1

DEPARTMENT OF HEALTH AND HUMAN SERVICES

FOOD AND DRUG ADMINISTRATION

CENTER FOR DEVICES AND RADIOLOGIC HEALTH

CIRCULATORY SYSTEM DEVICES PANEL

Thursday, March 18, 2004

9:00 a.m.

Hilton Gaithersburg Washington D.C., North

Salons A, B and C

620 Perry Parkway

Gaithersburg, Maryland

2

PARTICIPANTS

Cynthia Tracy, M.D., Acting Chair

Geretta Wood, Executive Secretary

MEMBERS:

Salim Aziz, M.D.

Mitchell Krucoff, M.D.

William Maisel, M.D., MPH

Christopher J. White, M.D.

CONSULTANTS:

Clyde Yancy, M.D.

Judah Z. Weinberger, M.D., Ph.D.

John W. Hirshfeld, M.D.

Thomas B. Ferguson, M.D.

Norman S. Kato, M.D.

Brent Blumenstein, Ph.D.

Charles Bridges, M.D.

L. Henry Edmunds, Jr., M.D.

INDUSTRY REPRESENTATIVE:

Michael Morton

CONSUMER REPRESENTATIVE:

Chrissy Wells

FDA:

Bram Zuckerman, M.D.

3

C O N T E N T S

Call to Order

Cynthia Tracy, M.D. 4

Conflict of Interest Statement

Geretta Wood 4

Introductions 6

FDA Presentation:

Julia Marders 8

Wolf Sapirstein, M.D., MPH, FACS 17

Kachi Enyinna 26

Open Public Hearing:

Randall Wolfe, M.D. 31

Robert W. Emery, M.D. 41

G. Phillip Schoettle, M.D. 50

Robert Frater, M.D., 55

Michael Mack, M.D., STS/AATS 66

Mark Slaughter, M.D. 76

Henry Frank Martin, M.D. 85

Bernard Hausen, M.D. 90

Prof. Uwe Klima 96

Open Committee Discussion 107

Summary

Cynthia Tracy, M.D. 262

4

1 P R O C E E D I N G S

2 Call to Order

3 DR. TRACY: Good morning, everybody. I

4 would like to call to order this meeting of the

5 Circulatory System Devices Panel. The topic today

6 is a discussion of type of data and study required

7 to effectively evaluate performance of aortic

8 anastomotic devices for marketing.

9 Conflict of Interest

10 MS. WOOD: The following announcement

11 addresses conflict of interest issues associated

12 with this meeting and is made a part of the record

13 to preclude even the appearance of an impropriety.

14 To determine if any conflict existed, the

15 agency reviewed the submitted agenda and all

16 financial interests reported by the committee

17 participants. The conflict of interest statutes

18 prohibit special government employees from

19 participating in matters that could affect their or

20 their employers\' financial interests. However, the

21 agency has determined that participation of certain

22 members and consultants, the need for whose

23 services outweighs the potential conflict of

24 interest involved, is in the best interest of the

25 government.

5

1 A waiver has been granted for Dr. Clyde

2 Yancy and a wavier was previously granted for Dr.

3 Judah Weinberger for their financial interests in

4 firms at issue that could potentially be affected

5 by the panel\'s recommendations. The waivers allow

6 these individuals to participate fully in today\'s

7 deliberations. Copies of these waivers may be

8 obtained from the agency\'s Freedom of Information

9 Office, Room 12A-15 of the Parklawn Building.

10 We would like to note for the record that

11 the agency took into consideration other matters

12 regarding Drs. Thomas Ferguson, Mitchell Krucoff,

13 Cynthia Tracy, Judah Weinberger and Clyde Yancy.

14 These panelists reported past or current interests

15 involving firms at issue but in matters that are

16 not related to today\'s agenda. The agency has

17 determined, therefore, that these individuals may

18 participate fully in the panel\'s deliberations.

19 In the event that the discussions involve

20 any other products or firms not already on the

21 agenda for which an FDA participant has a financial

22 interest, the participants should excuse him or

23 herself from such involvement and the exclusion

24 will be noted for the record.

25 With respect to all other participants, we

6

1 ask in the interest of fairness that all persons

2 making statements or presentations disclose any

3 current or previous financial involvement with any

4 firm whose products they may wish to comment upon.

5 DR. TRACY: Just before we get started, I

6 would just like to ask everybody to be sure that

7 you are speaking directly into the microphone,

8 including the speakers who will be coming up later

9 in the open public hearing. A transcript is being

10 made from these presentations today.

11 At this time I would like to ask the panel

12 members to introduce themselves.

13 Introductions

14 MR. MORTON: I am Michael Morton. I am

15 the industry representative. I am an employee of

16 CarboMedics.

17 DR. WEINBERGER: Judah Weinberger,

18 Director of Interventional Cardiology at Columbia.

19 DR. YANCY: Clyde Yancy, Director of Heart

20 Failure and Transplantation at UT Southwestern, in

21 Dallas.

22 DR. WHITE: Chris White. I am the Chief

23 of Cardiology at Ochsner Clinic Foundation.

