P R O C E E D I N G S

Time: 8:04 a.m.

ACTING CHAIRMAN MAISEL: Good morning. I would like to call to order this meeting of the Circulatory System Devices Panel. Today's topic is discussion of a premarket notification for the Cardica Inc. Cardica PAS-Port System, K030434.

I'd like to have Geretta read the conflict of interest statement.

MS. WOOD: Before I read the conflict of interest statement, I would like to remind the panel members that in your folders you will find a survey this morning. I would appreciate it if you would take it with you and fill it out and return it with your reimbursement vouchers. Thank you.

The following announcement addresses conflict of interest issues associated with this meeting, and is made a part of the record so preclude even the appearance of an impropriety.

To determine if any conflict existed, the agency reviewed the submitted agenda and all financial interests reported by the committee participants. The conflict of interest statutes prohibit Special Government Employees from participating in matters that could affect their or their employers' financial interests. However, the agency has determined that participation of certain members and consultants, the need for such outweighs the potential conflict of interest involved, is in the best interest of the government.

Therefore, waivers have been granted for Doctors Mitchell Krucoff, John Somberg, and Clyde Yancy for their interests in firms that could potentially be affected by the panel's recommendations.

Dr. Krucoff's waiver involves two consulting interests on unrelated matters for which he receives an annual fee of less than $10,001, with a competing firm, and with a firm that receives funds from a competing firm.

Dr. Somberg's waiver involves a mutual fund with holdings in competing firms. Because of the type of investment, values of the holdings are not known.

Dr. Yancy's waiver involves consulting services for a competing firm on unrelated products for which his fees are less than $10,001 annually.

The waivers allow these individuals to participate fully in today's deliberations. Copies of these waivers may be obtained from the agency's Freedom of Information Office, Room 12A-5 of the Parklawn Building.

We would like to note for the record that the agency took into consideration other matters regarding Doctors Krucoff, Yancy, Jeffrey Borer, and Thomas Ferguson. These panelists reported past or current interests involving firms at issues, but in matters that are not related to today's agenda. The agency has determined, therefore, that they may participate fully in these deliberations.

Dr. Eugene Blackstone reported his institution's interest with a firm at issue. Since Dr. Blackstone was not personally involved and there is no continued financial interest, the agency has determined that he may participate fully in the deliberations.

In the event that the discussions involve any other product or firms not already on the agenda for which an FDA participate 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 may wish to comment upon.

ACTING CHAIRMAN MAISEL: Thank you. I would like to have the panel members introduce themselves.

I am William Maisel, a cardiologist at Brigham and Women's Hospital. Dr. Zuckerman?

DR. ZUCKERMAN: Bram Zuckerman, Director, FDA Division of Cardiovascular Devices.

DR. HIRSHFELD: John Hirshfeld. I am an interventional cardiologist at the University of Pennsylvania.

DR. YANCY: Clyde Yancy, heart failure/heart transplant cardiologist at UT Southwestern in Dallas, Texas.

DR. KRUCOFF: Mitch Krucoff, interventional cardiology at Duke University and the Director of the Cardiovascular Devices Unit at the Duke Clinical Research Institute.

DR. NORMAND: Hi. I am Sharon-Lise Normand. I am a Professor of Health Care Policy and Biostatistics at Harvard Medical School and Harvard School of Public Health.

DR. BLACKSTONE: Eugene Blackstone, head of clinical research, thoracic and cardiovascular surgery at the Cleveland Clinic.

DR. BORER: Jeff Borer. I am a cardiologist at Weill Medical College of Cornell University in New York.

DR. FERGUSON: Tom Ferguson, cardiothoracic surgeon emeritus, Washington University, St. Louis.

MS. WOOD: Geretta Wood, Executive Secretary.

DR. SOMBERG: John Somberg, Professor of Medicine and Pharmacology, Rush University, Chicago.

