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

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

Donna Buckley, lead reviewer 51

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

Open Public Hearing 195

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

Open Public Hearing 210

 Sponsor Presentation: NMT Medical, Inc.

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

Donna Buckley, lead reviewer 258

John E. Stuhlmuller, clinical reviewer 261

Cynthia Tracy, M.D. 269

Open Public Hearing 377

  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 distincti