24 DR. HIRSHFELD: John Hirshfeld. I am an

25 interventional cardiologist in the University of

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1 Pennsylvania.

2 DR. KATO: Norman Kato, cardiovascular

3 surgeon, private practice, Encino, California.

4 MS. WOOD: Geretta Wood, Executive

5 Secretary.

6 DR. TRACY: I am Cindy Tracy,

7 electrophysiologist, George Washington University.

8 DR. EDMUNDS: I am Hank Edmunds, Professor

9 of Surgery at the University of Pennsylvania.

10 DR. FERGUSON: Tom Ferguson,

11 cardiovascular surgeon, Washington University St.

12 Louis.

13 DR. KRUCOFF: Mitch Krucoff,

14 interventional cardiologist, Duke University

15 Medical Center; Director of Devices Trials, Duke

16 Clinical Research Institute.

17 DR. MAISEL: William Maisel,

18 electrophysiologist, Brigham & Women\'s Hospital.

19 DR. BLUMENSTEIN: Brent Blumenstein,

20 biostatistician, Seattle, Washington.

21 DR. BRIDGES: Charles Bridges, Chief

22 Cardiovascular Surgery Pennsylvania Hospital,

23 University of Pennsylvania.

24 MS. WELLS: Chrissy Wells. I am the

25 consumer representative on the panel.

8

1 DR. ZUCKERMAN: Bram Zuckerman, Director,

2 FDA, Division of Cardiovascular Devices.

3 DR. TRACY: Thank you. At this point we

4 will have the FDA presentation, and Julia Marders,

5 from the Office of Surveillance, will be the

6 opening speaker.

7 FDA Presentation

8 MS. MARDERS: Good morning.

9 \[Slide\]

10 My name is Julia Marders, and I am a nurse

11 analyst in the Division of Postmarket Surveillance,

12 Office of Surveillance and Biometrics.

13 \[Slide\]

14 I will present an analysis of adverse

15 event reports received by the FDA on aortic

16 anastomotic devices. My presentation will begin

17 with a brief description of the Medical Device

18 Reporting System, MDR, which is a system for

19 adverse events and product problems, and include a

20 discussion of its limitations.

21 Next, I will describe the database, search

22 methodology used to obtain the reports of aortic

23 anastomotic devices and provide a summary of

24 findings and analysis of conclusions. Then I will

25 finish the presentation with conclusions,

9

1 considerations and questions for the panel to

2 contemplate.

3 \[Slide\]

4 The Medical Device Reporting System is a

5 nationwide passive surveillance system which

6 includes both mandatory and voluntary reporting.

7 Since 1984 manufacturers and importers have been

8 required to submit reports to the FDA of

9 device-related deaths and serious injuries, as well

10 as events involving device malfunctions that may

11 cause or contribute to death or serious injury.

12 The Safe Medical Devices Act of 1990

13 introduced mandatory reporting of device-related

14 deaths and serious injuries by user facilities,

15 most notably hospitals and nursing homes.

16 Voluntary medical device adverse event and problem

17 product reports, most often submitted by healthcare

18 practitioners, consumers, patients or family

19 members, are received through the FDA\'s MedWatch

20 program. In general, approximately 95 percent of

21 the reports received by FDA are from manufacturers,

22 one percent from importers, and the remainder is

23 equally split between voluntary and user

24 facilities.

25 \[Slide\]

10

1 The Medical Device System, which is the

2 MDR system as most people know it, while providing

3 signals of actual and potential device-related

4 problems, has some limitations. Under-reporting of

5 adverse events to hospitals, manufacturers and the

6 FDA by healthcare practitioners is a well-known and

7 recognized phenomenon. Thus, events reported

8 through MDR represent a subset of the total

9 occurrence of events.

10 In addition, manufacturers are not

11 required to submit denominator information such as

12 number of devices manufactured, distributed and

13 implanted. Thus, due to under-reporting and lack

14 of denominator data accurate incidence rates are

15 unable to be determined based on MDR data alone.

16 Furthermore, reports received may not be

17 representative and reflective of a variety of

18 reporting biases. Thus, for example, reporting may

19 vary by manufacturer or by the presence or absence

20 of publicity.

21 Although there is a regulatory requirement

22 for a minimum data set, event narrative

23 descriptions vary in completeness and complexity.

24 For example, one aortic anastomotic device report

25 indicates failure of the connector as the entire

11

1 event description and no further details are

2 provided. In addition, many reports do not contain

3 results of manufacturer failure analyses. Often

4 devices are not returned to the manufacturer for

5 evaluation because they are discarded or remain

6 implanted. Thus, root causes for reported events

7 are often unable to be determined.