DR. KATO: Norman Kato, cardiothoracic surgery, private practice, Los Angeles, California.

DR. PAGE: Rick Page, head of cardiology, University of Washington, Seattle.

DR. JEEVANANDAM: Val Jeevanandam. I am Chief of Cardiothoracic Surgery, University of Chicago.

MS. MOORE: Deborah Moore, Vice President of Clinical and Regulatory for Proxima Therapeutics.

ACTING CHAIRMAN MAISEL: Thank you. At this point, I would like to invite the FDA to give their brief presentations. The first one will be Dr. Susan Gardner, who is Director of the Office of Surveillance and Biometrics, who will be talking on condition of approval studies.

DR. GARDNER: Thank you. Good morning. I am glad to be your kickoff speaker this morning. I am going to spend a few minutes telling you about a measure of programmatic change in CDRH, and the operational piece of that is the move of the Condition of Approval Studies Program to my office, which is the Office of Surveillance and Biometrics.

Briefly, if you are familiar with CDRH, you think of OSB as being the seat of the post-market piece, but in fact we play a major role in premarket review also, by virtue of the fact that the statisticians are in our office, and you hear from the statisticians at all of your panel meetings.

We also have the epidemiologists in our office, and as you will hear, they are going to start playing a larger role in the premarket piece.

Also in the Office of Surveillance and Biometrics, we do signal detection by use of the various tools we have to monitor the post-market arena. That includes all the medical device reports that come into our office, the MedSun program and other tools that we use.

We are also responsible for characterization of the various risks by virtue of reviewing post-market data, and we coordinate a center of response to post-market issues, if that is sort of a risk communication response. In addition to that, we are responsible for interpretation of the medical device reporting regulation.

A regulatory authority for condition of approval is in 21 CFR 814.82, which says that post-market requirements can include continuing evaluation and periodic reporting on the safety, effectiveness, and reliability of the device for its intended use.

A sort of kickoff event to this major change started a couple of years ago when CDRH took a hard look at our condition of approvals program. The initial look was actually to go and evaluate the quality of the studies that we have been ordering for condition of approval, but as we started to walk this evaluation, we found a much bigger problem.

We looked at all the studies, PMA studies, that -- I'm sorry, all the PMAs that were approved between 1998 and the year 2000, and we found 127 PMAs. Of those, 45 had orders for condition of approval studies.

Unfortunately, we were really unable to do a very thorough evaluation of how those studies were done, because we found that we really didn't have a standardized tracking process in the Center, and we essentially couldn't find the studies -- all the studies.

We turned to our lead reviewers and found, as one might expect, that during the last couple of years many of them had moved on to different positions. So they also were not a way that we could track these studies. So that was one big message.

We also found that we -- we think, although again the tracking was poor, that we hadn't received results for about 22 percent of the studies, and some of them probably had not been started at all. So it was not a very good message, and it was certainly a wake-up call to us to try and improve this program.

So the strategy for change: First of all, what is our goal? I think the goal is somewhat easy. We want to get good post-market information as the device enters the market, to continue to assure the safety and effectiveness of the device as it moves mostly from clinical trials into real world use.

That should help us better characterize the risk/benefit profile that we looked at in the premarket trials and, obviously, add to our ability to make good scientific decisions.

The strategy for change: As I say, the big operational piece was to move the program from ODE to OSB, and that official move was on January 1st, although this has been preceded by a pilot that has gone on now for almost three years, working with one of the divisions to sort of iron out some of these procedures.

Again, another obvious first step was to develop an automated tracking system so we would be able to find these studies, but this also will allow us to acknowledge to industry that we received the reports and also to follow up with them if the reports have not been received.

The second big change is that we have added an epidemiologist to the PMA teams when we anticipate that there is going to be a condition of approval study. The role of the epidemiologist on the team is to develop the post-marketing plan during the premarket review, and this is sort of to step back and take a good look at all the post-marketing tools that we have in place and, again, think about a coordinated plan to monitor the product once it goes into the market.

