic, chronotropic and vasopressor agents, the occasional use of temporary trans-venous pacing and cardioversion, these complications are readily reversible.

Our strategies for management, therefore, include general anesthesia for all cases because of the risk for adverse events. Also because we share the airway with the echocardiographer during TEE and for vascular access issues.

Resuscitation drugs and equipment should be prepared and immediately available for every case, and we have ICU backup for every case.

In conclusion, the transcatheter device occlusion of a complex VSD is a challenging environment and a challenging intervention with potential for adverse effects. However, with appropriate anticipation, patients are safely managed through this procedure.

Thank you. Next I would like Dr. Jenkins to come and talk regarding the clinical trial overview.

DR. JENKINS: My name is Kathy Jenkins. I have no financial interest in NMT Medical, Inc. I paid for my expenses to attend the session today.

What I would like to do now is to show you this source of the information that was presented to you in the Panel Packet and was presented for this PMA application.

There were five separate cohorts of information presented for the PMA application. These five cohorts were derived from two separate studies. The first cohort, and by far and away the most important, which is referred to as the pivotal cohort, includes patients undergoing ventricular septal defect closure using the CardioSEAL device as part of a study that I'll describe in detail known as the High Risk Study. This information includes detailed information about device safety and efficacy.

In addition, there are four additional non-pivotal cohorts. The one that we will describe in some detail includes patients that underwent closure of a ventricular septal defect using a prior generation of the device known as the Clamshell I.

All of the data from both studies used for indications other than VSDs are also presented as well as information in a small number of prospective patients where the device was used to close post-infarction ventricular septal defects, although the focus of all of the non-pivotal cohorts is primarily to provide additional information about device safety as well as longer term follow-up.

As I mentioned previously, the pivotal cohort was derived from a study known as the CardioSEAL High Risk Study. This is a prospective multi-center study that began enrollment in 1996 for which the Children's Hospital in Boston is the study sponsor.

This study is overseen by a safety and data monitoring committee chaired by Dr. Thomas Haugen and is currently ongoing. Enrollment in the study through 2/1/00 was submitted as part of the PMA application.

As I mentioned previously, this study includes patients with ventricular septal defects as well as other types of cardiac defects. The safety data from this study were used to support HDE approvals for fenestrated Fontan closure, ventricle septal defect closure, and PFO closure in recurrent stoke patients.

The design of the CardioSEAL High Risk Study was to determine the safety and efficacy of the CardioSEAL device in patients with limited acceptable alternatives. The study is a prospective cohort of implants patients without a concurrent control group.

However, patients were entered into the study by an independent peer review process whereby an uninvolved, meaning uninvolved with the patient or the study, cardiologist and cardiac surgeon were required to approve the enrollment of patients in the trial.

The criteria that were used by peer review team to make the device determinations are shown on this slide. The peer review team had to ascertain that the patient had one or more cardiac defects of sufficient hemodynamic derangement to warrant intervention and that the patient had either a type of defect that is technically difficult or impossible to close surgically, or an overall medical condition such that the surgical risks were sufficient to justify the known and potential unknown risks of the device.

The outcome evaluation was performed prospectively on an ongoing basis at baseline, discharge, 1, 6, 12, and 24 months following the procedure and included a clinical evaluation, chest x-ray, echocardiogram, and a fluoroscopy at 6 and 24 months after implantation.

A core laboratory was responsible for the final interpretation of all chest x-rays and echocardiograms in this study.

The efficacy assessments for patients enrolled in this trial was performed in three different ways that I will describe in detail. The first, which we call Clinical Status, by Lesion, uses a combination of information from two ordinal scales. The second Clinical Status by Patient, uses a combination of information from 8 scales. The third, Echo Closure Status, is defined more traditionally categorically.

In all cases these efficacy assessments were evaluated as a change from a patient's preimplantation baseline to the six-month follow-up time point such that each patient served as his or her own control for this assessment.

The assessments include a degree of flow by echocardiography as well as other clinical information. As I mentioned previously, all echocardiograms were assessed by an independent core laboratory.

To apply the Clinical Status Scale, by Lesion Assessment, a scale value was assigned to the patient at each of the assessment time points using one of two applicable scales. Either an anatomically based scale, or a physiologically based scale.

The use of two parallel but equivalent scales allow longitudinal assessment of patients despite interim surgeries such as removal of a previously placed pulmonary artery band. A change by one category in the scale assessments is considered to be clinically meaningful.

This slide shows the actual scales that were used to make this assessment. I should mention that the point of this overall efficacy assessment was to determine the change in the patient's status that was specifically related to closure of the ventricular septal defect.

All patients for whom the hemodynamic consequences of the ventricular septal defect were a left-to-right shunt were made by assigning the patient a value of zero to five on this physiologically based scale.

Since quite a number of patients in this study have had prior placement of a pulmonary artery band, we created an anatomical but intended to be equivalent scale for those patients in whom the VSD no longer resulted in the left-to-right shunt. This assessment was based primarily on the actual diameter of the ventricle septal defect in relation to the aortic annulus diameter.

Patients who died or had the device explanted were categorized as -1 regardless of whether the death or the explant was due to the device or the procedure.

So as an example, if a patient had a congenital muscular ventricular septal defect and had undergone prior placement of a pulmonary artery band, and then was enrolled in the study and had a VSD closed with the device, and then subsequently had the band removed two months later, the patient would have been assessed on the Anatomical Scale for the three assessments that were made prior to the band removal and on the physiologically based scale after the band had been successfully removed.

Two, go one step further and evaluate changes in the patient's status that went beyond the simple consequences of closure of the VSD. We also looked at efficacy using a Clinical Status Scale by patient.

This assessment was also made as a change from the patient's pre-implantation baseline at the six-month follow-up time point, but now included a status assessment based not only on the VSD but also on other clinical factors and, therefore, is a more global assessment of patient improvement or decline.

This slide shows the additional information that was included in this assessment. There's a total of eight scale that were used. The first right to left shunt was rarely applied to this population. The second two are the VSD scales I described previously.

In addition, patients were assessed as to their risk for systemic emboli, on hemodynamic compromise not due to shunt most usually either ventricular dysfunction or AV valve regurgitation, the presence of arrhythmia, elevated pulmonary vascular resistance, or additional medical illnesses.

This slide shows the possible assessments for the arrhythmia category, again where patients would be given a scale assignment according to the type of arrhythmias that they had at that time point.

So in each case a scale value was assigned to the patient in each of the eight categories but the overall assignment for the patient was the lowest value in any of the applicable categories.

To clarify with an example, if there was a patient with a medical illness of sufficient severity to be rated as a Category 2 as well as a ventricular septal defect of sufficient severity to be rated as a Category 2, if this patient then underwent successful device closure such that the VSD categorization improved to a four but with no change in the medical condition, the patient would have been assigned a score of 2 at baseline based on the presence of both the VSD and the medical condition, but again would have received a score of 2 post-procedure based on the condition only.

The difference in the patient, therefore, would be rated as zero and the procedure would not have been considered successful on the clinical status by patient assignment. The same patient evaluated using the Clinical Status, by Lesion assignment would have improved by two categories and the procedure would be considered a success under that efficacy criteria.

We also used the much more traditional measure of efficacy for device trials, namely Echo Closure Status whereby residual flow was categorized as trivial to absent, small or more than small according to strict criteria used by the core laboratory.

To assess safety for this group of patients, the safety assessment is primarily descriptive but did include a comprehensive definition of adverse events very similar to the definitions used in drug studies whereby all adverse events occurring at any point during follow-up in all patients in whom an implant was attempted were recorded.

Each of the events then underwent an independent assessment by the safety and data monitoring committee who was responsible for the final attributability and seriousness classifications.

The committee graded events as serious, moderately serious, or not serious using strict definitions that were shown in your protocol. And also categorized events as definitely, probably, or possibly related to initial device positioning, to device fraction, otherwise to the device specifically to the implantation part of the cath procedure or otherwise to the catheterization as well as using a variety of unrelated categories.

It's important to understand that the committee used the possibly related category for these assignments very similar to the way that category is used in drug studies where the possibly related category was intended to mean plausibly related where the committee used probably or definitely related for events that they thought were likely to have been attributed to the device of the implant or whatever.

The primary measure of safety that we defined for this study was the proportion of patients with at least one moderately serious or serious device or implantation related event as assigned by the committee.

I would now like to switch and describe for you the second source of data that was presented as part of the PMA implication. This data comes from a different study that is known as the Clamshell I Follow-Up Study and is part of the non-pivotal part of the submission.

This particular data is a registry of all patients that were implanted with Clamshell devices at the Children's Hospital during prior regulatory trials. The database was retrospectively created in 1994 and since that time patients have been following prospectively to screen for a device related and other major clinical events.

This study also includes patients with ventricle septal defects as well as other types of cardiac defects. These data are included primarily for ascertainment of late device related events.

In this study the information is solicited from all patients who consented to participate according to a recommended follow-up schedule. It's in the form of a registry so the testing was recommended but not required but included annual evaluation for the first five years after implant and less frequently thereafter.

Adverse events are classified similarly to the CardioSEAL High Risk Study but were not reviewed by an independent safety and data monitoring committee. In the more recent prospective portion was included identification of device in fracture related events only.

An Echo Closure Status is also categorized similarly in the prior study but, once again, the Echo Closure Status for this cohort has not been reviewed by an independent core laboratory.

I would now like to introduce you to Dr. Kim Gauvreau who is the biostatistician for both of these studies and she'll talk about the sample size assumptions as well as review and show the actual data from the study.

DR. GAUVREAU: My name is Kimberlee Gauvreau. I'm a biostatistician at Children's Hospital in Boston. I have no financial interest in NMT although they did reimburse me for my travel expenses today.

My portion of this presentation will focus on three things. I will first give a brief description of our sample size calculations. I will then summarize the efficacy and safety results from the VSD pivotal cohort which is part of the CardioSEAL High Risk Study. Finally, I'll present some efficacy and safety results from the VSD non-pivotal cohort that is part of the Clamshell I registry.

Beginning with the sample size calculations, for efficacy we wanted to have a sample size that would be sufficient to detect a median improvement of two categories from baseline to the six-month follow-up time point on the Clinical Status Scale by lesion.

For example, we would want to be able to detect an improvement from category one, heart failure symptomatic to category three which represents a moderate shunt.

Since the data are measured on an ordinal scale and are paired each subject serving as his or her own control, we use the nonperimetric Wilcoxon signed-rank test to evaluate the null hypothesis of no improvement.

In order to achieve 90 percent power, we found that we would need a sample size of 35 patients. Given full information on our VSD pivotal cohort of 57 patients, we would have 99 percent power to detect a two category change.

Our safety analysis was primarily descriptive and here we wanted to be able to construct a 95 percent confidence interval for the primary safety outcome which is the proportion of patients experiencing moderately serious or serious device or implantation related events with a specified degree of precision.

Using the normal approximation to the binomial distribution, we estimated that our sample of 57 patients in the VSD pivotal cohort would allow us to estimate a confidence interval with length of plus or minus 13 percent.

I'll now summarize the results from the VSD pivotal cohort. There were a total of 74 patients with a VSD enrolled in the CardioSEAL High Risk Study through February 1, 2000. Implant of a CardioSEAL device was attempted in 58 of these patients and successfully placed in 57. There were six patients who had multiple procedures and 26 who had more than one device placed. A total of 107 CardioSEAL devices were implanted.

The CardioSEAL device was not implanted in 17 patients. In 13 patients device implant was not attempted in most cases because the defect was smaller than anticipated. In one patient the implant was attempted but a device was not placed due to unfavorable anatomy.

Because the STARFlex device became available in the late phases of this study before February 2000, three patients with a VSD actually received a STARFlex device rather than a CardioSEAL device. These three patients are not included in any of our subsequent analyses.

For the 57 patients who actually received the CardioSEAL device, 46 percent had a congenital defect and 54 percent had a post-operative residual defect. Approximately 80 percent of the group were less than 10 years of age.

The cohort as a whole was quite sick. Eighteen percent had significant arrythmia, 35 percent elevated pulmonary vascular resistance, 25 percent significant medical illness, and 60 percent significant hemodynamic impairment not due to shunt. Seventeen patients had prior placement of a pulmonary artery band which was later removed in 16 patients. Approximately 83 percent of the 107 implanted devices were either size 17 mm or size 23 mm.

Just to remind you, we have three efficacy outcomes, Clinical Status Scale, by Lesion; Clinical Status Scale, by Patient; and Echo Closure Status. I'll begin by looking at the Clinical Status Scale, by Lesion for the VSD pivotal cohort.

What you see in the top histogram are the values on this Clinical Status Scale prior to device implantation. Below that are the values of the six-month follow-up time point. You can see that the distribution shifts to the right indicating an improvement on this Clinical Status Scale.

There are six patients who have the value -1 at the six-month follow-up time point. These are the patients who either died or had their device explanted before the six-month follow-up. They were each assigned the value -1 on this scale regardless of whether their death or explant was due to the device or the procedure.

Note that the most common value that occurs prior to implantation or the mode of the distribution is the value 1 which represents heart failure symptomatic, while the value that occurs most frequently at the six-month follow-up is 5 which represents trivial or no shunt.

Fifty patients were measured on the Clinical Status Scale, by Lesion by prior to implantation and 47 at the six-month follow-up. There were 44 patients who had measures at both time points. These 44 patients had a median improvement of two categories on this scale. This improvement was statistically significant at the .0001 level.

Here you can see the changes in the Clinical Status Scale for the 44 patients measured at both time points. The positive changes from one to four represent improvements in clinical status on this scale.

The one patient with a value of zero did not change scale value prior to implantation to the six-month follow-up. The patients with negative values, the negative change all decreased on this scale. These include the patients who died or explanted before the six-month time point.

Defining a successful procedure as one in which Clinical Status Scale improved by one or more categories by the six-month follow-up, 84 percent of these procedures were successful.

I'm going to now turn to the Clinical Status Scale, by Patient which is a more global assessment of a patient's health status. Here again you can see the distribution of values prior to implementation and at the six-month follow-up time point. Once again, the distribution has shifted to the right suggesting an improvement in clinical status.

Here there were 53 patients who could be assessed on the Clinical Status Scale, by Patient at both time points. Again we saw a median improvement of two categories. Not only was this a clinically important improvement for the patients, it was also statistically significant.

These are the changes in Clinical Status Scale for the 53 patients who were measured at both time points. Again, a positive change represents a successful procedure. Here 72 percent of the procedures were successful by the six-month time point.