8 \[Slide\]

9 Now I will describe the search methodology

10 used to obtain the data set of aortic anastomotic

11 device reports in this presentation and present the

12 findings. First I searched the database by product

13 code. All medical devices approved or cleared for

14 marketing have a unique three-letter identifier

15 called the product code. Next, I narrowed the

16 search by date. This search includes events of

17 aortic anastomotic devices that were reported from

18 May 24, 2001, the first marketing clearance date

19 for these devices, to March 1, 2004. I also

20 performed additional database queries by brand

21 names to validated that I had captured all aortic

22 anastomotic device reports that have been entered

23 into the database.

24 \[Slide\]

25 Now the findings, a total of 213 reports

12

1 are in the database and most reports were received

2 in 2003. The number of death reports is 23;

3 injury, 185; and malfunction, 5. The vast majority

4 of these reports, that is 203, came from

5 manufacturers, with 2 from user facilities and 8

6 voluntary.

7 \[Slide\]

8 Patient age was provided in 129 of the 213

9 reports and ranged from ages 35 to 83 years, with

10 most in the 50-65 age range. Slightly over half of

11 these events are noted in males, a quarter in

12 females and a quarter were gender unspecified. One

13 hundred and seventy-three events, or 81 percent,

14 occurred with patients in the U.S. and 14, which is

15 7 percent, with patients outside the U.S.; 26 event

16 reports, 12 percent, did not specify whether the

17 event is foreign or domestic.

18 \[Slide\]

19 Of the 23 death reports, 22 were from

20 manufacturers and one from a user facility. All

21 patient deaths occurred within 18 days of

22 implantation and 15 of the deaths occurred within 3

23 days of implantation. Interestingly, one patient

24 actually had both a dissection operatively and a

25 detachment postoperatively and is included in 2 of

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1 the problem categories listed on this slide.

2 Additionally, another patient had both thrombus and

3 aortic detachment that was discovered on

4 postoperative day 2 when the patient coded.

5 Twelve reports indicate the problem of

6 occlusion or thrombus at the connector site. One

7 report describes the patient was noted to have a

8 predisposing hypercoagulable state, and 2 reports

9 indicate that patients had atrial fibrillation.

10 Aortic dissection associated with deployment or

11 after the connector is placed was noted in 7

12 reports. Device detachment, resulting in

13 hemorrhagic shock, occurred in 6 reports. None of

14 the devices associated with death were returned to

15 the manufacturer for evaluation and the

16 manufacturer has not been able to determine the

17 root cause of the events.

18 \[Slide\]

19 Now I will present an actual report to

20 illustrate these findings in a more clinically

21 relevant way. A patient was implanted with an

22 aortic anastomotic device during an off-pump

23 procedure. No difficulties were encountered with

24 loading or deployment of the device. Recovery was

25 good for approximately 40 hours when the patient

14

1 suddenly lost consciousness after a dramatic drop

2 in blood pressure. CPR was initiated and blood

3 appeared in the drains. At re-operation, the

4 aortic connector was detached from the aorta and

5 the patient died after 10 minutes. The autopsy

6 revealed the cause of death was hemorrhagic shock.

7 \[Slide\]

8 A total of 185 injuries were reported.

9 Stenosis and occlusion are overwhelmingly noted to

10 be the first and second most frequently reported

11 problems respectively. Although infrequently

12 reported, events involving device detachment have

13 also resulted in serious injury. Clinically, the

14 reported outcomes of stenosis and occlusion

15 resulted in life-threatening conditions resulting

16 in shortness of breath, chest pain, arrhythmias,

17 subsequent myocardial infarction and/or hemodynamic

18 instability requiring either surgical or

19 interventional treatment including catheterization

20 for PTCA and stenting.

21 The time from implantation to injury, as

22 noted in 37 of the 185 reports submitted, of the 30

23 noting stenosis or occlusion most, or about 60

24 percent, occurred within 90 days; 4 events occurred

25 within 4 days. The other 7 are associated with a

15

1 variety of patient problems other than stenosis or

2 occlusion. Three reports of device detachment

3 occurred within one day of surgery, and another

4 event atypically occurred after 97 days, possibly

5 due to a fragile aorta and placement of the

6 connector on a pseudoaneurysm. Of all the

7 injuries, only 2 devices were returned to the

8 manufacturer for evaluation, both of which resulted

9 in manufacture evaluation indicating no device

10 failure detected.

11 \[Slide\]

12 Five reports indicated a device

13 malfunction. One report states the device was not

14 able to be used because the anchor tip was closed.

15 Two reports indicate the aortic plug was not seen

16 by the surgeon upon inspection of the device. Both

17 of these patients have not experienced any adverse

18 consequences. The fourth report indicates a device

19 malfunction resulting in an aortic laceration

20 requiring repair. It is not clear why the user

21 facility reported this event as a malfunction

22 rather than an injury, and no information was

23 included about the patient\'s outcome. Follow-up is

24 ongoing. The fifth report indicates failure of the

25 connector, with no other details, other than

16

1 indicating no consequences to the patient.