The epidemiologist will also have a lead in developing a well formulated post-market question, and that is extremely important. We really want to focus on thinking about what we are asking these companies to do in the post-market period.

They will have the lead in the design of the condition of approval study protocol and the lead in the evaluation of the study progress and the results after approval. I want to emphasize that they will continue to work in the PMA team and have close contact with their colleagues in ODE and other parts of the office.

So then the question is: Given the fact that it looks like we have a fairly poor track record in getting these studies done, what do we think now is going to be the motivation for compliance?

Well, the first thing is, if we do a good job, I think, in formulating our post-market hypotheses and asking the right questions, I think that industry is going to be more motivated to carry out the studies, because they are going to be getting information that is going to be important to us.

Second of all, I think the acknowledgment and feedback to industry when they do perform their studies is, obviously, an important piece of the plan. It is not particularly rewarding to do work and then to have it in and have no response, but we are going to be very involved in giving feedback and interacting on what we are finding on these post-market studies.

Third, we are going to be posting the status of these studies on the CDRH website. Hopefully, this will be a positive thing for the folks that are doing it well, but if they are not doing it well, it won't be positive.

Also, we have the ability in CDRH to mandate post-market studies under Section 522. This also allows us to apply penalties for studies when they are not done by leveling civil money penalties and misbranding.

So if we have formulated a good post-market question when the product moves onto the market, if industry does not comply, then being able to implement 522 will be possible.

So what is the impact on the Advisory Panel? The first thing is that during the approval process -- and this will vary a lot depending on what product we are looking at. But we want to attempt to lay out some of the important post-approval public health questions and, certainly, have you help us in giving us feedback on formulating some of those questions, and at times the possible approach for panel consideration.

I think some of the reasons that we do post-market studies are fairly obvious. We obviously look for rare events, events that have not been well characterized premarket. For implants, we want to do long term follow-up. We worry about user error as these products move from the clinical trials into the community practice.

So as those issues become apparent as we have discussions about products, discussion about those, and again helping us to sort of characterize this and think about a post-market approach, if that is appropriate. It is going to be very helpful to us as we move into the condition of approval protocol considerations.

Then the last piece but, I think, an extremely important piece is we want to be able to give feedback to you, and either we will do that as FDA or we will ask industry to do that. So after you have approved a product or not approved a product, but after a product goes to market and we have ordered a condition of approval study, we think that coming back to you a year or two years or whatever after that and giving you feedback on how the study is going, what we've found out, is really an important piece of this.

So that's it, if you have any questions. Thanks.

ACTING CHAIRMAN MAISEL: Thank you, Susan. Our next speaker this morning will be Dr. David Buckles, also from FDA. He is the Branch Chief of the Peripheral Vascular Devices Branch, and will be giving us an update.

DR. BUCKLES: Good morning. I would like to give you an update on a panel meeting that we had this past January.

MS. WOOD: Pull your microphone just a little bit closer. Thank you.

DR. BUCKLES: Okay, I'll try to use my adult voice.

At the panel meeting in January, we discussed the Gore Thoracic Aortic Aneurysm Stent-Graft, which is commonly known as a Gore TAG Device. For this device, the original PMA was submitted to FDA on October 4, 2004. The PMA was granted expedited review status, and the device was also the first of its kind. So we had a somewhat compressed schedule in reviewing the device and getting the device to panel.

The Cardiovascular Devices Panel met on January 13th and voted eight to two to recommend approval of the device. The application was, in fact, approved on March 23rd of this year.

The indication that was approved for the device: It is intended for endovascular repair of aneurysms of the descending thoracic aorta. This indication was modified slightly from the original application in that we added some anatomic specifications to the indication. This is consistent with the advice we received from the panel.