Our final measure of efficacy for the VSD pivotal cohort is Echo Closure Status. Prior to implementation 94 percent of the patients had a more than small residual flow represented by Category 3. At the six-month follow-up time point only 9 percent of the patients had more than small flow.

This median decrease in the scale value from 3 to 2 is statistically significant or, in other words, for more than small residual flow to a median of small residual flow.

Summarizing the efficacy data for the VSD pivotal cohort there were successful defect closure and shunt reduction in 84 percent of patients by six months after device implantation.

Improved clinical status was observed in 72 percent of patients. While there was more than small residual flow in 94 percent of patients prior to implantation, only 9 percent had more than small flow at the six-month follow-up.

I'll now look at safety for the VSD pivotal cohort. Using the comprehensive definition of adverse events that was described earlier, 57 out of 58 patients with the device implant attempted experienced at least one adverse event through the most recent follow-up.

There were a total of 222 events. 32 of these were related to the device and include events which were definitely, probably, and also possibly related to the device. 35 events were related to the implementation procedure, 85 to the catheterization, and 70 were unrelated to the device implantation or the catheterization.

Our primary safety outcome was the proportion of patients with at least one serious or moderately serious device or implementation related event. 22 patients were found to have an event of this type which represents 38 percent of the VSD pivotal cohort. Again, we are including events that are definitely, probably, or possibly related to the device or procedure.

Here we can see of the moderately serious or serious device or implantation related events there were 16 device related events, 12 of which were detected within two days of the implementation procedure. Of the 17 moderately serious or serious implementation related events, 16 were detected within two days of the procedure.

I would like to take a moment to point out that there is an error in the data in the Panel Package which affects mainly Tables B7 and B9 in Section 5.D. If you look at those tables, we actually have one implantation related event in the one to six-month time frame and a second implantation related event in the greater than six month time frame. Both of those late events were mitral vulvar regurgitations.

What we discovered was that there was actually one patient who had ongoing mitral vulvar regurgitation. That patient we mistakenly recorded multiple events for that one patient. It really should have been just a single event.

Looking more specifically at the moderately serious or serious device related events, those that occurred within two days of the implantation procedure included four device embolizations. All four embolizations occurred in a single patient who is 70 years of age diagnosed with tetralogy of flow and had an AICD.

There was one device malposition which was repositioned at the time of a planned surgery. There was one mitral vulvar regurgitation where the valve was stretched at procedure.

There was also one perforation of the heart which was detected between two days and one month after the implantation. That was an incidental finding at a planned surgery. There was one vessel dissection that occurred between one and six months after the implantation. That took place during device removal at a subsequent catheterization.

One more thing I would like to point out is that the events listed in white are either definitely or probably related to the device and those in yellow are only possibly related to the device.

Looking at the moderately serious or serious implantation related events, the events occurring are being detected within two days of the implantation procedure included five cases of third-degree heart block. Four of these cases resolved within one week of the procedure. The fifth case I will discuss in a minute.

There were three cases of ventricular tachycardia two of which resolved with lidocaine and cardioversion. The third case was that same patient that we will come back to in a minute when we talk about the deaths.

There were two hypertensions requiring intervention. There was one event that was detected late, more than two days after the implementation procedure and what an aortic vulvar regurgitation.

Most moderately serious or serious device and implantation related events resolved as noted in the previous slides. However, there were ongoing device or implant related event present in two out of 58 patients or 3.4 percent.

These were mild to moderate mitral vulvar regurgitation in one patient in mild to moderate aortic vulvar regurgitation in a second patient.

Device related events which were categorized as not serious by the safety and data monitoring committee including five device malphysicians, one device delivery system malfunction where there was a difficult release but it was ultimately successful, one kink in the delivery system or sheath.

There were four deaths in the VSD pivotal cohort and these deaths are described in detail in the Panel Package Section 5.D.1.2. Only one death was considered to be due to the catheterization procedure. This was in a three-and-a-half-month-old child with single ventricle misdiagnosed as Swiss cheese septum. The patient has severe congestive heart failure, low output, and complete heart block after cath and died of multisystem organ failure at attempted PAB and pacemaker placement.

There were two additional death that were due to the underlying cardiac disease and one that was due to the underlying noncardiac medical condition. There were four device explants. Again. these are described in more depth in your Panel Package. Two were at heart transplantation, one at a Fontan surgery after a failed septation, and one at catheterization due to device instability.

There were 17 device arm fractures among the 107 implanted devices. This represents 16 percent of the devices. No adverse events were attributed to device arm fractures in this VSD pivotal cohort.

We next looked at the VSD non-pivotal cohort which was part of the Clamshell I registry mainly to evaluate the long-term safety issues associated with device placement.

There were 87 patients in this cohort who received the device. There were a total of 140 devices implanted. In this cohort the median follow-up was 4.6 years and the maximum was 11.5 years.

There were a total of 25 device related adverse events, 10 of which were serious, eight moderately serious, six not serious, and one of unknown seriousness.

Looking at the 18 serious or moderately serious device related events, eight were detected within one week of the implantation and included two device embolizations, one device malposition, and one new onset vulvar regurgitation. The events were quite similar to those noted in the VSD pivotal cohort from the CardioSEAL High Risk Study.

All events detected within one week to six months of the implantation procedure were only possibly related to the device. There were two device malposition detected between one and two years after the implantation.

The efficacy data available for this cohort was echo closure status at the most recent follow-up. You can see that 82 percent of patients had either small or trivial or absent residual flow at most recent follow-up. Again, the median follow-up was 4.6 years.

Additional data which I am not presenting includes information from three non-pivotal cohorts. The first is the CardioSEAL High Risk Study, patients without a VSD. There were 271 such patients with a device implanted. The second non-pivotal cohort is from the Clamshell I registry, again non VSD patients. There were 414 patients who received the device.

Finally, the CardioSEAL High Risk Study patients with acquired VSD following an infarction and there were five of those. Each of these cohorts is described in more detail in the Panel Package.

We would like to point out that in the entire series of 690 patients, only one device related adverse event led to device removal and that was in a 7-year-old with thrombus noted on the device nine years after PFO closure.

I would like to now reintroduce Dr. Kathy Jenkins who will summarize the conclusions.

DR. JENKINS: So in conclusion in patients at high risk for poor outcomes after surgery, VSD closure using a transcatheter CardioSEAL device resulted in successful defect closure and shunt reduction in over 80 percent of cases by six months after implantation.

Similarly, device closure resulted in an improved clinical status in 72 percent of patients. Device arm fractures were observed in 16 percent of implanted devices. However, all were identified incidentally. No clinical consequences have been attributed to fractures in CardioSEAL devices used to close VSDs.

Peri-procedure events occurred frequently but most were successfully treated. One infant death was directly attributed to the procedure. Only two patients have ongoing clinical impairment from moderately serious or serious device or implant related events both with valve injuries.

Late onset adverse events attributed to the device were not observed in the pivotal cohort. Extended follow-up in a similar series of patients implanted with a predecessor device suggest that late device related events are rare.

Thank you very much.

DR. TRACY: Thank you very much.

We'll move on to the FDA presentation.

MS. BUCKLEY: 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. I'm also the lead reviewer for the CardioSEAL Septal Occlusion System PMA submission, P000049.

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're 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 in to consideration by FDA in the evaluation of the application. Finally, you'll be asked to vote on the approvability of this device.

The FDA summary will provide a brief overview of the following:

The FDA Review Team, the device description, HDE approval, nonclinical evaluation, clinical evaluation, and the questions to the panel.

Members of the FDA review team include myself, 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.

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 to 1. 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.

The delivery catheter is 10F in size. The Qwik Load device, and I apologize for repeating, is attached to the delivery system. It is used to collapse and load the occluder into the delivery catheter.

A Humanitarian Device Exemption or HDE is an application that is similar to a premarket approval or PMA application, but exempt from the effectiveness requirements of a PMA. An approved HDE authorizes marketing of a Humanitarian Use Device where a Humanitarian Use Device is defined as a 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.

As previously indicated by the sponsor, the CardioSEAL device was approved under an HDE in September of 1999 for the same intended use as proposed in this PMA application, HDE No. H9900005.

In vitro or bench testing as outlined in Section 1.4 of the FDA Summary was performed to evaluate the mechanical integrity and function of the CardioSEAL System.

Biocompatibility testing of the device components was conducted in accordance with ISO Standard 10993. Studies in several different animal models were conducted with the CardioSEAL System. The results of the in vitro testing, biocompatibility and animal testing all demonstrate the integrity and functionality of the device for its intended use. There are no outstanding non-clinical testing issues at this time.

Now Dr. John Stuhlmuller will summarize the clinical evaluation of the device.

DR. STUHMULLER: Good afternoon. My name is John Stuhmuller. I'm 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.

The sponsor has provided information for five 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.

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, those 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.

A total of 74 patients were identified for inclusion in the pivotal cohort for VSD closure. Devices were placed in 57 and 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 for effectiveness was completed using the Clinical Status Scale. Patient outcome assessment for safety was by evaluation of potential anticipated and unanticipated adverse events.

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 eight nominal variables each using an ordinal scale for patient outcome assessment. Each ordinal scale was developed so that change of one in either direction on the scale represents a clinically meaningful change.

Effectiveness was determined at six-month follow-up using the Clinical Status Scale. Forty-four of 57 implanted patients completed follow-up. The Anatomical Scale was used pre-procedure and at six months in 14 patients. The Left-to-Right Shunt Scale was used pre-procedure and at six months in 22 patients.

Different scales were used in eight patients. The Anatomical Scale was used pre-procedure and the Left-to-Right Shunt Scale was used at six months in eight patients.

Based on the method of analysis provided by the sponsor, a median change of two categories was demonstrated and 84 percent of the procedures were considered successful at six months.

In terms of safety, patient evaluations were scheduled at one, six, 12, and 24 months. Adverse events by time of event are reported as with two days of implant, two days to one month, one month to six months, and six 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.

Adverse events were noted in 57 of 58 patients in which device placement was attempted. A total of 222 adverse events were noted. At lunch we corrected a typographical error for device arm fractures.

On your handout I believe it's going to read 34 of 107 and it was corrected. There were a total of 32 device related events, 35 implantation related, 85 catheterization related, and device arm fractures were noted in 17 of 107 devices.

Next Donna Buckley will review the panel questions that we would like to receive input on.

MS. BUCKLEY: The sponsor has submitted data to support approval of the CardioSEAL device for closure of ventricular septal defects 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 device.

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

A "Clinical Status Scale" was used to evaluate efficacy. The primary efficacy evaluation includes a comparison of the pre-procedure and six-month shunt using both the Left-to-Right and Anatomic Scales, also called the 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: Based on the data provided and your comments regarding questions 1 and 1, please discuss whether these data provide reasonable assurance of safety and effectiveness.

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.

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.

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 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 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 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 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.

The Panel Package includes the available two-year data for the CardioSEAL device in the pivotal cohort. In addition, data were provided from the Clamshell I follow-up study 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?

Thank you.

DR. TRACY: Thank you. We'll move on to the open committee discussion. Dr. David Skorton was the lead reviewer. We'll ask him to begin.

DR. SKORTON: Thank you and thanks for the presentations. Before I start my questions, I just want to take a moment to commend the sponsor and the researchers for tackling a very, very difficult clinical problem which doesn't have any easy answers. However, having said that, I have a few questions to ask. Philosophically what we're looking at is an uncontrolled study where the efficacy measures are largely semi-quantitative. The leap of faith is that you really cannot do surgery on these patients.

I have a question for the surgeon who spoke earlier. I apologize, I forgot the gentleman's name. The data that we're shown for the bad outcomes of ventriculotomy incisions were from the '70s and '80s. Of course, we don't see ventriculotomy incisions as much anymore because of those data. Please help me to understand what are the data for those few patients nowadays that do have to have ventriculotomy incisions.

Obviously, all of us occasionally do have to send patients for ventriculotomy. Maybe not for congenital heart disease but sometimes to close peri-infarction VSDs. Can you help us to understand what those data look like today?

DR. MAYER: That's a little bit difficult to answer actually. I will answer it the following way. Based on that information, we as an institution sort of went away from what had been the previous approach of doing a left ventriculotomy for patients with defects in this area.

We have a little bit of clinical experience with maybe seven or eight patients -- I can't remember the number exactly -- which we have approached through a lower sort of periseptal, if you will, incision but that is a subset of apical VSDs. I chose the words relatively carefully that the ones that are further back that are more posterior are ones that we continue to have problems with.

I don't have the data to tell you how many of those patients have been approached surgically, although I would say the numbers are relatively small at this point. Clearly it depends a little bit on the size of the defect and the location.

Clearly there are a number of muscular VSDs that we can approach transatrially or through a limited anterior ventriculotomy. That's why in particular those patients who would require a left ventriculotomy or an extensive right ventriculotomy are the ones that we are sending to the cath lab basically.

The other subset of patients, and there are a significant number in this series, are ones in which previous surgical attempts have failed typically in those areas. I guess that is one indicator that you have is that prior surgeons both in our own institution and elsewhere have failed to close the VSD because it was difficult to access surgically. A significant chunk of the total pivotal cohort are, in fact, post-operative VSDs with residua.

DR. SKORTON: Fair enough. Thanks. My next couple questions are truly like one big question. It has to do with a part Clinical Status Scale. It's probably a statistical question and partly clinical question.

I saw that you used a non-parametric rank test which I think is admirable because who knows what the distribution of these factors are.

I'm assuming that your assumption using a rank test across all of these is that one category in each row of the scale has equivalent clinical significance.

DR. GAUVREAU: By using a non-parametric rank test it's only assuming that the categories have a certain order to them but not that the difference between a two and a three is the same as the difference between a three and a four, but just that a three is better than a two and a four is better than a three.

DR. SKORTON: Let me restate it. It's a point well taken. The definition was, as I understand it, for each scale that one step is supposed to indicate something of clinical significance. Is that fair?

DR. JENKINS: Yes. Your statement the way you first made it is correct. When we tried to design the efficacy outcome for the trial, initially we proposed echo closure status for the complex cohort that included VSDs and other indications.

Actually, the FDA required us to create a more quantitative method to follow patients. It was a complex cohort with multiple indications. We actually did some consulting and one of the biostatisticians at the Harvard School of Public Health helped us construct the parallel but equivalent scales exactly with the assumption that you propose so that we could say something about the cohort overall.

When you carve out the subgroups, for example, in the clinical status by lesion assessment or some of the other subgroups, that problem falls away. In the clinical status by patient assessment, your assumption is exactly correct.