2 \[Slide\]

3 Conclusions\--the reports of serious

4 adverse outcomes related to aortic anastomotic

5 device use raises a signal of a potential public

6 health problem. Some of these occurrences are

7 catastrophic, such as aortic dissection or device

8 detachment, and not expected. Others, for example,

9 occlusion or stenosis, may be expected depending on

10 the patient\'s underlying condition of adequacy of

11 antiplatelet therapy, or may reflect device-related

12 events, for example, stenosis at the connection

13 site or thrombosis potentially related to

14 bioincompatibility or poor hemodynamics. Lastly,

15 the reported information to date reflects

16 short-term experience. Long-term failure

17 information is also important.

18 \[Slide\]

19 Considerations\--additionally, there are

20 two other important points to consider, first,

21 failure analyses of this adverse event data are

22 lacking or limited. The underlying root cause of

23 these events, particularly occlusion and stenosis,

24 is unknown. Multiple factors may be involved which

25 can make the evaluation of these events difficult.

17

1 Second, this adverse event data needs to be

2 factored into the risk/benefit profile for these

3 devices.

4 \[Slide\]

5 To conclude my presentation, I have the

6 following three questions for the panel to consider

7 that are based on adverse event report findings:

8 First is the question of collection of

9 long-term failure rate data. Should a longer

10 period of time for manufacturer collection of

11 device performance data post implantation be

12 required to fully understand aortic anastomotic

13 device failures?

14 Next, should studies comparing short- and

15 long-term patient outcomes between standard

16 suturing versus sutureless aortic anastomotic

17 devices to address risk/benefit issues be

18 undertaken?

19 Finally, should further study of

20 device-related events be considered?

21 I encourage the panel to consider these

22 questions before making final recommendations.

23 That concludes my part of the presentation and now

24 I will turn over to Wolf Sapirstein.

25 DR. SAPIRSTEIN: Dr. Tracy, panel members,

18

1 good morning.

2 \[Slide\]

3 The people listed up there are members of

4 the Division of Cardiovascular Devices. My name

5 is Wolf Sapirstein. We are mandated by statute to

6 regulate cardiovascular devices, and are hopeful

7 that this panel will generate guidance for us in

8 undertaking this activity for these new and unique

9 devices used in treatment of coronary-artery

10 disease.

11 \[Slide\]

12 Vascular suturing was introduced by Carrel

13 in 1903 and has changed little over the next 100

14 years, except for the replacement of catgut with

15 synthetic suture. After about 30 years of attempts

16 by various investigators internationally, an

17 automatic device to effect vascular anastomoses,

18 the Symmetry Aortic Connector, was cleared in 2001

19 for commercial use by the agency. The drive for

20 development of these devices has undoubtedly been

21 coronary arterial bypass graft procedure which also

22 underscores the clinical importance of assuring

23 safety and effectiveness for these devices.

24 Incremental modifications to the coronary

25 arterial bypass graft procedure are seminal to the

19

1 acceleration in development of these devices. The

2 surgeons among us will have the forbearance, I

3 hope, while I undertake a thumbnail sketch of the

4 changes that have taken place in the performance of

5 the coronary arterial bypass grafting procedure.

6 \[Slide\]

7 The CABG procedure was the earliest

8 surgical therapy validated with a randomized,

9 controlled trial, the Coronary Arterial Surgery

10 Study. Autogenous venous conduits remain

11 extensively employed with anastomosis performed to

12 the aorta and the coronary artery distal to the

13 obstructive lesion. Induced ventricular

14 fibrillation and anoxic cardiac arrest with

15 hypothermic protection were initially used to

16 provide the quiet field demanded by the challenge

17 of suturing vessels 1-2 mm in diameter.

18 Cardioplegia inducing perfusion of the coronary bed

19 has since produced cardiac standstill with improved

20 myocardial preservation during the ischemic period

21 of conduit anastomosis.

22 Resistance of the internal thoracic

23 artery, ITA, to the atherosclerotic degeneration

24 that seemed inexorable with vein conduits has led

25 to is preferential employment since the late 1980s.

20

1 This also provides the advantage of eliminating

2 need for an aortic anastomosis. Patient survival

3 has since been shown in several studies to be

4 closely related to the effectiveness of

5 revascularization achieved for the anterior surface

6 of the heart and left ventricle. These

7 developments, patency of the ITA and anterior

8 cardiac revascularization justified introduction of

9 the minimal access direct CABG procedure in the

10 1990s to perform an isolated LIMA-LAD bypass. This

11 was shortly followed by beating heart and finally

12 off-pump CABG with elimination of extracorporeal

13 circulatory support entirely. Thus, were the ill

14 effects of cardiac arrest, extracorporeal

15 circulatory perfusion and aortic clamp manipulation

16 of the aorta obviated.