This is a good topic to follow onto Susan Gardner's presentation, because this device did, in fact, have a condition of approval study. The panel recommended a post-approval study with an appropriate number of patients out to five years. The endpoint should include mortality, paraplegia, aneurysm rupture, and the endpoint should -- or recommended by the panel to be consistent with IDE studies.

The panel also recommended a training program, the details of which should be worked out between Gore and the FDA; and the panel's final recommendation was that the labeling should include inclusion and exclusion criteria as well as the anatomic criteria from ongoing studies.

The anatomic criteria, as I just mentioned, were included in the indications for use that were approved for the device.

The FDA approval order included some conditions of approval. The post-approval study was required to be at least 150 patients out to five years, consistent with the panel's recommendation. Endpoints included all cause mortality, aneurysm related mortality, morbidity and device related events that were designed to be consistent with the IDE studies.

In addition, Gore has developed a training program which we discussed at the panel meeting. One of the objectives of the post-approval study is to assess the effectiveness of the training program.

Other conditions of approval included that the company follow all IDE study subjects as well as all post-approval study subjects out to five years, as I mentioned. The company will also provide a clinical update to physician users at least annually, including information from the five-year follow-up and a summary of all available patient data.

So in summary, the final disposition of the PMA application as consistent with the panel recommendation to approve the application. The panel voted to recommend approval, and the device was in fact approved.

There were three conditions of approval that the panel recommended, and all of the conditions were included in the approval order, either in the indications for use or in the conditions of approval that were part of the approval order.

Consistent with the strategy for change that Susan Gardner elucidated, the post-approval study provides for continuing evaluation and periodic reporting on the safety, effectiveness and the reliability of the device for its intended use, as well as providing information on the effectiveness of the company's training program.

Thank you.

ACTING CHAIRMAN MAISEL: Thank you, David. At this point, I would like to move on to the open public hearing. Both the Food and Drug Administration and the public believe in a transparent process for information gathering and decision making. To ensure such transparency at the open public hearing session of the Advisory Committee meeting, FDA believes that it is important to understand the context of an individual's presentation.

For this reason, FDA encourages you, the open public hearing speaker, at the beginning of your written or oral statement to advise the committee of any financial relationship that you may have with the sponsor, its product and, if known, its direct competitors. For example, this financial information may include the sponsor's payment of your travel, lodging or other expenses in connection with your attendance at this meeting.

Likewise, FDA encourages you at the beginning of your statement to advise the committee if you do not have any financial relationships. If you choose not to address this issue of financial relationships at the beginning of your statement, it will not preclude you from speaking.

The first speaker this morning at the open public session is Terry Vanden Hoek.

Any other people wish to address the panel this morning in the open public hearing? Seeing none, we will close the open public hearing portion of the meeting.

We will move on to the sponsor's presentation.

DR. HAUSEN: Panel members, ladies and gentlemen, members of the FDA review team. My name is Bernard Hausen, and I am the President of Cardica. I would like to thank everyone for taking the time to join us here today to review the application from Cardica on the PAS-Port Proximal anastomosis System.

We are aware that the abundance in material that was submitted as part of the panel package has put a significant burden on you over the past few weeks, and we sincerely thank you for providing this service.

Cardica will be presenting information on the clinical need in some detail in order for you to answer the questions the FDA as phrased, give you a product information description, give you data from our clinical trials, a brief overview of approved products, and end our presentation with the clinical perspective.

This is the list of presenters. With me today are Dr. Harringer. He is the Chairman of the Department of Cardiothoracic and Vascular Surgery in Braunschweig, Germany. He was an investigator in our first trial and principal investigator in the second trial.

Also Professor Dan Bloch, who is a full Professor of Biostatistics at Stanford University, and serves as Cardica's Chief Statistical Advisor. And many of you know Dr. Michael Mack, who is the Director of the Cardiothoracic Surgery Associates of North Texas and a very active and well known practicing cardiac surgeon. Dr. Mack serves on many committees of the three main cardiac surgery societies in the world, EACTS, STS and AATS.