DR. SKORTON: Thank you. So following up on that, I just have a couple questions. I don't mean for these to be cheap shots. I'm really asking because I'm trying to understand how they were used. The anatomic scale that measures VSD diameter as a percentage of aortic root diameter, I'm assuming some of these VSDs were multiple holes near the septum near the apex or anterior septum.

How do you figure out in a multiple hole VSD what the diameter is that you have a single number to compare against aortic root diameter if there were, say four holes?

DR. JENKINS: I think that you might have noticed that the sample size dropped for the six-month efficacy assessment. The reason for that is that there were substantial number of assessments. It wasn't that only 44 patients achieved the six-month follow-up.

Actually, the follow-up is 100 percent in this study. It's that the assessments were considered to be inadequate to make a complete determination of VSD diameter or lesion shunt size.

The multiple jets that were greater than two were quoted as more than small. There were quite a number of cases where people didn't feel comfortable making an assignment and that's where the missing data comes from.

DR. SKORTON: Okay. Thanks. You just answered the next question, too. I appreciate that.

Could you review for me one more time in the assessment of clinical status by lesion? My understanding, and I apologize if I got this wrong, is that you use different measures for the initial assessment than for the follow-up assessment. Is that right?

DR. JENKINS: Not in all cases and not in most. Only in patients who had initially a placement of a pulmonary artery band so that they couldn't be -- our attempt was to create the entire scale with the physiological consequences of the whole. That was the intent.

Unfortunately for banded patients, that broke down because they might have known that shunt and still have a big hole in their heart. They would be neither "blue" nor have a right left shunt. We tried to formalize an anatomically based assessment that we felt would be equivalent to the shunt based scale.

In other words, what size hole would have resulted in what size shunt if you could do what you couldn't do which is take the band off and measure it. That was the numbers that we came up with there.

DR. SKORTON: Okay. The last question, which I've been told is fair game to the sponsor and not to the investigators, is it looks to me like the application is aimed at a relatively small number of the sickest of the sick, difficult to operate patients. I'm just curious what the motivation is to convert this from an HDE to a PMA? It's a question for the sponsor.

MS. KULIS: My name is Anne Kulis and I'm with Regulatory Affairs and NMT Medical. I would say that the primary motivation was that with an HDE there are significant administrative requirements such that IRB approvals are required for each institution before the site can receive devices. Our hope in converting this from an HDE to a full PMA approval was to reduce the burden both for the institutions as well as for the company.

DR. SKORTON: My understanding, and I could have this wrong, but I'm in charge of the IRBs for our university and my understanding on HDEs is that you go through IRB approval of the protocol but you don't need to take informed consent on each patient. You don't need to get IRB approval of every single case but of the protocol.

I agree it's certainly more of a burden than not doing it but it's not the same as a research protocol as I understand it where you have to get approval and informed consent of each patient.

DR. JENKINS: If I could just answer that because we've gotten quite -- when we got our original HDE approvals I was actually the recipient of multiple phone calls from all over the United States about this. It's very IRB dependent. It's very institutional dependent.

There are some institutions in our high-risk trial that chose to stay as part of the high-risk trial because they couldn't get the HD approved at their sites. It was actually more burdensome than having our trial approved.

There were some that treated it almost like it was an approved device that was on the shelf and it was an off-label use. Some of the academic centers who were maybe more fearful or more conservative really did place quite a few hurdles to investigators. We also have two investigators here who have enrolled VSD patients under HD approvals who might be able to talk about the issues at their center.

DR. SKORTON: That's okay. I'll take your word for it. I'm done.

DR. TRACY: I guess we started at that end of the table last time so I'll shift over and ask Dr. Crittenden to raise questions.

DR. CRITTENDEN: I, too, enjoyed reading the Panel Pack. I thought it was very interesting and I agree this is a cohort of patients who need a lot of help and surgery is probably not a good answer.

I, too, like Dr. Skorton, have some concerns. Not so much concerns but questions about this Clinical Status Scale. Have you done anything to look at the validity of this to see whether or not if you take a second group of patients and look at it whether or not this really makes any sense whether it's valid?

DR. JENKINS: No, we haven't done any interater or other types of validity checks. What we did do, though, is that the echo closure status was reviewed by the core laboratory and we did revise the clinical status assessments afterwards. This is a scale that was really designed specifically for this study. It doesn't really have any external validity beyond this other than face validity.

DR. CRITTENDEN: So the FDA didn't ask you to do it, you would have just presented the echo data, I presume, for efficacy?

DR. JENKINS: That's probably right.

DR. CRITTENDEN: The other question I had is there are a number of device fractures. Is there anything to be done about that or you just watch them over time?

DR. JENKINS: The rate of device fractures in this study is about half what it was with the predecessor Clamshell device. In the entire high-risk trial to date, we've actually scrupulously screened for fractures with out chest x-ray core lab review and with fluoroscopies.

We found them as an incidental finding in about 16 percent of this group of patients and in the cohort overall. As of yet, we haven't found any events that were definitely or probably related by the safety committee to the fractures.

There were three instances in the non-pivotal cohort, the non-VSD cohort where a patient experienced palpitations at the time or around the time that a fracture was detected at the same endpoint. In those three cases the committee quoted those events as possibly or plausibly related to a fracture but there was nothing else.

There had been a rare number of events in the original Clamshell I cohort that were attributed to fractures with masses in the heart or minor shifting of the device. We haven't observed that with the new CardioSEAL device.

DR. CRITTENDEN: Does this affect the endothelization of the device? Does it change that at all?

DR. JENKINS: I don't know for the CardioSEAL device but we did recently, and I think it's imminently about to come out in the literature, presenting a paper on the explant data from the Clamshell I cohort. In that analysis where we had really very good pathological information in all the explants, there seemed to be no association at all with endothelization in the presence of a fracture.

DR. CRITTENDEN: That's all I have.

DR. TRACY: Dr. Wittes.

DR. WITTES: I have very little also. It was very hard for me to calibrate the results against what one would have expected because there was not only no control but nothing that described what you would have expected. Not being a cardiologist I didn't know what to expect. That was very hard for me.

I also struggled with the very same issue that you brought up about making the assumption that changing from one to two on one row is the same as changing from one to two in another row. I would have been nicer obviously if you had been able to have everybody in one row or the other because then at least you would see -- then you would know whether you have improvement or not.

I am particularly uncomfortable about those people who changed rows and whether the improvement that you see is truly a clinical improvement. I mean, the improvement that you code is truly a clinical improvement.

DR. JENKINS: I think that the clinicians answer but not the data person's answer to that would be that most of the patients who changed rows on the primary assessment did so because they had a pulmonary artery band actually removed.

In general, that's not possible to do if you haven't successfully closed a VSD because you can take the pulmonary artery band off and the patient goes into congestive heart failure.

The fact that the patients were able to subsequently undergo pulmonary artery band removal is not quantitative but it is sort of a sign that the VSD was being at least partially successfully treated.

DR. WITTES: I actually was asking that clinical question. I guess the other issue then would be is if this moved into a different center, how center dependent. Again, it's an unanswerable question but it's a question that as I read I wonder.

DR. JENKINS: There were multiple interventionalists involved at one center but the bulk of the data was from one center. I think I would like to ask Dr. Hoyer or Dr. Boucek to talk about their experience under the HDE approval.

DR. HOYER: Hi. I'm Mark Hoyer from Riley Hospital in Indianapolis. I have no financial interest in NMT Medical. I was asked to come here today and my expenses are being reimbursed today.

To answer, I think, Dr. Skorton's question as well and then moving on, the HDE approval is very different than the PMA. I've actually had experience in two locations. I have been in Florida and had to get approval.

Fortunately, somebody had paved the way already with the HDE category of approval which allowed me to kind of get in much more easily. We still required informed consent for every patient. In Indianapolis the exact same thing has held true. It is indeed an IRB approval.

Actually, although the IRB approval was easier in Florida, it's been more difficult and there was an entire full review board there in Indianapolis. In fact, we still get informed consent for every one of those patients.

We've been involved in closing a few of these complex VSDs. Obviously not the 57 patients that have been reported in the high-risk protocol already. We actually have been involved with three closures in two patients so obviously one of those had multiple defects.

I think the logistics of that has actually worked out pretty well. It requires some training clearly. I was proctored initially in Florida for fenestrated Fontans so I had some device experience and then came to Indianapolis and was able to carry that forward. That's basically been my experience thus far. I'll let Dr. Boucek answer some more unless there is anything else specifically.

DR. BOUCEK: I would basically support what Dr. Hoyer said. I also have no financial interest in NMT. My travel arrangements were provided for.

We've done more like eight or so infants under the HDE. Frequently they are extremely ill children like you've heard about. Often they are referred to our institution for consideration of transplantation because they've had previous surgical attempts to close the VSD which have been unsuccessful in children who are quite symptomatic.

It would be virtually impossible to resubmit them to another operation to try to close residual VSDs. These are very sick children and I think because of the experience that we've learned from what the group at Boston Children's has done, we've actually not had near what appears to be the difficulty placing these as reported here.

I think there has been a learning curve which has been communicated to the community. We've not had the problems with heart block and things like that. I think we've learned from other's experience. This is certainly something I think can be done in an institution where there is an active interventional laboratory. I think we usually have the capability for surgical backup but we've never had to utilize it.

I think with appropriate anesthesia preparation and training, most of the adverse events that you've heard about can be anticipated. Now, in fact, we actually prevent them or prophylax them through anticipation rather than responding to them when they occur.

DR. TRACY: Dr. McDaniel.

DR. McDANIEL: Thank you for those comments. I had a couple of questions when reading through this in kind of a general -- let me figure out what the heading is here. Under CONTRAINDICATIONS I was just curious. It says, "Anatomy which the CardioSEAL size required would interfere with intercardiac or intravascular structure such as valves or pulmonary veins."

I guess the pulmonary vein is the part I don't understand. I know you have to do a trans-septal cath to get there but is it the whole procedure you are referring to so there may be injury to the pulmonary veins in that sense? Because the CardioSEAL sitting in a VSD position shouldn't interfere. It's in a couple of places and I'm just -- or is that more related to its use?

DR. TRACY: That doesn't correct for the VSD indication.

DR. McDANIEL: Okay. It's probably related to the ASD closure. I thought that.

Then a couple of comments on the patient's guide to device and the closure. Again, I read these fairly carefully. In the first sentence it's referred to as a ventricular septal hole. Most patients who by this time are pretty much -- they know it's a VSD or you could spell it out.

I think that is kind of unusual language. On the second page where you're talking about the use of TEE, it should probably say TEE involves using -- putting an ultrasound probe to a patient. I'm not sure what they would think that might be.

My only other comment on the patient or family information is that you don't at all refer to the trans-septal part of the procedure passing all the wires in and out of the body. I'm not making any comment whether it should be in there.

It's a very complex procedure but the illustrations really imply that it's a fairly simple procedure. You go from the neck, pop this thing through, and then you're done. I don't know if that needs further explanation or not but it was just something that I initially was confused because I knew they had to come from the left side. This was a bit confusing to me.

I have a couple more questions. I think that's it.

DR. TRACY: Dr. Laskey.

DR. LASKEY: I really have only congratulatory comments so I'll be brief. These are critically ill kids and, I guess, at some point adults, too. Anything you do for them that a surgeon doesn't want to tackle has to be respected.

I think that the clinical outcome measure that you struggled with is really overkill. I think the data kind of speak for themselves in terms of the unbanding, as you said, and just general clinical improvement.

There are so many more questions with the methodology that is so limited, as you said, that they almost had to do better. You started out by giving them the worse possible rank they could have had by giving them the minimum number and so forth, not just by reverse regression to the mean but the way it's set up they had to do better.

My question to you is you had a few people in your histograms who did worse. Is there something that you now know about how to tell who is going to do worse with this assuming it's a technically successful implant? Who should you not approach with this device?

DR. JENKINS: I guess I'll answer as well as anyone else in the room. I think that the technique needs to be very cautious in small infants as indicated by the infant who died directly as a result of the procedure. I also think that several of the failures were attempts at septation where septation was probably not possible.

I think that's a clinician learning curve as opposed to something technical. Hopefully we will eventually be able to refine our understanding of what is septable and what isn't. Those would be my main comments.

DR. BOUCEK: If I could just add frequently you are doing these in situations where there is nothing else to offer and the families are obviously quite interested in trying to avoid heroic therapy like transplantation. If you could effectively septate a child that the surgeons had refused to operate on for standard repair, then that would have a significant impact on that child.

There may be a child who you can't effectively septate but because the damage to the myocardium from previous surgery or such things will still go on to need a transplant or may not survive. I'm not sure that is a contraindication they are trying to help those children.

I think the children that probably should be excluded are the ones that they have in the panel where it's likely that the act of closing the defect is going to predictably result in damage to the myocardium such as the AV valves or the semilunar valves.

I think ultimately we would hope that many of the children whose hearts are damaged by attempts to close complex VSDs at surgery could be done primarily with catheter techniques and avoid some of the children who right now actually get damaged trying to do a standard surgical closure.

DR. LASKEY: Yes. These patients are beyond the pale so there are no rules here really. I think you are to be congratulated on what you have done.

I just have one other question. Is it an 11 French upper --

DR. BOUCEK: Ten French.

DR. LASKEY: No problems in kids?

DR. BOUCEK: I think size is an issue as has been indicated that if you get down to very small infants that's an issue but we put them in infants to six kilograms and it has been well tolerated and been able to go back through the internal jugular vein.

Of course, if we do procedures like ecmo where we put canulas into the internal jugular vein, they are much bigger than even that 10 French so there is precedent for putting large structures like that into the internal jugular vein.

DR. LASKEY: Thank you.

DR. TRACY: Thank you. This is obviously just a very incredible patient population. It must be just extraordinarily difficult to get consent for a procedure that has a 99 percent chance of an adverse event occurring, a 16 percent chance of a device failure occurring, and a 7 percent chance of death, that offers an 80 percent chance of closure and a 72 percent chance of clinical improvement.

It sounds like a very difficult thing to walk into somebody's room and explain that to them. I think this would have to be part of the physician training to tell people how they can deal with that.

DR. JENKINS: I think it really has to do with Dr. Boucek was just suggesting which is whether the alternatives that you're offering the family of this doesn't work.

The way that we normally approach it in Boston is by explaining to them that the cardiac anesthesiologists are going to be at their side and are going to walk them through the procedure and be there to hopefully take care of anything that comes up.

We don't send people into this procedure with a rosy hope that everything will be absolutely perfect but with the hopefulness that if the procedures are successful, that they may avoid needed to go through something that would be even worse or just not making it.

DR. HOYER: If I could say another thing. Mark Hoyer. That brings you to the issue that you're faced with a complex patient problem and options that you want to discuss with a family, whether that be surgery.