17 \[Slide\]

18 These modifications made to the CABG

19 procedure addressed its changing role in an era of

20 increasing catheter-mediated coronary treatment.

21 The MIDCAB is seen as reducing the morbidity of

22 incisional trauma, particularly in an increasingly

23 older patient cohort and patients with more

24 compromised coronary circulation not amenable to

25 percutaneous coronary interventions, and these

21

1 patients become candidates for operative

2 intervention. Dispensing with cardiopulmonary

3 bypass eliminated a potent activator of both the

4 systemic inflammatory response and the various

5 immunological cascades.

6 There is also increasing recognition of

7 the frequency with which neurocognitive

8 deterioration, apart from the more overt cerebral

9 ischemic events, occur with CABG procedures.

10 Extracorporeal cardiopulmonary bypass and

11 manipulation of the atherosclerotic aorta for

12 cardiopulmonary bypass perfusion, as well as

13 conduit anastomosis, have been indicted as

14 etiologic factors for these complications.

15 Anastomotic devices, by facilitating the various

16 modifications to the CABG that address morbidity,

17 can certainly play a major role in reducing this

18 illness.

19 \[Slide\]

20 Several studies during the development

21 stage of CABG evaluated the effectiveness of this

22 revascularization procedure measured as durability

23 of patency. While this slide presents a generally

24 accepted distillation of these study findings, it

25 should be noted that patency of CABG is dependent

22

1 on multifactorial elements that have likely been

2 affected by recent changes to the operation itself

3 that are still being evaluated, and by new measures

4 to inhibit the progression of coronary-artery

5 disease. This has to be considered when evaluating

6 anastomotic devices in a comparison to these

7 conduit patency rates.

8 \[Slide\]

9 Failure of the CABG conduit has been

10 attributed to several causes which are listed here.

11 They are broadly stratified by the period of their

12 most prominent effects: the perioperative failures;

13 6 months o 1 year, failure due to neointimal

14 hyperplasia; and the continuum from 6 months on are

15 both coronary-artery disease in the native vessel

16 and the conduit itself.

17 \[Slide\]

18 The advent of anastomotic devices carry a

19 promise for significant benefits in the performance

20 of the CABG procedure that go beyond simplifying

21 procedural mechanics for the benefit of the

22 operator. They have the potential for eliminating

23 many of the factors contributing to poor patient

24 outcome. It must be recognized that while the

25 precise benefit perceived for some of these recent

23

1 changes to the procedures, such as beating heart

2 and operations performed without cardiopulmonary

3 bypass, are as yet unresolved. The use of

4 non-suture constructed anastomoses will certainly

5 facilitate and increase the frequency of their use.

6 These are some of the benefits that seem intuitive

7 with anastomotic devices.

8 \[Slide\]

9 Well, Woody Allen has said every silver

10 lining has a dark cloud, and this is exactly true

11 with these anastomotic devices. Here are listed

12 some of the design characteristics that may

13 contribute to graft failure which do not obtain

14 with conventional sutured vascular connections.

15 \[Slide\]

16 In our evaluation of these devices for

17 clearance with a 510(k) notification, we have

18 required extensive preclinical data to support

19 limited clinical studies. The clinical material

20 was required to substantiate equivalence to

21 historical data for conduit patency, which was a

22 surrogate for correcting the deficiency in

23 myocardial perfusion.

24 We encountered some disagreement regarding

25 the study design, the duration of follow-up, and

24

1 the instruments for assessing effectiveness. While

2 general agreement exists regarding the use of

3 suture anastomosis as the gold standard to control

4 for patency, there is considerable advocacy to

5 employ measures of coronary perfusion for

6 assessment of patency. This is a reversal of the

7 original CABG use of patency as a surrogate for

8 perfusion.

9 With regard to duration of follow-up, the

10 initial concept was to take into consideration the

11 multifactorial causes of CABG failure by accepting

12 a relatively short period, such as 6-9 months, that

13 focuses on the adequacy of the anastomosis

14 constructed rather than the other factors in graft

15 failure. The changes made to the CABG procedure

16 itself and the introduction of measures aimed at

17 disease progression were not addressed. It was

18 also felt that a distinction could be made for

19 devices used on the proximal aortic or on the

20 distal coronary artery.

21 \[Slide\]

22 The problem encountered in designing a

23 study to evaluate these anastomosis devices goes

24 beyond the inherent problem of the multifactorial

25 causes of CABG failure. They involve in general

25

1 the device-specific variables listed here that may

2 frustrate attempts at one-design-fits-all study

3 design for the devices.

4 \[Slide\]

5 From our initial experience with cleared

6 devices, we now have the belief that the rigor of a

7 randomized trials may be required unless there are

8 very mitigating circumstances to justify otherwise.