This is Cardica's world headquarters. We were founded in 1997, and this is located in Redwood City, which is about 30 miles south of San Francisco.

The company's position is to develop proprietary, automated, anastomotic systems. While Cardica was one of the first companies to engage in research and development in this challenging area, we were one of the last to enter clinical evaluation. Actually, the PAS-Port product has been designed before the symmetry device.

Our perspective of the products that would be needed to make this enabling technology was quite different than that of other companies. With my background as a cardiac surgeon, I stress that any technology we develop would have to be in agreement with the basic principles of surgery, and particularly those pertaining to performing vascular anastomosis.

In the later presentation I will go into more detail, but I do want to stress that the company put forth an enormous effort and substantial resources to address these needs, adhere to these principles in the development of all its products, which may explain some of the good results we have obtained to date.

The company's vision is provide technology that will expedite procedures and reduce associated morbidity and mortality. Currently, Cardica has two approved products in Europe. The PAS-Port product has been approved more than two years ago, the C-Port or Distal Anastomosis System more than a year ago.

The PAS-Port product received approval in Japan more than a year ago, within this year has found tremendous acceptance from Japanese surgeons. Today 25 percent of all vein grafts used in cardiac surgery in Japan are used in conjunction with this product. Beating heart surgery is used very commonly in Japan, and our customers are very devoted to reducing neurologic injury.

Both products have been submitted for clearance to the FDA.

This gory slide -- excuse for the early time -- allows me to describe what we believe is the primary clinical need for a proximal anastomosis system such as the PAS-Port, a system which allows the surgeon to perform a proximal anastomosis without having to clamp.

What you see here is the intimal surface of a diseased human aorta from a 60-year-old female. These are ulcerating atheromatas that can be severed from the aortic wall and released into the blood stream through manipulation of the aorta, thus potentially causing cerebral emboli.

Neurological injury compromises the most serious complications following CABG surgery. The most severe form are strokes, which occur at one to three percent of our patients and are responsible for 21 percent of our operative mortality. Strokes add significantly to intensive care and length of hospital stay. Besides the terrible suffering of these patients, there is an enormous cost to our society.

There are a number of risk factors responsible for strokes, many of which you know and of which the extent of proximal aortic atherosclerosis, as I have shown you in the first slide of this presentation, comprises the absolutely highest risk.

This slide shows a linear association between the incidence of ascending aortic atherosclerosis and patient age with approximately 60 percent of patients 70 years in age presenting a significant degree of atherosclerosis. In light of the fact that patients are getting older and older, this is becoming a more imminent problem.

The mechanism of cerebral injury as a result of proximal aortic atherosclerosis during CABG surgery is described best in this chart from Barbut. The fraction of total embolic signals in the carotid artery is displayed as a function of various manipulations of the aorta, with the most significant release of emboli noticed during cross-clamp or side-biting clamp release.

Alternative strategies are -- Surgeons have been faced with the dilemma of stroke for many years, and have started to develop alternative strategies to reduce the amount of athero-embolization. Today we would like you to consider an additional treatment modality to potentially reduce the incidence of athero-embolization.

For those present here today who are not as familiar with coronary bypass surgery, a conduit such as the patient's own saphenous vein is harvested and then attached to the aorta, which is termed the proximal anastomosis, and to the coronary artery, which is termed the distal anastomosis, thereby bypassing a significant lesion in a coronary artery.

The PAS-Port produce we are discussing today replaces a hand-sewn anastomosis of the proximal anastomosis.

The PAS-Port produce is an integrated device that performs an aortotomy and implant deployment in one action by turning the knob at the end of the tool. This can be performed quickly, and the tool has been designed to be easy and intuitive to use.

One of the most important features is that this tool allows the completion of the proximal anastomosis without placement of a clamp, a process that, as I have shown before, carries with it the risk of embolization. The product has been designed to minimize metal exposure to blood and to provide a firm attachment of the graft to the target vessel.