We've already heard that the surgery may be extremely high risk. Then we bring into this that we have the possibility of maybe using a device to close a defect in the cath lab, albeit at somewhat higher risk than a normal diagnostic procedure would be. Then we have to kind of think about the issues of what the burden might be of the administrative aspects of an HD approval versus a PMA and more widespread application of the device. Occasionally what happens is we get lots of questions about insurance issues. It's extremely frustrating or disheartening, I guess, to see a family that might be faced with a decision of a financial burden versus a soul and heartfelt decision for their child.

I think that makes it a difficult thing. Obviously most situations they will opt for doing what they possibly can for their child. It does not -- it still enters into the equation and becomes a consideration in their minds and they do ask about it.

DR. BOUCEK: I agree with you completely. If I had to hear this list of potential adverse events from the procedure, I think I would run as fast as I could from the hospital.

What we usually do actually is put a side-by-side consent with surgical and device and try to compare the relative incidence of these complications or adverse events with either procedure since that is really their only two options since these children don't have the option of saying, "I'm just going to leave and pick my battle another day."

They really need something done and they have to make that decision. We go through each one, what is the incidence of an air embolus being on bypass, what is the incidence with this type of procedure, and try to give them what we think is the fairest comparison we can.

Then we have some parents that because this is still considered "investigation," they will say, "I'll stick with surgery." I think that is one of the reasons that this sort of onus may have an impact on a patient's decision about what may be best for them.

DR. TRACY: I think that the patient education material, I agree, I like the idea of having something to give but it just looks like you're going to pop that thing in there and pull that little thing back.

I think it needs to be redone to show the complexity of the trans-septal snaring, etc., etc. That may actually help with the consent because the patients can -- the family then can understand the complexity of the procedure that the child is about to undergo.

Just a couple others for my own curiosity. Why do upsize to a 1.7 to 2 to 1 size on the size of the occluder that's used? Do you stretch it out intentionally? That seems like you would be increasing the risk of mechanical problems or arrhythmic problems. Is that because they are sort of genestrated areas or why is that thing so big?

DR. BOUCEK: Well, you don't really stretch out the area with this type of device. With a sizing balloon you try to get an indentation in the balloon so you know what the size of the balloon is. Of course, the center pin on this device does not impinge upon the edges of the VSD.

The flanges tend to reach around the edges of the VSD so you don't expand the size of the defect the way that some other types of devices do when they are designed to fill the defect from the inside. I think that is a fundamental different.

We found actually that those criteria which were based primarily on closing an atrial septal defect, I think that 1.7 to 2, are probably very conservative when it comes to a ventricular septal defect since the muscle tends to construct down and actually become smaller during the time when the heart would be generating the most pressure which would like result in the device moving.

I think those are very conservative. When you size these VSDs most end up being a relatively small. Some of the sizing choice in the defect ends up being can you cover adjacent VSDs when there are multiple -- excuse me, VSDs in the same location.

DR. TRACY: One other thing. In several places I see that the ACT is 200 milliseconds. You might want to go through and change that.

Dr. Aziz.

DR. AZIZ: Again, I think I would like to commend the investigators for tackling a difficult problem in these young infants and kids. I want to sort of focus my comments on the adult population, the post-VSD. At least, those are the patients that I have some experience with.

This is a group of patients who can be very difficult to manage. I think the management surgically of that condition has evolved over the years with people saying you should wait for a while before you operate on them because hopefully the tissue had sort of scarified so the sutures would stay there.

I think the contraindication to that is if you wait, the guys who really need it most die early. Most people have been forced to operate on these patients earlier.

I see that you have a small subset of patients who have had post-infarct VSDs. My comments are going to be directed to these patients. A lot of these elderly patients also have concurrent coronary artery disease. In the patients who you propose or think of doing this VSD closure, what is the thought process about handling the coronary artery disease that is present at the same time? Anybody on the panel?

DR. BOUCEK: I would imagine Dr. Lock has probably the most experience with the post-MI VSD. I have no experience with it.

DR. JENKINS: I'd like to say that post-infarction VSD was not considered as part of the labeling indication for this submission. Primarily because of the small amount of data that we had, we really didn't think it was sufficient to show safety and efficacy in that small group.

DR. LOCK: I have two comments on the post-infarction VSD patients. Most of the patients that have been successfully managed using the entire series of devices that we used have all been post-operative patients.

MS. MOYNAHAN: Could you please introduce yourself?

DR. LOCK: I'm sorry. My name is Jim Lock and I'm from the Children's Hospital in Boston.

MS. MOYNAHAN: And any conflict of interests?

DR. LOCK: I'm on the Board of Trustees of

-- Board of Directors, actually, of Nitinol Medical Technologies. I don't own any stock in the company, although I do -- I am assigned options. I receive compensation for serving on the board which I donate to the Children's Hospital.

My institution receives royalties for the commercial sales of a series of different devices that were developed at the Children's Hospital. As an individual I'm assigned some of those royalties from the Children's Hospital.

Having said that, I would say that this is not a good device to close unoperated post-infarction VSDs and I wouldn't do it.

DR. AZIZ: What about in the primary situation?

DR. LOCK: Post-infarction VSDs that have not already undergone surgery to fix their coronary artery disease, our results have not been good and I don't think this is a good device for that clinical situation. The holes are all 10 mm, 12 mm.

When you put a device in the septum continues to resorb and the infarct gets bigger and the hole gets bigger. While you may stabilize them for 12 to 36 hours, the holes invariably have come back in the unoperated first five-day post-infarction VSDs.

The successes that we've had, and I don't know what the number is but it's maybe half, I think have all been post-operative, or all but one have been surgery to fix the coronaries, to fix the VSDs, the defect has recurred and that's when we have gone back and made those patients better.

DR. AZIZ: You couldn't see this being used as a bridge to sort of stabilizing the patient for five or six days and then going in?

DR. LOCK: I think there is a new device that's in development which is much larger and has partial self-centering characteristics and might, in fact, be a very successful device for stabilizing. We hope to start using that device for post-infarction VSDs but not device. I'm not going to use this device for post-infarction VSDs anymore.

DR. AZIZ: Thanks.

DR. HOPKINS: I'll echo some of the other panelists. I don't think you see a lot of surgeons fighting for these patients. I think the major outcome of significance is really the survival some six to 12 months after you've had to do something of which this is a good choice.

I am interested about the thoughts about the post-infarction VSD. I, too, was going to ask about that. In your indications for use, there's no specific either indication or contraindication for its use in that subset of patients.

If you feel strongly that it should not be used, I just wonder. I just throw it out and suggest that perhaps that should be put in as a contraindication to its use or, at least, a lack of indication.

A question of there were two devices. As I read through the various sections it appeared that in the pivotal series there were two devices which were explanted at surgery that were not one of the mortalities. Does anybody know the story on those two patients or why?

DR. JENKINS: Two were at heart transplantation for ventricular failure. One was a failed septation that was taken out at the time of a Fontan operation. It was basically a failed procedure. The fourth explant was done in the cath lab. It was that same patient who had the four embolizations. One of the devices got taken out late and that patient ultimately went to the operating room.

DR. HOPKINS: That was taken out transcatheter.

DR. JENKINS: Yes, it was.

DR. HOPKINS: There were two.

DR. JENKINS: There were three. Two at transplant and one at Fontan.

DR. HOPKINS: Two surgical.

DR. JENKINS: And one at Fontan.

DR. HOPKINS: Okay. Thanks. In the summary of safety and effectiveness, as well as in the indications for use -- and there have been a number of references to this. Some references to poor anatomy as being a contraindication or bad anatomy or unfavorable anatomy for its use -- and sort of left it at that in terms of a qualitative sort of statement. Can you provide more precise guidance for what constitutes bad anatomy for its use or should that be more specifically part of the training component? Is there some quantitative approach within 2 mm of the mitral valve, etc.?

MS. KULIS: Certainly we can add additional detail as far as what anatomy is unfavorable.

Dr. Jenkins?

DR. JENKINS: It will primarily be with relation to the valves. I don't know if one of the interventionalists could comment on anatomy where it's just not technically possible to pass a sheath or a wire through such an extraordinary pathway.

DR. HOPKINS: I just want you to know it's being used now in just a couple of superb centers. As it spreads out, I'm just wondering if there doesn't need to be a little bit better guidance for those.

MS. KULIS: I'd just like to make one point as far as you said used in a couple of centers. We have a total of 30 centers right now in the United States that do have institutional approval to perform VSD closures using this device.

DR. HOYER: Mark Hoyer again. As far as location of defects and difficult ones to get to, obviously I told you we have done three so I don't have an extensive experience that I'm going to be able to convince a lot of people but I can tell you that down at the apex of the heart it can be very cumbersome.

There's a lot of trabeculations in the right ventricular side of the septum. In fact, the device won't necessarily even open completely so that it's flat on both sides but it will be darn close. But you still have accomplished the task of opening the left ventricular side and then releasing the device as you open up the right ventricular side before letting go of it and is in a stable position. Perfectly stable. That, again, is a muscular defect much closer to the apex but well away from semilunar valve or AV valve.

DR. BOUCEK: Yes. I think you're correct that there are some locations where it is more difficult in the anterior portion of the septum sometimes it's difficult to get the sheath to go up into that portion. These are difficult procedures to begin with. I think they represent the sort of new unfortunate era, if you happen to be an interventional cardiologist, of where pediatric cardiology interventions are going.

I think with experience with other types of complex interventional procedures in pediatrics, it's just a matter of a problem to be solved rather than an insurmountable problem. It tends to be lengthy. Sometimes you have to try the sheath from a different approach rather than from the neck. Maybe from below. It ends up being problems that need to be surmounted rather than ones that shouldn't be attempted. They tend to be long cases. They are like some of the more complex oblation procedures or some of the more complex stent procedures that we do in terms of the duration of time that we're in the cath lab. I finally understand how much I respect the surgeons for spending eight hours in the operating room.

DR. HOPKINS: Well, don't misunderstand me. I'm not going to sign up to get trained on this device. I think that, in fact, I am on your side on this. I want this to succeed as it rolls out. I'm just concerned about the training. I think we'll probably talk about training a little bit later, but that there be a little bit more precision in the guidance of this.

I think, also, knowing these patients and looking at the study information and also reading between the lines, these are patients that are being managed in centers that have full cardiac surgical backup.

In the indications for use and guidance documents, it basically says surgical support should be readily available. I think that may be more bland than it needs to be. I think this needs to be done in centers where it is truly complete support.

Also you talk about the transient hemodynamic compromises. It sounds to me like the reason the mortality rate in this extraordinarily difficult group that you presented being so low is that they are managed by cardiac anesthesia, cardiology, interventionists simultaneously.

I wonder if there shouldn't be a little more stronger guidance about that either in the training document or in the indications for use because this is not your standard coronary stent that's going in. You're using a whole team approach here.

Like others, I congratulate you.

DR. TRACY: Dr. Zahka.

DR. ZAHKA: This is certainly a very diverse group of patients and a very challenging group of patients. You all deserve congratulations as well. The assessment of them is not always easy as evidenced by the child with a single ventricle that was attempted to be septated, and the 12 patients who were felt to have larger VSDs and turned out to be small. Did those patients have a band on that made it impossible to really judge the VSD size, the 12 patients that got enrolled but did not get implants.

DR. JENKINS: Had no intent of planting a device. Part of that is factual just in the way that we set up the study because we had to have the prior pier review. There was a lot of paperwork that had to be done just to have it possible to put a device in at the time of the procedure.

In order to have the procedure go forward in a timely fashion, we tried to anticipate cases where it might be necessary even before the hemodynamics had been done. Obviously everyone is always hoping these defects go away on their own and they sometimes do.

DR. ZAHKA: Does that then reflect our inability to really assess these people, these children accurately and how does that speak to the follow-up data?

DR. JENKINS: I think assessment has to be made in the cath lab once the final pictures are there. For the band patients it's very difficult for the echocardiographers to always judge appropriately. Even for the nonbanded patients I think the angiograms and the hemodynamics help a lot.

I think in this case, though, it's partly an artifactual reflection that if there was even a small probability like 15 or 20 percent likelihood we might want to close a defect. We did peer review of the patients so then they are counted as enrolled in the study.

DR. ZAHKA: It's also been my sense, in fact, that infant cardiac surgery has progressed dramatically over the last 12 years. Although there's not a lot in the literature about closure of multiple muscular VSDs and that there are still problems with that, that this process has, in fact, progressed and that there are probably more children who could be done surgically as well.

I look at the illustration in the operator's manual of this ventricular septal defect which looks like it would be good to close by intervention or by surgery. Perhaps what is the risk benefit of each at what age.

I think about the process you have for reviewing who should be enrolled in this approach and notice that you have a surgeon and a cardiologist review every case beforehand. Is that surgeon and cardiologist also part of Boston Children's Hospital or are they kind of separated from this whole process?

DR. JENKINS: They are within our institution. The reason we did that was simply for expediency except for the adults enrolled in the trial where the peer reviews are done by adult cardiologists at partnership centers. The peer reviews at all the centers in the trial, that was similarly the case.

I think that some of it is taken as a success if the surgeons get better partly because of some of the alternatives that patients have available. I think in response to Dr. Skorton's earlier question, I did do a pretty extensive literary review looking for almost anything that was more recent than what Dr. Mayer presented.

What I found was a series of 11 cases in Dr. Bovey's paper that was buried between categories where they weren't really broken down by ventriculotomy. That group of 11, according to the authors of that manuscript, it does suggest that maybe some left ventriculotomies are doing a little better than they were, you know, 10 or 15 years ago.

There was only one other single case report from the European literature where a large ventriculotomy was presented as a good outcome short term. There was a series of letters to the editor afterwards, you know, kind of worrying about late results. That was all I found in the literature.

If it's true that the surgeons are doing better, it's not out there where we can review it and see the results. I'm sure there's going to be a series of defects that are always difficult to close surgically, a series that are easy to close surgically and a series in between where, you know, the cardiac surgeons will evaluate the best outcome as time passes.

DR. TRACY: Dr. Williams.

DR. WILLIAMS: Well, my questions will be related to what is the best way to transfer the experience at Boston Children's Hospital to other institutions as they become involved. And if there should be any limits on the kinds of patients that are attempted by hospitals earlier in their learning curve or who have a lower total volume experience with surgery, echo, and the other factors that are important to this process.

The first one was the illustration showed passage of the catheters through the simplest kind of lobe and muscular defect. Then we heard that the adverse events were more related to technical issues. I have a suspicion that maybe technical issues were greater in the far interior or far posterior or apical positions. Were you able to look at those separately to see if those kinds of defects had a higher incidence of adverse events than the more favorable position?