9 To this end, we would like input on an appropriate

10 template for study design that could be modified to

11 accommodate some of the variables intrinsic to

12 their use. This slide lists some of the

13 considerations we have encountered for designing a

14 study template and it is just put up for your

15 consideration as a straw man.

16 \[Slide\]

17 This slide represents a sample size

18 estimation for a one-armed study with the endpoint

19 for effectiveness based on the historical values

20 listed here for conduits performed with hand

21 suturing. For instance, a point estimate of 95

22 percent patency, with a lower confidence level

23 accepted as 5 percent, would require a sample size

24 of 150 patients for study. This is just placed

25 here for your consideration or evaluation for even

26

1 a one-armed study.

2 This completes my introduction to the

3 FDA\'s request for this panel\'s input in formulating

4 an appropriate regulatory approach for devices that

5 present the potential for critically affecting the

6 treatment of coronary arterial disease, which is

7 the wound stripe of modern society.

8 Kachi Enyinna, our lead engineer reviewer

9 for these devices, will now present or crystallize

10 some of the comments that I have made in the form

11 of questions that we would like this panel to

12 address in helping us wrestle with the regulation

13 of these devices. Thank you very much.

14 MR. ENYINNA: Good morning. My name is

15 Kachi Enyinna, biomedical engineer and lead

16 reviewer, Division of Cardiovascular Devices. I

17 will be presenting the questions we have come up

18 with and seeking some kind of guidance from panel

19 on how to evaluate clinical studies of these

20 devices. I would like to remind the panel members

21 to keep these questions in mind while I go over the

22 questions and to keep the questions in mind until

23 discussion time this afternoon allow members of the

24 medical community, as well as sponsors and industry

25 to speak before we discuss the questions.

27

1 \[Slide\]

2 Regarding trial design, the first

3 question, please comment on the choice of control

4 in the clinical trial required to evaluate vascular

5 anastomosis devices for CABG. The gold standard of

6 sutured CABG anastomoses has a well-documented

7 history of over thirty years.

8 \[Slide\]

9 Can historical data from sutured CABG

10 anastomosis device trials be used as the control in

11 the device studies?

12 \[Slide\]

13 Alternatively, are concurrently performed

14 CABG controls necessary given the multifactorial

15 causes of CABG failure, for example, technical

16 construction, extent and progression of native

17 vessel disease, condition of conduit and

18 progression of intima hyperplastic and atheromatous

19 degeneration, and the introduction of drugs for

20 mitigation of atherosclerotic disease?

21 \[Slide\]

22 If these trial designs are inadequate,

23 should randomized, controlled clinical trials be

24 performed?

25 \[Slide\]

28

1 With regard to device placement and device

2 design, please address the following: Given the

3 considerable differences between the proximal and

4 distal CABG anastomoses, what, if any, differences

5 in study criteria should be required?

6 \[Slide\]

7 Are there certain aspects of the clinical

8 study design, for example length of follow-up and

9 endpoints, that should be required for all devices

10 irrespective of device form and function? For

11 example, the U-clip performance closely duplicates

12 that of a suture, whereas the Symmetry has greater

13 similarity to a stent.

14 It is rarely possible to determine the

15 cause of conduit failure. Can you suggest criteria

16 to determine whether failure is device related?

17 \[Slide\]

18 Number three, do you believe that the

19 significant differences between an arterial conduit

20 and a venous conduit warrant distinct study

21 criteria and assessment for each? If so, please

22 identify these criteria and analyses.

23 \[Slide\]

24 Four, should the primary effectiveness

25 endpoint be graft patency alone, or include both

29

1 graft patency and myocardial perfusion?

2 Five, with regard to device safety, what

3 criteria, that is, acceptable adverse event rates

4 as compared to that for suture should be applied to

5 the evaluation of device safety as distinguished

6 from device effectiveness? For example, myocardial

7 infarction, reoperations, neurologic events,

8 incidence of aortic complications.

9 \[Slide\]

10 Regarding endpoint evaluation, number six,

11 with regard to appropriate patient follow-up, in

12 view of the possible persisting risk of failure of

13 some mechanical anastomosis sites, distinct from

14 the progression of native vessel disease, what

15 duration of follow-up is advisable for premarket

16 evaluation?

17 \[Slide\]

18 Should postmarket follow-up be required to

19 assess long-term device effectiveness? If so,

20 please define the appropriate length of follow-up

21 after primary patency evaluation.

22 \[Slide\]

23 The last question, can non-invasive

24 measuring instruments, for example,

25 echocardiography, ultrafast spiral CT, MRA, EBT,

30

1 etc., be used for primary assessment of graft

2 patency or is angiographic follow-up necessary? At

3 what time points should patency be assessed? Thank

4 you.

5 DR. TRACY: Does that conclude the FDA

6 presentation? Does anybody on the panel have a

7 question for the FDA at this point?