The package consists of a tray that serves as a loading platform to facilitate conduit loading, delivery tool, cartridge, an implant, a poke-through tool, and a pull-through tool.

This animation shows how the system is deployed. After conduit loading, the tool is placed on the aorta without the need for any preparation of the target vessel, and with a simple rotation of the knob at the end of the tool, first the aortotomy is created and then the wall and then the implant inserted through the aortotomy and deployed and secured. All this occurs within a few seconds without the need for any placement of clamps.

This is a video showing the inside of the human aorta that is hooked up to a water pressure system with an endoscope on the other ends, and you see in the picture and picture view the same deployment videoed from the outside.

For deployment, the surgeon places the tool on the aorta, rotates the knob, which creates the aortotomy, inserts the implant, seats the implant, and then the tool is pulled off.

As you know, there are many factors that impact graft patency. These include the technical quality of the anastomosis, comobidities such as the presence of diabetes or hypolipidemia, vein graft in an arterial circulation. Also, graft patency is affected by graft quality and target vessel selection. It is affected by the amount of trauma to the graft during harvest and loading, dependent on the amount of blood exposed on the endothelial surface, the size of the effective orifice of the conduit at the anastomotic site, and finally graft kinking and long term anticoagulation have been proposed as important variables that impact graft patency.

In the following slides, I will focus on factors that are specific to the use of anastomotic technology. And because the symmetry device was the subject of so much discussion at the last panel and will be addressed in the FDA's presentation, we felt it was important to show you differences between our device and the symmetry device.

This video shows the amount of vein endothelial trauma during loading deployment as the comparison between symmetry device and PAS-Port. This is the symmetry device where the conduit is loaded over a transfer sheet, exposing the entire endothelial surface of the conduit to a metallic surface.

After the conduit is attached to the implant and deployed in the aortic wall, a rod used in the deployment is again pulled through the lumen of the graft, potentially damaging the endothelial surface of the conduit.

In contrast, in the PAS-Port system the section of the conduit pulled through the implant is cut off and discarded. You see here the conduit pulled through the cartridge, exiting at the implant end. The section we just used to pull the graft through is cut off. The surgeon everts the graft over a reduced diameter of the implant, and a poke-through tool with a little membrane pushes the graft onto the implant, thereby allowing the tines to pierce.

This section of the graft that was touched by forceps will end up in the aortic wall, will not be in touch with the endothelial with blood. I think this is a very important fact.

This slide depicts a PAS-Port implant next to a symmetry implant on the left, both deployed in the same human cadaver aorta, both using segments of the same human vein. The amount of blood exposed non-endothelial surface with the symmetry device is approximately 350 percent more than the PAS-Port implant.

More importantly, while there is no metal inside the orifice of the PAS-Port Device, there is significant amount of metal protruding into the lumen of the graft with the symmetry implant. The amount of blood exposed non-endothelial surface of the PAS-Port implants are similar to those of hand-sewn anastomosis.

What we see here is the difference in effective orifice between the two products for the same conduit where especially for small vein grafts, the orifice of the PAS-Port implant is approximately 150 percent larger than the symmetry orifice. This is due to the fact that in the symmetry device, much of the potential orifice of the graft is used up as a flange to connect the graft to the device, shown here. This is graft lumen that gets lost as effective orifice after the deployment has been completed.

The simple eversion of the conduit over the PAS-Port implant avoids this effective loss of graft orifice.

As a last major difference between the two products, I would like to spend a few minutes on the potential for graft kinking. This has been an issue that was raised in the FDA -- by the FDA.

Design of all proximal anastomotic connectors theoretically allow for the creation of a right angle take-off of the graft from the target vessel with the potential of graft kinking at the anastomotic site.

One of the design goals of the PAS-Port implant was to reduce the probability of kinking by minimizing profile height of the implant. This image shows a comparison of profile height of the symmetry device and the PAS-Port implant.