DR. JENKINS: We looked at the differences in outcomes by the post-operative residual defects versus the congenital defects and we didn't really find any differences in our safety or efficacy outcomes for those two groups but we never looked by the specific location in the septum where the defects were.

DR. WILLIAMS: I wonder if Jim Lock, who has such large experience with this, has an impression?

DR. LOCK: I think Dr. Williams is correct. One can predict where the trouble will occur from choosing catheter passage. I do believe that most of the catheter induced -- most of those five patients with catheter induced heart block were posterior muscular VSDs near the tricuspid valve.

I do think that the patients with the catheter induced mitral regurgitation were also posterior muscular VSDs. That is the particular -- if you were going to -- I think actually the anterior septum turns out to be the easiest and the safest place to fool around.

I think if you were going to apical muscular VSDs, mid-muscular VSDs, intramural VSDs near the aortic valve are actually pretty safe. I think the one place where people should be more cautious really in their experience is in the posterior muscular septum near the attachment to the tricuspid valve.

DR. WILLIAMS: Thank you. You might want to keep your seat because I've got another question coming up.

It seems to me that considering the difficulty sometimes in telling the difference between multiple VSDs and a patient who really truly has no septum but has bundles that are running at different angles to each other, essentially have no wall but a collection of bundles, in high referral centers by echo you often see this as a misdiagnosis from other centers. I think even in the best of hands it's possible to miss it. I think probably it was.

I would say that probably echo is superior to angiography in recognizing this lesion if it's done very, very carefully. I think MRI in some circumstances can also add some information.

My question is really what should be the experience requirements for the echo cardiography who is evaluating these patients prior to attempt or prior to talking to the family about the potential for doing a device closure.

And if there might be some way where the mother institution could produce a teaching tape or a series of teaching evaluations to show echocardiographers how to recognize this lesion -- it ought to be done anyway -- in order to avoid this particular pitfall.

Or how to recognize what you would view as the higher risk defects and how to recognize that margin along the posterior -- that posterior margin of the defect, where you think the pitfalls are so they are not going to be able to recognize this with their lower volume and lower experience. Is there a way to shorten the experience, the learning curve?

DR. LOCK: Yes. You're exactly right. I mean, if you look carefully at the data, we made that mistake three times. We thought there were three patients that were septable that probably really weren't and they had exactly the anatomy that you describe, and that is that you could sort of talk yourself into thinking there was a septum but then when the surgeon goes in, there just is not a septum. We will and have analyzed those three patients and will continue to do so.

I think you are right. Sophisticated echocardiography and probably 3-D reconstruction is a better way to assess this than angiographically which was inferior to those two techniques in deciding who is septable and who isn't. I would agree that is part of our responsibility.

DR. WILLIAMS: And I think that will be part of the general recommendation on my part that when you talk about what are the institutional requirements to carry this out, that it specifically states training and experience requirements for the echocardiographer and the cardiac anesthesiologist since the total outcome is so dependent upon those individuals as well as the main operator.

Could I just ask in the far anterior and far posterior defects, I recognize that this device is flexible and soft. It's not likely to impinge on structures so much. Has there been any indication of interference with the anterior or posterior descending coronary artery and would you have recognized it given the kind of surveillance? What would you expect to have seen if you had encountered that?

DR. LOCK: We haven't done selective coronaries in any of the patients. The only thing that I tried to do, and I'm not sure this is an adequate test, obviously we tried to look at ventricular performance in all of the patients and haven't recognized to my knowledge localized ventricular dysfunction.

There's no question that the device can sit right next to the septum and, therefore, you know, one of the anterior or posterior descending arteries. We just haven't seen it.

DR. WILLIAMS: Okay. So you haven't seen segmental wall motion?

DR. LOCK: We look pretty carefully for it because obviously it was one of the clinical concerns about ventriculotomy patients.

DR. JENKINS: We haven't seen signs of ischemia on the electrocardiograms or things like that on the surveillance.

DR. WILLIAMS: Okay. Great. Do you believe the best use of this device in those patients who have complex conal truncal abnormalities or pulmonary artery bands is ultimately to do the catheter closure after you've attempted to do the surgical closure or to do the catheter closures of the more difficult defects in preparation for attempting as a stage before deciding whether to attempt a complete repair?

DR. LOCK: We do it both ways. I think that if the patient has a band in place, then we tend to close everything we can close safely in the cath lab. If the patient doesn't have a band in place rather than commit the patient to two cardiac operations, the surgeons decide if they think they can close most, if not all, of the defects.

If they think they can close most, if not all, the defects using John's requirements without a left ventriculotomy or without an extensive right ventriculotomy, then they get the first crack at those patients. It's really very patient dependent.

DR. WILLIAMS: Given the variation of surgical experience with these lesions, do you recommend to other institutions that they do it one way before doing it another?

DR. LOCK: I think the safest technique now is bands for people with multiple muscular VSDs.

DR. WILLIAMS: But rather if you anticipate you might need to do both, which one to do first for those institutions that may have variable surgical experience?

DR. LOCK: I think the risk of catheter closure in banded patients is actually pretty small.

DR. WILLIAMS: And since the indications of the catheter closure are so closely related to the ability of the surgeon to close defects, particularly if you're going to do the surgery anyway, do you have any recommendations on the volume experience of the surgical team or the institution in terms of surgical experience knowing that by your studies and others have been directly related to surgical outcome? I'm sorry to be asking all these questions.

DR. JENKINS: The wrong hat, Roberta. I'm not sure what specific volume standard for that would be or whether a volume standard is the correct measure. I do know that through the Agency for Health Care and Research that there is going to be a proposed volume standard of around 100 surgical cases a year being dictated to pediatric cardiology based on relatively little information. Whether that would apply to a specific patient with complex ventricle septum I think would be hard to say.

I think at this point one would need to emphasize that if the surgeon is wrong and they can't close these multiple defects safely, that the patient is likely to be very sick and the patients where we did it in the opposite direction and the VSD was left are often taken to the cath lab for a VSD closure on a fairly urgent basis.

I think in those cases where people were less certain about what they could do, it would be important to have really all of the alternatives available in order to get safely to the other side. It's a bit of a judgment call whether you would do the device first or the surgery first and hope for the best with the device later if the surgeon wasn't able to accomplish everything they had hoped to do.

DR. WILLIAMS: In the larger scheme of things whether one should use device closures at all in centers that are not large volume experienced centers. I think this comes to the question of whether one should electively regionalize the sickest of the sick patients with known complex disease.

One easy question to end. There seems to be more fractures for the PFOs, 37 percent, than for the ASDs, 15 percent. Is that because the septum flops around more and it bends it more or is that incorrect?

DR. GAUVREAU: We've actually noticed that larger devices are more likely to fracture. Larger devices are needed to close the PFOs and that's why you see the larger fracture rate and the higher fracture.

DR. WILLIAMS: Thanks.

DR. TRACY: Dr. White.

DR. WHITE: What are you planning to do about nickel allergy?

DR. JENKINS: We actually have a lot to say about nickel and also nickel allusion. I think I'm going to refer that question to Carol Ryan, the engineer on the project because there are issues beyond nickel allergy.

MS. RYAN: We've gotten that question many times and actually looked at that very early on in the design process. Significant studies were done to look at the medal ion to solution rates to be assured that they were very low. Significant literature searches have been done and discussions with multiple consultants regarding nickel allergy.

The one paper I tend to refer cardiologists to now when they ask that question because they have a patient with nickel allergies, a paper written by Katherine Merritt who actually works for the FDA. She did a nice summary on immune responses to metallic devices and their leechables.

Her conclusions were that -- she basically looked at all the literature that's out there as well as her own studies -- that there is no obvious relationship between a dermal response and a systemic one.

Her recommendation is that surgeons or clinicians should not deviate from their normal surgical practices based upon if a patient has a nickel allergy or an allergy to any sort of metal ion. Devices should be designed so that the metal ion to solution rates are kept to the lowest possible amount and that was pretty much our conclusion.

I can think of at least 10 accounts to date where we've been approached because a patient was allergic to nickel and they've received a device and we've had no adverse reports from that usage. The ion to solution rates for this device are actually extremely low. All the possible metal ions that could leech out of it were evaluated. In most cases they were undectable levels.

DR. WHITE: The second thing I have to say is a minor one. In Section 49.2 you describes the device as being 11 French and I think you've said today that it's 10.

MS. RYAN: It's 10.

DR. WHITE: You need to fix that.

Can you tell me, just educate me, in your tables about how well the patients did on one of the slides here, it says, "Clinical status CL by patient VSD pivotal cohort." Why did you assess the benefit by median scale value? Why did you not use mean? Is there something about an ordinal scale evaluation that I don't understand?

DR. GAUVREAU: When you're working with an ordinal scale it's more appropriate to use medians rather than means. One reason is that the data are usually not normally distributed. The second reason is something I had mentioned earlier where the difference between a two and a three is not the same as the difference between a three and a four. It doesn't make sense to use means.

DR. WHITE: Fair enough. In terms of the doctor training in Section 5 you have several classes of physicians outlined. The third class is a fellowship trained doctor who you state may or may not have had a lot of experience. You were going to have your representative decide whether he needed to have Category II or Category IV training.

DR. JENKINS: I think that would depend on where the fellowship training was. For example, there are some people who spend an entire year in interventional training fellowship.

DR. WHITE: What I'm suggesting is that you delete the class and that you make your decision based upon whether the physician is qualified with implant or not. He's either a two or a four.

DR. JENKINS: Okay. I understand.

DR. WHITE: Take away No. 3. There's no point in that. You save the embarrassment. You save your company walking up to a young doctor who thinks he knows what he's doing and you have to tell him he doesn't. It's never very pleasant.

The other thing is that under No. 4 you talk about proctoring doctors but you don't specify the number of cases that will be done. Have you given that any thought? How many cases will a proctor take an experienced physician and when is it enough?

MS. KULIS: Certainly, I'll ask Dr. Jenkins or one of the other clinicians to elaborate but as a company we thought that a minimum of five proctor cases would be what we would consider acceptable before we would certify the site to receive devices.

DR. WHITE: Given that this busy hospital did 57 in four years, how long is it going to take somebody to get proctored?

DR. JENKINS: I think we would be very open to suggestions about how the training should be done for this project.

DR. WHITE: Okay. I think that it's a very complicated procedure. I don't do this procedure but it looks as if more than half your patients had multiple devices placed and that more than two operators participated in 67 percent of your cases. It sounds like a little bit different than closing an ASD. I'm a little concerned about the infrequency of the procedure and then how are you going to get people trained to do this.

I don't want to be rude but I would challenge your primary endpoint. Everybody here seems real happy that you've done this but I'm not happy. I'm used to endpoints that say that we had a procedure success and no major complication.

If you subject your data to that analysis, how many of your patients were successfully closed and walked or crawled out of the cath lab without a major complication? It seems to me like so many patients had big complications that not very many people got out of this unscathed.

DR. JENKINS: I guess the question would be whether you mean a manageable complication or something that would meet a definition of a serious hemodynamic impairment. I think if you use --

DR. WHITE: Most of the time we don't get to make excuses. I mean, you set an endpoint and you say procedure success or technical success is deployment of the device. Procedure success is successful technical deployment with no major complication. You get to pick what your major complications are. Under those criteria what would be your --

DR. JENKINS: In those criteria I would have personally chosen probably survival as my outcome so we might have disagreed on what was the major complication.

DR. WHITE: I guess what I'm saying is that your ordinal scale has its own merits or demerits but you're not balancing a successful procedure with a pretty bad complication may not be such a desirable outcome.

DR. JENKINS: We didn't create a composite endpoint for this study. We gave the safety data and the efficacy data in parallel without an overall measure that combined the two.

DR. WHITE: I don't want you to think I'm being unreasonable. I understand that you can take a band off the kid and, you know, the baby is better than he was without the band off.

It's just that everything else we think about has to be graded according to the risk benefit and so you don't get to claim a success if you have a major complication even if technically the procedure was effective.

What is a STARFlex? You had three patients crossover to STARFlex. Is that a competitive device or is that just another iteration?

DR. JENKINS: It's the third generation of this one that has been introduced.

DR. WHITE: Of this device?

DR. JENKINS: Yes. There's not as of yet sufficient STARFlex data to put before our panel.

DR. WHITE: Why did you cross patients to the newer device?

DR. JENKINS: They weren't crossed over. The device was introduced within the time frame where the CardioSEAL was -- the CardioSEAL is still available in this study and it's the selection of the implanting cardiologist whether a CardioSEAL or a STARFlex is chosen.

They weren't crossed over to a STARFlex but we were just being strict that when we gave you information on all VSDs enrolled through 2/1 2000 there were three that were not enrolled with CardioSEALs that were not included in this data summary. Maybe I'm not being clear. They didn't crossover into a STARFlex.

DR. WHITE: How did they get a STARFlex and get reported in this database?

DR. JENKINS: They are not reported in the database. That's the point. We gave you data through 2/1 2000, all of the VSDs that were enrolled in the trial.

DR. WHITE: In this trial?

DR. JENKINS: In this trial. Everyone that was enrolled through 2/1 2000 but we're only reporting on -- excuse me?

DR. WHITE: Where are the three STARFlex patients?

DR. JENKINS: The STARFlex was introduced into the study in the early part of 2000. There happened to be three patients who met that definitional criteria who had a VSD who were enrolled in the study who were included in the overall dataset. But because this particular part of the data was intended to show the performance of CardioSEAL, the STARFlex patients were not included in the 57. However, just to be maybe ultra conservative in our reporting, we told you that there were three that fell within the time frame of our enrollment.

DR. WHITE: So have you now gone past the CardioSEAL device and are using STARFlex for this disease?

DR. JENKINS: At the Children's since we have the STARFlex device for the high risk trial on an ongoing basis, VSDs are being done with both of the devices but quite a few of the recent ones are being done with the STARFlex.

DR. WHITE: Why did you choose not to include the catheterization complications when you reported the adverse events? You told me that out of the 222 total adverse events, there were 32 that were device related and 35 that were implantation related and 85 that were related to the cath. But when you went to look at the summary of the adverse events, you didn't include cath complications in that.

DR. JENKINS: They are all in the Panel Pack in exhaustive detail.

DR. WHITE: I mean in the --

DR. JENKINS: In the primary income.

DR. WHITE: You said you were interested in the --

DR. JENKINS: The reason is that we chose -- the reason is that most patients would be having a catheterization anyway. That's the spirit of choosing the outcome as the specific part of the study whereby the device was placed or the implant procedure was done.