8 \[No response\]

9 At this point, we will move on to the open

10 public hearing. Both the Food and Drug

11 Administration and the public believe in a

12 transparent process for information gathering and

13 decision-making. To ensure such transparency at

14 the open public hearing session of the advisory

15 committee meeting, FDA believes that it is

16 important to understand the context of an

17 individual\'s presentation. For this reason, FDA

18 encourages you, the open public hearing speaker, at

19 the beginning of your written or oral statement to

20 advise the committee of any financial relationship

21 that you may have with the sponsor, its product

22 and, if known, its direct competitors. For

23 example, this financial information may include the

24 sponsor\'s payment of your travel, lodging or other

25 expenses in connection with your attendance at this

31

1 meeting. Likewise, FDA encourages you at the

2 beginning of your statement to advise the committee

3 if you do not have any such financial

4 relationships. If you choose not to address this

5 issue of financial relationships at the beginning

6 of your statement it will not preclude you from

7 speaking.

8 MS. WOOD: I have just a couple of

9 announcements for the open public speakers. We

10 have asked today, due to the number of speakers

11 that have requested time, that you limit your

12 remarks to five minutes each. I would also ask

13 that you provide me with either an electronic copy

14 or a hard copy of your presentation for the benefit

15 of the summary writer and the transcriptionist. If

16 you could see me at lunchtime, that would be great.

17 Thank you.

18 DR. TRACY: There are a number of speakers

19 and I will call them in order. The first is Dr.

20 Randall Wolfe, from University of Cincinnati.

21 Open Public Hearing

22 DR. WOLFE: Members of the panel, ladies

23 and gentlemen, good morning.

24 \[Slide\]

25 Thank you for honoring my request to speak

32

1 before you. My disclosure is that I was the

2 principal investigator on the multicenter U-clip

3 distal anastomotic trial. Those results were

4 presented at AATS two years ago. There is no

5 financial relationship.

6 I was a past consultant for Ethicon in

7 laboratory and clinical evaluation of proximal and

8 distal anastomotic devices, and in the past was a

9 consultant to Ventrica in helping set up their

10 clinical distal anastomotic connector trial.

11 I am currently on the steering committee

12 of the Prevent IV Core Gentech E2F Decoy trial

13 which uses synthetic DNA to prevent aortic coronary

14 venous graft atherosclerosis. That study is closed

15 with over 3,000 patients enrolled. I mention that

16 because I think we are going to be educated on true

17 graft patency of the results of that trial which

18 will be opened first quarter of next year.

19 \[Slide\]

20 My primary interest is that I have been

21 presenting summary of anastomotic devices at our

22 national meetings, both AATS, STS and ISMICS. In

23 the next five minutes I would like to summarize

24 some of the things that have been presented at

25 these meetings.

33

1 \[Slide\]

2 Overall, there are a lot of anastomotic

3 connector devices, and this shows a convenient way

4 to classify these into proximal and distal and

5 subsequently into automated versus manual. There

6 are 13 to 15 different devices in these different

7 categories but I find this a convenient way to look

8 at connectors.

9 \[Slide\]

10 There are different value propositions

11 with the connectors and they range from traditional

12 CABG all the way to total endoscopic CABG. I don\'t

13 have time to go over this in detail but only to

14 point out that there is a possibility of

15 eliminating the heart-lung machine by using certain

16 connectors and also reducing ischemic time. In the

17 endoscopic evaluation there is a potential to

18 reduce patient pain and trauma and to truly enable

19 endoscopic surgery.

20 \[Slide\]

21 This is a summary that you will probably

22 hear more about from other presenters, but vein

23 graft failures could be a bad vein; the vein could

24 be too long; it could be too short; there could be

25 a poor run-off bed; or it could be a distal or

34

1 proximal anastomotic problem.

2 \[Slide\]

3 I think this is an important slide. This

4 is some of the science and this is based on some of

5 the work of the E2F Decoy trial but there is an

6 initial wave of inflammation in a venous graft.

7 There is injury. There is activation of smooth

8 muscle cells. There is migration proliferation and

9 intimal soil, if you will, for atherosclerotic

10 plaque and ultimately accelerated atherosclerosis.

11 However, this initial wave is in the first two

12 weeks after the venous graft has been harvested

13 from the leg and placed on the heart.

14 \[Slide\]

15 This is a summary of how I look at graft

16 failure. I divided it into three distinct

17 categories. The first is immediate, that is a

18 technical graft failure. These are all venous

19 grafts, by the way; it could be arterial as well.

20 Technical failure would be identified in the first

21 week. In other words, if one obtained a

22 postoperative coronary angiogram in a patient in

23 one week technical failures would be disclosed.

24 The next is intermediate, and this is what

25 I relate to devices. This is usually in the first

35

1 six to eight weeks. So, a six-month angiographic

2 evaluation should pick up device failures.