You see that the profile height, which is basically going from here to the top of what you saw protruding into the lumen, is approximately twice as high as with the PAS-Port. For that length, the graft is constrained and can only go in one direction. It cannot take off at an angle.

The video shows here two PAS-Port devices -- one, two -- next to a hand-sewn anastomosis, and there is very little difference in take-off angle between the hand-sewn and the proximal anastomosis developed by the PAS-Port.

Based on early experiences from symmetry, we instructed our users through the instructions for use where to place proximal anastomosis, depending on which area of the heart is planned to revascularized. For grafts going to the left side, we recommend the left or concave surface of the ascending aorta, for grafts to the right, on the ascending part.

So to summarize, the key differences between the two devices that could explain the differences in outcome, as we will show you later, we believe, are the amount of endothelial trauma experienced with the PAS-Port device is minimal, the amount of blood exposed non-endothelial tissue is minimal. The effective orifice area is large, and any incidence of graft kinking due to low profile height of the implant is low, and the occurrence of any negative late sequelae negligible.

One last comment on the sequence of performing the proximal or distal anastomosis first, as this is a question again raised by the FDA. There is no necessarily correct order for performing a proximal or distal anastomosis. Most surgeons do perform the distal anastomosis first, but with the event of beating heart surgery, there are a number of advantages in doing the proximal anastomosis first.

One of the most compelling arguments is that, if you do your proximal anastomosis first, once you have completed the anastomosis and take the bulldog clamp off the graft, you are immediately reperfusing your target vessel, thus reducing the time of temporary ischemia.

The grafts can be distended with physiologic pressure and blood, both of which will optimize endothelial viability. And when patients are operated on pump, repeated cardioplegia through the aorta will provide cardio-protection to grafts already anastomosed.

To conclude this section of my talk, the advantages of the PAS-Port system are that this system allows for rapid deployment, and it is these time savings that will affect total operating times. The system avoids clamping of the aorta, by inference may also affect neurological outcome.

Because this is an automated system, much of the variability between surgeons, intra- and inter-individual variability is eliminated. The design provides surgeons the greater choice in anastomotic sites, making the surgeon less dependent on surgical access.

Performing the proximal anastomosis first has inherent advantages in beating heart surgery, and the PAS-Port Device design addresses, we believe, many of the potential shortcomings of other anastomotic technology.

Before we go into the details of the clinical study we have performed, please allow me to recapture some of the major statements you as the panel had made last year at the Anastomotic Technology Panel.

First of all, the statement was: It is best for patients to undergo as few invasive procedures as possible. Angiography is important, but should be kept to a minimum. Non-invasive methods of patency detection, such as CT or MRI, can be used for intermediate assessment. Clinical trials should assess functional outcomes as well as anatomic outcomes. Primary endpoints should be patency. Secondary endpoints can include major adverse cardiac events and neurological events.

Panel members expressed concern that new guidance from the agency could negatively affect ongoing studies, such as the PAS-Port studies. Dr. Zuckerman stated that the agency would work with the sponsor to ensure that their work to date would not be discarded, and the fact that we are here today, I think, is proof of that.

Cardica completed enrollment in its pivotal trial in 2002, a trial that is referred to in your documents as Cohort I. Based on this data, Cardica submitted the 510(k) for the PAS-Port Device in February 2003, now more than two years ago, using the Symmetry device as a predicate, with the data that was very similar in terms of quantity, length of follow-up, to what has been submitted for the Symmetry approval.

The PAS-Port Device was approved in March of 2003, based on the data from Cohort I for sale in Europe, with the notified body requiring post-market evaluation.

In January 2004 the enrollment for a second prospective trial, a trial that is referred to in your documents as Cohort II, was completed. It is important to note that this was two months before this same panel met to determine objective performance criteria.

Based on the criteria, Cardica discussed pooling of Cohort I and II with the FDA to address this new guidance. The FDA stated that pooling would be acceptable as long as the two studies were comparable and the data was homogenous.