What we did instead is that our safety committee spent an inordinate amount of time figuring out if a specific event was due to the implant part of the procedures, or do just having a catheterization. They made that distinction.

With them having done that, we counted as the primary safety outcome just the device or the specific part of the procedure where the large sheaths and the wires and all that were in the heart rather than simple things that were just the result of a patient having a cath.

DR. WHITE: Well, the problem with that is that because you're not comparing this to anything else and the catheterization is integral to the device implantation and delivery, it's a little bit disingenuous. It makes the procedure seem safer than it might actually be.

If you want to know what's the risk of this baby or this child to undergo this procedure to take the cath complications out when, in fact, they were -- maybe they weren't as serious but they outnumbered the number of other complications.

DR. JENKINS: There are a large number and they are all listed in the Panel Pack in a lot of detail.

DR. WHITE: When you look at the primary safety outcome, it looks like that number may be less than it really was if you count the cath complications into it.

DR. JENKINS: One could have used a different definition That's true.

DR. WHITE: I'm really troubled by the fractures of the device. I'm really troubled by -- I mean, I know that you tell me that it hasn't called a problem but it bothers me that devices are breaking and I want to know what the company is doing about that. Are you making them so they won't break or you want me to keep putting them in to break?

DR. JENKINS: Again, I would like Carol Ryan to come up and talk about that.

MS. RYAN: We're actually -- the device, as I said, is made from MP35n and MP35n is the material that is used in pacemaker leads and pacemaker leads fracture and their fractures are unacceptable and usually have significant clinical sequelae.

The vendor who makes the MP35n for all of us who use MP35n wire in the medical device industry has a significant program that's ongoing to improve the quality of the raw material. We work very closely with them in evaluating each new generation of this material that comes out and implementing it into the product.

Kathy could probably comment to this better than I but an analysis was done of devices made from a variety of generations of this wire. We have shown that there is a statistically significant improvement in the fracture resistance of devices of the recent generation that has been incorporated.

We are continuing currently to evaluate future generations of the material that the vendor has provided us so we expect over time that the fracture rate will only get lower. Maybe Dr. Jenkins can comment on her analysis.

DR. JENKINS: We actually did do an analysis maybe three-quarters of the way through the data that I showed you looking at determinants of fracture to figure out if there was specific manufacturing issues, specific device design issues, or issues related to implantation that could be associated with fracture. It was a little bit of a fishing experiment. We looked at quite a few variables. We actually found three that were significantly related to fractures. By far and away the most important one is device size as Kim pointed out earlier and as is shown in the fracture section of your Panel Pack whereby larger devices are more fracture prone than smaller ones. That confounder actually confounds a whole lot of other analyses that one might do looking at fractures.

The second one was a specific lot of devices that seemed to have an especially high fracture rate which was part of the impetus for Carol to go back and continue to look at the specific metal that's being used for manufacturing.

The third one was a very broad stroke variable whereby somewhere in the cath reports are follow-up letters. The procedure was described as a difficult device placement leading us to believe that pushing devices around bends in the sheath and things like that may actually also be part of the determinate of fracture.

That was the most easily avoidable one. But we've done quite a bit to try to look into this. I think as clinicians having watched a large number of patients have fractures in the original Clamshell I cohort that we have also done extensive analyses on, and now quite a few patients experience this later. We've had an increasing level of comfort around the issue that fractures really are incidental in the vast majority of cases probably because most of them are, in fact, occurring after the devices enthothelialize and are completely covered. Just so you're aware, in the original Clamshell I registry series, there were seven events that were attributed to fractures in the hundreds of events that occurred in that cohort.

Those events were three masses that were associated with a fractured arm friction lesions, three devices that moved, and one arm that actually broke off and impeded in the free wall of the RV. I think we all wish that fractures would just go away and not keep happening.

Even in the large number of patients in that original series who had fractures, the overall even rate was fairly small and fortunately we just haven't seen it all since 1996 despite screening extensively for them.

DR. WHITE: That's all.

DR. TRACY: Maybe this is a stupid question but why is the arm on the surface and not some place within so that it can't break lose and fly into the free wall or wherever it wants to go?

MS. RYAN: The predecessor, the Clamshell, where a piece of an arm migrated is somewhat of a mystery. It had to have been some sort of manufacturing defect. That device was made under a completely different processing controls than the current product.

The CardioSEAL device actually has each individual coil sewn to the fabric which did not happen with the Clamshell device. The nature of a fatigue fracture once one occurs in an arm, that arm really isn't under any significant stress at that point. You shouldn't have a fracture at two points. With the coil sewn down there shouldn't be any migration.

DR. TRACY: Thanks.

Do any of the panel members have any additional questions they would like to ask the sponsor?

Dr. Williams.

DR. WILLIAMS: Just one very brief one. Under the contraindications, I think it would be reasonable to say the anatomy in which the CardioSEAL size required or position would interfere with intracardiac or intravascular structures because of the issue that you do select defects in which the position of the device would not interfere. I would put that specifically on the contraindications.

DR. TRACY: Any other members of the panel?

DR. LASKEY: Did I understand you correctly to say that you have not had a fracture since 1996?

DR. JENKINS: No. We haven't had any adverse consequences of a fracture in the entire high risk cohort.

DR. LASKEY: Just for my own clarification, two hours ago I asked the question who should this not be put in. I got a rather cursory answer which wasn't helpful. Now I come away hearing that there are defects where it shouldn't be approached.

Can you just give me a Reader's Digest summary of who this is appropriate for vis-a-vis which patients are not surgical candidates which, of course, you have in your IFU, but more specifically the anatomic subset which is not likely to do well with this procedure.

DR. JENKINS: That are not likely to do well with the cath procedure? Is that what you're asking? I think that the subgroup of patients that are not likely to do well with this procedure would include patients with VSDs in locations that are within 5 mm of semilunar or AV valves or valve apparatus. Or patients who are too small to have placement of 10 French catheters in their vasculature.

DR. LASKEY: And the postero-septal defects that are perhaps a little too close to the base and to the insertion of tricuspid leaflets. I took something away from that discussion as perhaps being not as ideal a situation as other regions.

DR. JENKINS: I'm going to ask Dr. Lock to answer this question.

DR. LASKEY: Over the last couple of hours the answer to that question changed.

DR. WILLIAMS: My interpretation of his answer is it's harder than the other ones but it may be the only alternative. The question we have to determine is whether in hands other than Dr. Lock's it is likely to be successful.

DR. LASKEY: And that summarizes my concern. Dr. White, thank you for getting my adrenaline going again. You guys are experts beyond two standard deviations of the average interventional cardiologist. If you expect this technology and capability to penetrate into the lower levels or the lower echelons of this profession, I don't have any desire to do this. I'm not even sure I could but if I wanted to.

Frankly, I'm intimidated and I've been doing intervention in sick people for 20 odd years but this is a whole other order of magnitude here. I don't know if I speak for the profession or just for myself, but I get the feeling that there is a body of knowledge here and the level of expertise which desperately needs to see the light of day in order to make informed judgements about who should get this. It has to be done in the context of expert surgery, expert anesthesia, a whole group of experts which is to be found only in 30 centers, did you say? This all started out with my unease as the afternoon developed about, well, it's going to work better in some than in others. I think that's not clear from this material. I think users other than you need to know what to expect.

DR. ZAHKA: I would agree with you but disagree in the sense that the community of interventional pediatric cardiology is a very broad one. We heard about one center who has done three successful ones. I think that Dr. Lock is probably very articulate, because he is very articulate, at telling what are the tricks of the trade.

There's a great body of experience in pediatric interventional cardiology that I think can be brought to bear on this so that the situation is perhaps not as bleak as it might seem from the adult world.

DR. LOCK: This is probably gratuitous and unnecessary, but there was a period of time 20 years ago where there was really only one place in the country that did hypoblast surgery. There was a period of time when really it was thought that only a few places could successfully perform that procedure. It did take five or 10 or 15 years for that operation to become a national standard. Now, it isn't done in every center in the country but it is done in quite a few centers around the country. I expect exactly the same transition will happen with this kind of complicated intervention in children. There will be more complicated interventions in children like this that won't be done in two or three hundred places but will be done in 50 or 80 or 30 or 20 very successfully as time goes on.

DR. TRACY: I think there is some difficulty because the only real concrete thing here is the death rate which was about 7 percent. But you're talking about a procedure that has a 99 percent adverse event rate which anybody could go out and say, "I'm going to do a procedure now because there's almost a 100 percent chance that something will go wrong."

I think that in the education of the physicians, all of these intangible things really have to be conveyed very clearly. Who best is this suited for? Who is this not suited for? What are the things that we have learned from our experience?

That kind of information has to be passed along because not even well-trained interventional cardiologists will have had that much experience doing transeptals. There's about a 1,000 pitfalls in this procedure where things can go wrong.

Each of those steps require some training. It's not everybody who should be taking on this type of procedure. I think that is the unease that many people feel about this procedure.

Dr. Williams.

DR. WILLIAMS: This is getting a little bit more into the domain of discussion than question so I'll include Dr. Lock in this discussion point.

It seems to me those of us who have looked at surgical outcome relative to institutional and operator volume know that in general there is a difference between large and small but there are many, many exceptions that have to do with institutional organization accumulation of learning curve.

One option that we would have is to try to put some very arbitrary volume limits on this. But I wonder whether in the end more patients would be served if we put very, very heavy educational requirements on the team and institutional record keeping. And if there were very, very careful post-market surveillance and that perhaps taking the most difficult type of VSD which would be the posterior muscular VSD and say in order to qualify to do that type of VSD, that institution would have to have both efficacy and safety record equivalent to Boston Children's Hospital. Now, that would be tough but it would be -- you know, you could earn your --

DR. LOCK: I intend to make it impossible.

DR. WILLIAMS: Of course it would. At least equivalent to the average of the institutions of the group which would be a lower target. The indications to this, who is going to do it, is whether you belong to the tribe that believes in no stone unturned in a dying patient, or you belong to the tribe that says above all do no harm.

That's a matter of philosophy. That is also a matter of what your other alternatives are. It is an imponderable when we talk about different institutions because the resources of those institutions are different and every patient is like a snowflake. They are different.

I personally would feel more comfortable saying go ahead, but putting these stringent requirements on education of the team on post-market surveillance and letting that be as close as we can get to what is the right thing.

MR. DILLARD: Dr. Tracy, Jim Dillard. Just a point of reminder for the advisory panel is that we are sort of skirting that line and going over and coming back a little bit in terms of practice of medicine and just to remind you that we really don't get involved with a lot of the practice of medicine. I think Dr. Williams brought it back a little bit to say what some of those training requirements might be which is something we'll work obviously very closely with the company on.

A number of these in terms of who's going to do it and how many you have to do, I think, really gets in much more to the practice of medicine and something that I think their profession needs to regulate a lot more than the agency is going to. I just wanted to remind everyone.

DR. TRACY: I would agree with that except to the extent that this is a team approach and I think that part of the physician training -- what I would take from this as a concrete thing is part of the physician training has to include all the different pieces of the team that are going to be present or potentially present including the cardiac surgery team.

DR. HOPKINS: I just want to say thank you. I'm just about ready to raise that issue. We're talking about 57 patients here in four years. I mean, we can get so stringent that no patient ever -- the patients are out there dying because they don't have access to this device because we've created this philosophically stringent.

When I first went to medical school at Duke, the only place in North Carolina that did aneurism surgery was Mr. Duke's hospital and now it's probably done in every hospital that has 50 beds or more.

I think we are getting way afield of labeling and indications and what is intended here which is moving a device that has been remarkably effective in a very tough set of patients from a humanitarian device to a premarket approval. All of the other stuff that sort of in the last 20 minutes has been very philosophical but I don't think has anything to do with this.

I agree with requesting of the company to do rigorous training but that's different than limiting access of the device to some subset of a subset of a subset.

DR. TRACY: I think there is one more question from the panel.

DR. WITTES: I feel like I'm in Never Never Land. I don't understand. I need to hear some numbers about what the mortality would have been. What we're hearing is this is remarkably effective, what the mortality would have been had the device not been here.

What would the shift have been in the clinical efficacy? I worry exactly as Dr. Laskey does about whether -- how much of this is regression to the mean. It may be none of it is but I need to hear you tell me that if I had 57 patients and I didn't give them this device, X number would die within six months and nobody would shift over in the improvement. Otherwise, I'm feeling like it's a matter of faith.

DR. JENKINS: I think we should have John answer that.

Fifty-seven patients, John. Half had failed VSD surgery elsewhere. The other half had passed a peer review whereby a surgeon, maybe yourself, maybe someone else, and a cardiologist had declared that the VSD would have been very difficult to approach in the operating room

DR. MAYER: Well, I guess what was running through my mind there is to give you some context about what's the natural history. Forget surgeon, cardiologist, or anybody.

The natural history of patients with large ventricular septal defects, large defined as having a big left-to-right shunt is as follows. There's a large number of those patients who will die from congestive heart failure.

There's a huge volume load placed on the heart. There's three times as much blood going through the lungs every minute as go through the body. Those patients are highly susceptible to pulmonary infections.

A virus that you or I would throw off will kill those children. You know, they can't grow because they are wasting so much metabolic energy pumping all that extra blood around that they can't devote energy to getting bigger like babies are supposed to get.

And there are a significant number of those patients who have elevated pulmonary blood flow so a lot of extra blood going through the lungs at very high pressure who will then progress to develop what is called pulmonary vascular obstructive disease. The natural history of an untreated large ventricular septal defect in children is particularly unfavorable. That's why 40 years ago when cardiac surgery started, cardiologists were willing to send patients to surgery even who had surgically easily accessible VSDs because the mortality rate was 25 percent with an operation, but it was still better than what the natural history was.

So that's the sort of floor context. If we take the subset of patients who had a pulmonary artery band which is a palliative procedure that you can do that will limit the amount of pulmonary blood flow drops the pulmonary artery pressure down strained to the band, keeps them from getting pulmonary vascular obstructive disease, and we don't have an adjustable band.

What might work pretty well for a baby age six months, by the time that child is three or four years old, they're not going to have left-to-right shunt. They're going to have right-to-left shunt.

They are going to be blue. They are going to be exercise limited. They are going to be at risk for strokes and all the things that kids with cyanotic heart disease get. That's another subset of what can happen.

Certainly the patients who went to surgery to have a VSD closed in whom it didn't work -- the surgeon couldn't get access to it because it was in a difficult location or whatever other reasons there might be, complicated anatomy -- those patients presumably went to surgery because there was an indication for doing an operation.

From my standpoint, and I guess I would hearken back to the practice of medicine question versus what is the device related issue, at least in our place this has been a pretty rigorous process because you have to get a surgeon and a cardiologist both to agree that this is something that is the best course of action, least risk path of treatment for this particular patient. It's really done on a case-by-case basis. That's always informed by a whole variety of personal experience, literature experience, so forth.

I guess from my perspective, and having been a reviewer on a number of these cases as they have come along and, to be honest with you, having kicked some out saying, "I think I can close that hole," ones that came through, and some of which I actually did operate on and close the whole, I think all of those factors make it, I think, extremely difficult to construct a control group.

In the same way that there were difficulties with having what is clearly a multiple clinical presentation set of patients, and trying to figure out a scale how you deal with the banded patients who then got their device closed and then had their pulmonary band taken off, and construct a scale that is also consistent with the patient who had multiple ventricular septal defects and hadn't been banded and had one or more VSDs closed by device, I mean, it inherently is just a complicated set of patients.

I think that is the problem with -- I mean, I understand from a statistical standpoint why one would like really to have a comparable group of patients.

DR. WITTES: Well, I'm not even asking that much. I'm asking for a number. I'm hearing essentially 11 percent, six-month mortality in this group is what there is. Is that right?

DR. JENKINS: Four patients died and one died because of the catheterization for a mortality of 1.7 percent. One patient out of 58 patients died directly due to the procedure.

DR. WITTES: But, to me, it's still four out of 57. However --

DR. LOCK: Can I interrupt for a second?  The other three patients who died died from their underlying disease.

DR. WITTES: That's what I'm asking. What percentage of people -- if you had 57 --

DR. LOCK: Those were the patients who weren't made better necessarily. For all the patients who were made better, it improved their overall survival.

I don't know how to put this but there have probably been 10 patients who were in one fashion or another didn't come for the device and I know of three who died waiting. This is a very difficult patient population to get mortality rates on. If we gave you a number, it would be arbitrary.

DR. WITTES: I don't care if it has a 20 percent spread. I just want to know --

DR. JENKINS: The old-fashioned number that is widely taught to cardiologists was that there was a 20 percent of patients with this disease that didn't come off pump.

I actually tried to track down where that number came from because it's been widely quoted. I had trouble actually finding it so I tend not to give information I can't find.

It's wide quoted that the mortality rate of not coming off pump, if you take somebody with multiple VSDs to the OR and you don't close all of them, it's 20 percent.

DR. TRACY: Okay. I think I'm going to ask Mr. Morton and Mr. Dacey if they have any additional questions. I know there are many sort of unanswered questions here but unless there is something very specific that can be answered by the sponsor, I think we need to move on to the FDA questions.

Can I ask the sponsor to stand back and we'll move on to the FDA questions if somebody can flash those back up.

The first question is dealing with the complexity of the VSD in patients entered in 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 of "complex VSD" as the defining indication for use of the CardioSEAL for VSD closure.

I think in the indication in Section 2, I think it is, the indication is the CardioSEAL inclusion system is for use in patients with a complex ventricular septal defect of a significant size to warrant closure, but that based on location cannot be closed with standard trans-atrial or trans-arterial

approaches, which is a little bit more simplistic than what Dr. Mayer detailed or than the patients that are actually included in this study.

I would suggest perhaps using something that is a little bit more reflective of Dr. Mayer's, I believe, sixth slide that listed the definition of high risk which included low probability of satisfactory surgical exposure, left ventriculotomy, excessive right ventriculotomy, high probability of residual VSD, failed previous VSD, multiple apical and/or anterior muscular VSDs, and posterior apical VSD covered by trabeculae.

I think maybe more specifically stating in the indications the actual patients that were included would be helpful.

MR. DILLARD: Can I ask -- excuse me. Jim Dillard. Can I ask a real quick question, which is is that all encompassing? I mean, are we even missing anything with that that may be important if we don't have the general statement. That would be my only question.

DR. SKORTON: I think there were a couple of other things that will be in the transcript from Dr. Lock's remarks that should be folded into there too about post-infarction VSDs and posterior versus anterior. I think the sense of what she brought up is right.

DR. WILLIAMS: But the indications, I think, are, as you say, are good. The contraindications may indicate the post-infarction VSD. I think defects that interfere with the valve would be in the contraindications. It happens that most of those defects are accessible so I think that is the correct -- you have the correct definition for indications.

DR. WHITE: I don't think we saw any data about contraindications. Did we? I mean, I think we just don't want to list it as an indication but I don't think we saw any data regarding the contraindication.

DR. TRACY: I think the contraindications are what are listed here, the obvious things on clots, etc. I believe Dr. Lock's comments have to be reflected somewhere in there. I don't know that I would put them down as contraindications but perhaps data is less than optimal results or some type of qualitative statements could be made regarding that.

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

I think you've heard the discussion. There is no control group. It's what it is in a very high-risk patient population.

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

Again, I think you've heard the discussion about that. It's difficult to get a handle on it but, again, it is the definition that was used. There are data here that are useful. Any other comments specifically on that?

DR. WHITE: I'm just troubled by the fact that there is no composite endpoint that should be -- I mean, I'm not asking for a randomized trial there. I'm asking for a very conventional way that we assess outcomes and this didn't do that.

DR. WILLIAMS: I would suggest that this isn't a conventional group and that's why we can't because there really is no composite. They were asked to do it and they did the best that they could under the circumstances.

In truth, to mix the indications of left-to-right shunt in more complex right-to-left shunts is probably meaningless and I think they made as good an attempt as they can possible do.

DR. WHITE: I don't think that's true. I think given the data here I could tell you how many people had the procedure done, a technically successful procedure, and had a major complication. I mean, it's just a matter of how you measure the data and whether you accept or whether you require the fact that success happened without or with a major complication and whether you're willing to let that happen.

DR. WILLIAMS: You could look at technical success with closing the hole but if the issue is the effect on the patient's course, then you cannot mix those two things together, I don't think.

DR. SKORTON: I think the answer to No. 3 sort of resolves the issue of No. 2.

DR. TRACY: 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.

I think that's obviously what we're struggling with. This is not a safe group of people to be working. However, it does appear to be a viable option for treatment in this very high-risk group of patients.

DR. WHITE: I think that is the reason for an HDE.

DR. TRACY: Anything else troubling? Ms. Moynahan seems troubled by that. I'm not sure why.

DR. JENKINS: It's kind of the pivotal question and I think a couple of the comments might help.

What do you think, Jim?

MR. DILLARD: Well, I mean, I think we heard Dr. White have perhaps a little bit different perception. There's not a right or wrong answer even to the question I think that you're raising, which is how do you differentiate what is an HDE versus what is a PMA.

Let me try to boil it down into something pretty simple which is this product is on the market at 30 institutions because the company has demonstrated that there is reasonable assurance of safety and that there is probable benefit.

Now today what we're saying is the data that we're looking at today pushes over the line from reasonable assurance of safety and probable benefit to reasonable assurance of safety and reasonable assurance of effectiveness.

I think that is perhaps the pivotal question here today which is the data now presented here with 57 patients enough to say there is reasonable assurance of effectiveness.

At the time we looked at the HDE a lot of that information wasn't complete. Safety seemed to be there. Is this really enough to judge effectiveness of the product for this patient population.

DR. HOPKINS: I would have to say for me the answer to that is yes, that there is reasonable assurance and that one suppose. I can actually give you my answer to your question because I'm not bound by the data. As a surgeon who would have to make a decision whether to operate on these patients, I would typically quote these parents 25 to 50 percent mortality so if that gives you a figure compare.

DR. WITTES: Yes, that's the sort of figure I needed.

DR. WHITE: But the question then, Dr. Hopkins, is what has persuaded you that they need more than an HDE, you know, if this device isn't ready for prime time? I'm not arguing that this device shouldn't be used and I'm not arguing that you have a need for this in your patients. What I'm suggesting is I haven't been convinced that there is a need more than a HDE.

DR. HOPKINS: I think Jim Lock actually referred to it. The actual dynamics of what happens with these patients is that if you don't have such a device available, you either get pushed towards surgery or the patient sits waiting for resolution in terms of referral to a center that does have this available.

DR. WHITE: This device is available in 32 centers of which we received no data. We don't know how those people performed. One of my concerns is that this all-star group here who had significant problems is not going to be translatable to those other 32.

DR. HOPKINS: Yes, I share those concerns. I think in the questions to come is where I would recommend that we resolve that. That is, in the training issues and then perhaps the post-release surveillance issues rather than in the PMA.

DR. TRACY: So I'm going to leave the answer as being within this very small group there is some assurance of the effectiveness of this procedure as well as the safety.

Moving on to the training program. The summary of that is in Section 5 of the Panel Packet. Question 4a. Please discuss any improvements that could be made to the training program.

I think it's just a very, very difficult thing to come up with a training program that will reflect getting trained as a superb and highly talented interventional cardiologist who has access to the world's best cardiac surgeons in the presence of a highly trained and expert group of cardiac anesthesiologists, but somehow you have to convey that all of those pieces are needed in this training program.

I think to reflect all of our concerns, the training has to somehow haul in all these people and get them to understand the seriousness of the clinical situation. I don't know exactly what to do with the fact that in this protocol a group decision was made between surgery and cardiology as to whether the person was a candidate for this device.

Is that something that we would recommend that that discussion be held on each individual patient, or is this the decision that the cardiologist is going to make and then the surgeon is going to have to live with? I don't know. I'm asking the surgeons whether they would like that.

DR. HOPKINS: I would have to say the nature of the practice of pediatric and adult cardiac surgery is actually very different in terms of the dynamics between the cardiologist and the cardiac surgeon.

I would think that in every center where I have ever been and have ever visited, the decision on therapy, particularly invasive therapy for pediatric patients, is done in concert and as a group and rarely done in the same fashion that adult decisions are made where a single cardiologist makes a decision and refers the patient to a single cardiac surgeon.

I think the actual general dynamics of the clinical care model is so different that it takes care of that.

DR. WILLIAMS: I would add in terms of the training, I certainly agree with what Dr. Hopkins said. I think in terms of training requirements I would specify that there be a locus of responsibility, echo, anesthesia, surgery, and cath. They meet as a team, and that the learning curve be concentrated in those individuals because it's terribly important starting out to accumulate the learning curve under one umbrella.

DR. SKORTON: I have a question about that from doing this a few times. It's one thing to suggest that a person who does that has no teeth whatsoever. Once the thing is marketed you can do anything you want. You can put it in the very first person you see.

A question for you. If we bought into Dr. William's ideas is it practical or doable to insist that before being given access to the device someone go through a particular training program? Because if it is or it isn't, that would have a big effect on whether this is a practical idea or not.

MR. DILLARD: Jim Dillard. I think that one of the responsibilities on the part of the agency is to certainly work directly with the sponsor to try to come up with a reasonable training program.

I think our first approach to that is much of what you have already discussed here which is what have the world's experts learned in terms of the initial clinical approaches as well as what the data says and how do we translate that then to the general teams that might be at the other institutions.

I think we are at maybe a little bit of an advantage than we usually are at this stage because perhaps they have already done it 29 more times than they would have otherwise done because they have been through that training and there are other institutions based on the HDE.

They probably learned even a lot more than the companies who would be sitting before us here saying, "We've only trained a couple three centers that we've done the clinical study on."

I think actually the sponsor may have some additional comments on that, No. 1, but beyond that, No. 2, we would work very closely with them, we would learn from what their experience is, and that would be part of our conditions of approval to come up with a training program that is satisfactory to the agency.

DR. WHITE: If we simply required that a physician be proctored for three cases, which is common in many devices and other things, you could pocket veto this PMA because there aren't enough cases out there for the physicians to be proctored for three each. I think that is one of the big issues here. Who is going to save three of these up for a proctor?

DR. TRACY: However, there are 30 centers that somehow have managed to get the device up and running so there is a way to do this.

I was just concerned because the verification form only deals with the interventional cardiologist. There must be something, as Mr. Dillard says, that the company and the mentors already know that have permitted this thing to expand out to a number of centers.

DR. WHITE: I'd be careful about what you think the 32 centers are doing. I think we haven't seen any data regarding that.

DR. WILLIAMS: But I'd also be careful -- I'm not myself interested so much in pocket veto. I'm more interested in helping the company set out the conditions that will end up with the best result because I think this is something that should be propagated safely.

DR. HOPKINS: I think the sense is that the group wants some rigor in the training. Ultimately in the latter questions of the post-market evaluation we are going to deal with some of those issues.

DR. TRACY: Okay. 4b. More than one device was placed in 26 patients. Please discuss training issues regarding the placement of multiple devices in a single patient.

Obviously, the more you do the more complex it is. The more training you need, the more sponsoring you need.

DR. WILLIAMS: But you might not always know when you're going to have to do that so I don't know that you can necessarily in advance decide that.

DR. WHITE: Remember that two-thirds of these procedures had two guys working. You talked about your anesthesiologist and other people but this is somebody pulling on this wire and somebody pulling on that wire and they are a team. This isn't what one good guy can go do. This is a real tour de force, I think, to do these well.

DR. TRACY: Again, emphasis on the team approach.

Product labeling and that information is contained in Section 2.

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

I think we already discussed that.

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.

The only thing that I would add there is that the thrombus that's mentioned is in various vessels but if you have somebody with a clot in the left atrium, you probably shouldn't be doing this either.

I think that -- I had written in my notes posterior muscular defects are at higher risk. I don't know if this necessarily rises to the level of contraindication but probably comes somewhere down in the warning section to just state that.

DR. WILLIAMS: But position that would interfere with the function of a valve, any of the cardiac valves, would be in addition.

DR. TRACY: Right. One of the contraindications that is already listed is anatomy in which the CardioSEAL size required would interfere with other intracardiac or intravascular structure such as valves or pulmonary veins.

DR. WILLIAMS: That only says size. It doesn't say position so I would say size or position.

DR. TRACY: Okay. I think we had discussed pulmonary veins as not appropriate to this particular application so we would probably take that wording out.

Any other specifics on contraindications?

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.

I think this would likely be where we would add those other anatomic caveats.

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.

I read through this and thought that it was quite good but a picture is worth a thousand words and I think this is where the education would come in.

5e. 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.

Any additional comments?

Post-market evaluation. Question 6. 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 CardioSEAL device? If so, how long should patients be followed and what endpoints and adverse events should be measured?

This is extraordinarily hard to come up with something like that in a population that is so limited to start out with. The numbers are so small to start out with. I think to recommend in a group of patients that are going to die of their underlying cardiac condition or other conditions anyway, it's extremely difficult to come up with a concrete recommendation on this.