Finally, clinical protocols to Cohort I and II required amendments to allow for the collection of long term data, as the original protocols followed the patients for six months and the amendments allow data collections at 24 months in Cohort I and 12 months in Cohort II.

The intended use for the PAS-Port proximal anastomosis system is to create an everting anastomosis between the aorta and the autologous vein graft. Evaluation of this device was performed, as I said, in two clinical trials. Patients in Cohort I were enrolled in June 2002 and September 2002.

In July 2003 a prospective trial was initiated to test safety and efficacy of the C-Port Distal Anastomosis System we are also developing to perform distal anastomosis.

The clinical trial was designed in such a way as to allow the use of the PAS-Port system in patients requiring more than one vein graft, to prospectively collect data to satisfy European post-market requirements. It is important to note that these two products were never used in the same graft.

Both studies, Cohort I and II, were therefore prospective, non-randomized, multi-center trials, which were approved by the Ethics Committees, had similar selection criteria and the same endpoints for evaluating safety, efficacy and follow-up time points.

Follow-up in both studies consisted of patency evaluations at discharge and at six months and, where these evaluations were, per protocol, included, angiogram, CT and MRI. The studies were designed to compare patency to outcome to historical control.

In the report you have received from the FDA as part of the panel package, the FDA states that these data were collected retrospectively. This is not the case. Data were collected prospectively, primarily to meet European post-market requirements, as I have said, and as the FDA objective performance criteria had not been formulated until after the enrollment of this trial had been completed.

The notified body specifically requested that post-market data be collected using the same study design and endpoints as the pivotal trial.

The C-Port study protocol specifically provided for concurrent use of the PAS-Port Device in patients requiring more than one vein graft. Due to the confidence in both products performing well with low morbidity and mortality, the sponsor and investigators believe that to be an acceptable study design to allow concurrent use of both devices.

Another question raised or implied in the report from the FDA was if there was a target vessel selection bias in favor of PAS-Port index grafts. We have done an analysis, and this flow chart shows the distribution of patients enrolled in the C-Port trial.

One hundred thirty-three patients were enrolled, of which 54 patients received at least one PAS-Port graft. Fifty-two of these patients also received a C-Port vein graft. It is of interest that one patient who could not receive the C-Port due to having a porcelain aorta was successfully implanted with three PAS-Port vein grafts. The decision on which target vessel the respective devices should be used was left to the discretion of the surgeon, and per the criteria set forth in the instructions for use of the device.

This flow chart compares the target vessels, their diameters and native artery stenosis. The C-Port grafts were routed more frequently to branches of the circumflex and to the diagonal vessels than PAS-Port grafts in this subset. Fifty-one percent of the PAS-Port grafts went to the right side, versus 13 percent of the C-Port grafts.

As many of you know, grafts placed to the right side of the heart have historically shown poor patency rates than grafts placed to the left side, such as the circumflex, LAD and diagonal. In addition, the target vessel diameters and the amount of native artery stenosis were very similar.

These data suggest that, if there was a selection bias, it was against the PAS-Port index graft.

Another important question raised was if there had been significant device changes between Cohort I and II which were motivated by the desire to improve the delivery system reliability fall in Cohort I. I believe this is something the public expects a supplier of a product to do, is continue to develop and improve function.

There were a number of small changes made to the deliver system to decrease friction and deployment forces and improve ergonomics. These include changing the lubricant inside the delivery system, making the case halfs differ, increasing clearances within the internal components, adjusting spring forces and making small changes to the torsion shaft. In addition, there was a change to the manufacturing specifications for the cutter speed.

The ergonomics of the delivery system were improved by adding a quarter of a turn to the knob, changing the shape of the knob to improve the ability for the user to grasp it, and by slightly changing the shape of the case to improve visibility.

There was only one minor change to the implant to improve manufacturab