I personally think that -- I hate to use the word registry but I personally think that something of that ilk is probably the right way to do this but I don't know. Do any of the other panel members have better comments than mine?

Dr. Wittes.

DR. WITTES: Well, can we take up Dr. White's suggestion that there are 29 centers out there with presumably data. Can those data be looked at? Is that legal? I mean, that actually would be part of the training. If those centers are having trouble, there may be information in the data that is already there.

DR. HOPKINS: There's really two questions that are being asked here, and that is the outcome of the individual patient in which that is probably known within six months of the implantation of the device or certainly within 12 months.

The other is the issue of the center efficacy as opposed to the patient based efficacy. That is sort of more of a registry, I think, type of approach. Maybe the follow-up should be suggested to be 12 months for the individual patient and a number picked for a center.

The center has to maintain appropriate records and report them to the company and ultimately thus to the FDA for 15 or 20. Just pick a number. You are really measuring two completely different things here.

MR. DILLARD: I might make just a real quick comment and then the sponsor may just want to address it, too. I'm not sure, Dr. Wittes, whether or not those other institutions really have "data" per se. They may have information and they might come up and even say they could go so far as to say whether or not they actually have some mortality information on perhaps what I would expect to be a very small number of patients even at some of those other centers.

I don't know how much we will actually glean from the knowledge of what we may know up to this point in time, but I think what might be important is if you are sitting here today, and I heard some issues that came up about what might be nice to know even in the future if we come back three, four, five years from now, what is going to be important to be able to say about the CardioSEAL device for VSDs, especially complicated VSDs, that U.S. clinicians might want to know about, about how the product is doing and how would we assess it in a little bit longer term. Would that then be important to the post-market period to look at.

DR. TRACY: Dr. Skorton.

DR. SKORTON: I think it would be and I wonder in the interest of efficiency when I make the motion if I could present some specific ideas how to do that in the motion.

DR. TRACY: Do you want to wait until we get to the --

DR. SKORTON: Instead of discussing it twice because I have a motion.

DR. TRACY: That's fine. Okay. I think that is all of the FDA questions unless the FDA has any additional questions at this time or comments.

MR. DILLARD: No, thank you.

DR. TRACY: Does the sponsor have any additional comments they would like to make at this time?

Mr. Morton, Mr. Dacey, any additional questions or comments?

Okay. Dr. Skorton, would you like to

make --

MS. MOYNAHAN: You need to do open public hearing.

DR. TRACY: Oh, I apologize. Is there any member of the public here present who would like to make any comments at this point at an open public hearing?

If not, I'll close the open public hearing. Sorry I forgot that.

MS. MOYNAHAN: In case any of you forgot since this morning, I'll read them again.

The Medical Device Amendments to the Federal Food, Drug, and Cosmetic Act as amended by the Safe Medical Devices Act of 1990 allows the FDA to obtain a recommendation from an expert advisory panel on designated medical device premarket approval applications that are filed with the agency.

The PMA must stand on its own merits and your recommendation must be supported by the safety and effectiveness data in the application or by applicable publicly available information.

Safety is defined in the Act as reasonable assurance based on valid scientific evidence that the probable benefits to health under conditions on intended use outweigh any probable risks.

Effectiveness is defined as reasonable assurance that in a significant portion of the population the use of the device for its intended use as conditions of use when labeled will provide clinically significant results.

Your recommendation options for the vote are as follows:

(1) Approval if there are no conditions attached.

(2) Approvable with conditions. The panel may recommend that the PMA be found approvable subject to specified conditions such as physician or patient education, labeling changes, or further analysis of existing data. Prior to voting all of the conditions should be discussed by the panel.

(3) Not approvable. The panel may recommend that the PMA is not approvable if the data do not provide a reasonable assurance that the device is safe or if a reasonable assurance has not been given that the device is effective under the conditions of use prescribed, recommended, or suggested in the proposed labeling.

Following the voting the chair will ask each panel member to present a brief statement outlining the reasons for their vote.

DR. TRACY: Right. At this point, Dr. Skorton, I'll ask if you have a motion to make regarding this application.

DR. SKORTON: Yes. I move that the device be approvable with conditions and then, at the appropriate time, I have four conditions to suggest.

DR. TRACY: Go ahead.

DR. SKORTON: We have to have a second first to the motion.

DR. WILLIAMS: Second.

DR. SKORTON: Okay. My first condition is that I believe there should be mandatory post-market studies for five years, that the studies should be annually, that a patient should annually get fluoroscopy and echocardiography, and that the six endpoints that should be looked for are the status of the device arms where fractures have occurred, thrombosis, global and regional ventricular function, endocarditis, evidence of ventricular arrhythmias or conduction disturbances, and evidence of residual shunt.

DR. HOPKINS: Could I address the issue of fluoroscopy? I don't think the arm fractures as we know it are really that important late because while it sounds like a bad engineering thing to have happen, actually late the device is locked in by the fibrous ingrowth.

From a practical standpoint an echo can be done in multiple outpatient facilities where fluro requires bringing them in to the hospital. Adding fluro adds a real increment of difficulty in the follow-up of these patients. I'm not so sure it's as important as the other criteria that you mentioned.

DR. SKORTON: I don't feel strongly about it but I'm responding to what I heard the investigator say was the way they discovered the fractures. Since there will be new ones put in and since I thought I heard the engineering aspect of the sponsor say there was a little bit of a moving target in terms of the materials they were made out of and the way they were constructed, I'm uncomfortable not following up in some fashion.

If there is something that can be done besides fluoroscopy to look for arm fractures, that's great with me but I don't think echo would be the right way to do it.

DR. WILLIAMS: Would it be okay just to not specify the technique but to say what is best in that institution because even fluro if it's not done by the same person might not be as adequate.

DR. HOPKINS: I think mandating echo annually for five years is not inappropriate.

DR. SKORTON: Something, however, to look at the presence and outcome of device fractures because there were 16 percent fractures. Even though I agree with what you said from the data we've seen here, this is now going to be open to a much broader denominator and I'm just uncomfortable. Maybe the device fracture rate is a lot lower but I don't know that.

DR. HOPKINS: But even if it is, I think the point is the arms could be absorbable and the ultimate outcome once it's locked in doesn't really matter.

DR. WHITE: I don't think you know that it's locked in. I think you -- I mean, I worry about that. I think we wouldn't be considering any device that had a one in five chance of breaking or a one in seven chance of breaking for most other applications.

I think it's a little cavalier anyway. This is an opportunity if we're going to do this to at least track it and at the end of five years be able to say whether any came out or not.

DR. HOPKINS: I was just pointing out that fluoroscopy is much more of an impediment to the mandated follow-up that you are suggesting.

DR. SKORTON: Maybe it's a certain kind of x-ray. I don't know, but I would ask that the condition be discussed with the sponsor and the investigators who have collected pivotal data.

DR. WHITE: An impediment to the patient to come back, you mean?

DR. HOPKINS: Yes.

DR. WHITE: I mean, these are kids that are looking at getting transplanted. I mean, this is serious stuff. I mean, I don't think that's a big deal.

DR. HOPKINS: If they're out five years, they are doing pretty well.

DR. TRACY: Mr. Morton.

MR. MORTON: Regarding the diagnostic that's used and the effect it might have on the patient, might we not ask what is the result of the fracture and maybe look for those sorts of things rather than look for the fracture itself? We examine for fractures and we leave that up to the sponsor to get back.

DR. TRACY: I think, though, that the point regarding that is that we don't know what the consequences of the fractures are. We don't know if that later on that this will lead to some kind of an edge that can create even a rupture in the endothelialized surface that could lead to thrombus formation. We don't know.

There are other devices that have had fracture type of instances with them and they are followed by cardiac fluoroscopy. It is cumbersome but we do this. I don't think it's unreasonable in a device that has a 20 percent problem rate to request that fluro be done.

I personally would support that. I'm not committed to saying that they have to do fluro but I do think that is something that we don't know where that's going to go.

DR. SKORTON: Would you be more comfortable with, say, fluoroscopy or an equivalent technique?

DR. TRACY: Okay. So then your condition is that --

DR. WHITE: I'm running through those equivalent techniques here. There's fluoroscopy and fluoroscopy and fluoroscopy.

DR. TRACY: Well, you could get a flat PA and lateral. If you saw a big thing sticking off of it, you would know there was a big thing sticking off of it.

DR. SKORTON: I heard the investigator say that they discovered some of the fractures with chest x-ray and some with fluoroscopy. I would be comfortable understanding that this is only advice for the agency and for the agency to work with the sponsor.

DR. WHITE: I've had the experience of looking at the fractures for the valves. The York-Shileys and the chest x-ray is not of the same -- I mean, you miss the little things with the chest x-ray so it's an underestimation, whereas with the fluro, and even sometimes sine is necessary depending on the thickness of the wires in order to be able to see that break. I think that it's not the same.

DR. TRACY: All right. Then for this particular condition, shall we vote on this particular condition for a five-year follow-up with the details as stated by Dr. Skorton.

MR. DILLARD: Jim Dillard. Just one quick question. I thought I heard the answer, but I'm not sure. It sounds like you're advocating, in addition to potentially following the cohort of patients that we currently have, you're talking about new patients that otherwise would receive the device? Is that correct?

DR. WHITE: Yes, that's correct.

DR. TRACY: So for new patients also. All in favor?

MS. MOYNAHAN: Ten in favor.

DR. TRACY: So that's unanimous. Any additional conditions?

DR. WHITE: Yes. I don't know exactly how to state it without taking three hours to do it but all this stuff that Dr. Williams said about augmented training procedures, something that could be boiled down by the agency and the sponsor I think needs to be added as a condition.

DR. TRACY: Okay. I won't even attempt to summarize the three hour discussion but some type of augmented training as a condition. All those in favor?

MS. MOYNAHAN: That's unanimous at 10.

DR. TRACY: Any additional conditions?

DR. SKORTON: I guess just one more, and that is as one condition all the labeling clarifications that we mentioned under indications, warnings, and so on, all those together to be made as a condition.

DR. TRACY: Okay. So the third condition is verification of the changes in the labeling that we've suggested. All in favor?

MS. MOYNAHAN: Okay. That's 10.

DR. TRACY: All right then. The motion has been made that this is approvable with conditions. The conditions have been stated and voted on. At this point let's vote on the major motion approvable with conditions. All in favor?

MS. MOYNAHAN: Is your hand up, Dr. White?

DR. WHITE: No, it's not.

MS. MOYNAHAN: Nine.

DR. TRACY: Opposed? Can I then ask each of the panel members to individually state what your vote was and the basis for your vote.

We'll start with you, Dr. White.

DR. WHITE: Well, I think I was the only one who thought this was not approvable. It's not because I don't think the device is good or doesn't have a good use and it isn't valuable, but I was not convinced that it needs to be more than an HDE.

The administrative inconvenience of HDE to me doesn't justify the release of this device. I think we have a lot of chance to do a lot of harm here without doing a lot of good. I think the efficacy endpoint really was not -- didn't satisfy me.

I think the safety is questionable. I would have a lot of concern being on record for a device that has this fracture rate and approving that.

DR. TRACY: Dr. Williams.

DR. WILLIAMS: Well, from my clinical experience, I believe this is a group that has few other options. I believe that they have demonstrated reasonable efficacy and safety relative to what I understand the natural history of this disease to be. I believe that our conditions have set forth protections for the significant multiple operator dependence for this particular type of device placement.

DR. TRACY: Dr. Skorton.

DR. SKORTON: I voted for approval for two reasons. One is that I've had the experience of not knowing what to do with a handful of people like this. It's just been a handful and I've become more convinced today that the surgical options are quite limited.

Secondly, I believe, although I do agree absolutely with safety concerns, which is why I brought up one of the conditions, I think this is not going to be one of those procedures that people are going to be running to do.

I think it will be somewhat self-correcting because of the very difficult nature of it. I have confidence that the agency before issuing an approval, if it chooses to, will develop some sort of training and surveillance system that will make me more comfortable.

DR. TRACY: Dr. Zahka.

DR. ZAHKA: I voted for approval because I think this is a difficult group of patients who need this kind of approach. After I convinced myself that there would not be slippage of an approach to patients who, in fact, would be better done surgically. That was a major concern for me. I did come away convinced that this device would, in fact, find it's way only into patients for whom surgery was not a good option.

DR. TRACY: Dr. Hopkins.

DR. HOPKINS: I voted for it for the reasons that the two folks preceding me mentioned. I actually think it will increase the efficacy or the outcomes. Also for the surgical patients because of the kinds of conversations that the clinicians will have by having this device availability will foster the team approach.

DR. TRACY: Dr. Aziz.

DR. AZIZ: Well, I voted for it because I think this may be an option for a very difficult group of patients who really don't have much else even though I think I echo Dr. White's concerns that it does have a lot of questionable issues.

DR. TRACY: Dr. Laskey.

DR. LASKEY: Well, I voted for approval as well with the qualifications noted but I'm terribly uneasy because this is the first time I've certainly reviewed anything which was not rigorously controlled.

I think that many of us were responding emotionally and overreaching and, yes, this is a desperate population and, yes, it is nice to have another option and, yes, this probably will be used correctly by a small handful.

I think that ultimately came down to saying yea rather than nay. I just don't see hundreds of people using this device. I see it centrally controlled in expert hands. I hope it is as efficacious as we all hope.

DR. TRACY: Dr. McDaniel.

DR. McDANIEL: I voted to approve with conditions as stated for the same reasons as my colleagues. I think that it's a limited number of patients. It will offer something to some children that may be expiring in institutions without the ability to do this. It's critical that the FDA follow some of our suggestions in terms of the training, but I agree that it's not going to be done in a tremendous number of patients.

DR. TRACY: Dr. Wittes.

DR. WITTES: I voted yes for much the same reason. I became convinced that this is a desperate group that needs something. I wish there had been some more control data of one kind or another.

DR. TRACY: Dr. Crittenden.

DR. CRITTENDEN: I voted for approval with conditions. Again, I share a lot of the concerns voiced by previous panel members but this is a desperate group of patients who have few options so I think we've done the right thing.

DR. TRACY: Mr. Morton, any comments?

Mr. Dillard?

MR. DILLARD: Yes. I would just like to thank not only the two sponsors today but certainly this group of individuals who came in mostly for this day. There will be a few that I think will be back tomorrow, but I appreciate you all coming in today and taking a look at these occluder devices with us. Appreciate it.

DR. TRACY: Thank you, everybody. I'll adjourned this meeting.

(Whereupon, at 6:00 p.m. the meeting was adjourned.)