3 The third is chronic and this relates to

4 accelerated atherosclerosis and this really takes

5 years. In the E2F Decoy trial we are looking at

6 one year but, in fact, it probably occurs over five

7 years. In my opinion, if the St. Jude device had

8 been evaluated at six months by angiography

9 stenoses and occlusions would have been discovered

10 that related to the device. In other words, the

11 intermediate category.

12 \[Slide\]

13 We now have second generation anastomotic

14 devices. They have proven to be more reliable than

15 hand sewn. There is a consistent orifice size.

16 They are easier to use. I think, importantly,

17 another change that has happened with the second

18 generation is a lack of vein manipulation. So,

19 these should be evaluated with six-month

20 angiographic equivalency and we should also look at

21 performance outcomes.

22 \[Slide\]

23 In summary, I believe the science supports

24 six months angiographic data for the intermediate

25 or device failure area. Proximal stainless steel

36

1 devices have demonstrated excellent patency, which

2 will probably be discussed. And, second generation

3 distal devices demonstrate excellent patency. I

4 think we have to keep in mind as we think about

5 this is that unlike stents for coronary-artery

6 disease, these devices do not rearrange plaque

7 morphology. Thank you.

8 DR. TRACY: Thank you. Are there any

9 brief questions for Dr. Wolfe from the panel?

10 DR. EDMUNDS: What data do you have for

11 that last statement?

12 DR. WOLFE: Which part of it?

13 DR. EDMUNDS: The last statement, how do

14 you know that the device doesn\'t rearrange plaque?

15 I mean I don\'t know. I would just be interested in

16 your data.

17 DR. WOLFE: The last statement is

18 concerning distal devices. This is assuming that

19 the device is placed to a target site that is

20 relatively free of atherosclerotic debris. The

21 second bullet point is for the proximal devices.

22 The third bullet point is specifically for distal.

23 DR. EDMUNDS: That is what I am talking

24 about. Are you talking about magnetic coupling?

25 DR. WOLFE: Any type. What I am trying to

37

1 relate is that stents and anastomotic devices are

2 not equal in that a stent is supposed to rearrange

3 plaque to open up a stenosis. For devices that we

4 are using that is not their purpose. We are not

5 rearranging the plaque. We are connecting,

6 hopefully, a fairly normal vein or artery to a

7 fairly normal coronary distal target.

8 DR. BRIDGES: I have a question about the

9 second bullet point. Can you also inform us what

10 data that is based on?

11 DR. WOLFE: I think that will be presented

12 by others, but I believe that the difference is

13 that stainless steel is stronger, and in a proximal

14 position where there is atherosclerotic disease a

15 stainless steel device can actually hold the aorta

16 open, whereas a nitinol device may not; it may

17 buckle and close. So, it is really the strength of

18 the material. The proximals are different from the

19 distals. In fact, the people that may need the

20 proximal devices the most are the ones who have the

21 worst aortas. They have disease in a situation

22 where it is maybe not safe to clamp the aorta.

23 DR. AZIZ: With the proximal devices, if

24 you do get narrowing, how do you propose that be

25 handled? Let\'s say in six months you find that you

38

1 have osteal narrowing, how would you handle that?

2 DR. WOLFE: I don\'t know the answer to

3 that.

4 DR. AZIZ: Can they be dilated in the cath

5 lab?

6 DR. WOLFE: I don\'t know the answer to

7 that.

8 DR. AZIZ: And is there intimal

9 hyperplasia that you are seeing, if you do see it?

10 DR. WOLFE: I believe so with the second

11 generation devices. With the first generation

12 devices I think it was a more complicated situation

13 where the graft could actually embrocate over the

14 device. But in the second generation devices it

15 should be more related to disease in the aorta.

16 However, if a large lumen is maintained then there

17 shouldn\'t be significant stenosis. So, let\'s say

18 you get neointimal hyperplasia in every graft,

19 let\'s say you get a millimeter in every

20 graft\--well, if you get a 1.5 mm opening, that is

21 significant. If you get a 3 mm opening that is

22 maintained, it won\'t be significant.

23 DR. AZIZ: Let me ask you one other thing,

24 with the proximal anastomotic devices, the angle

25 that the graft comes off is really at right angles

39

1 to the aorta. Right?

2 DR. WOLFE: In some of the products, that

3 is true.

4 DR. AZIZ: You mean there are ones where

5 you can have it coming off as a cobra head?

6 DR. WOLFE: That is correct.

7 DR. KRUCOFF: Have you actually retrieved

8 any of these devices and looked at them under a

9 microscope when they have failed?

10 DR. WOLFE: I have not\--well, I have seen

11 the slides, I certainly have.

12 DR. KRUCOFF: Whose slides are those?

13 DR. WOLFE: St. Jude. I did go over those

14 at one point and, again, that is a first generation

15 device and I believe the mode of failure of that is

16 different from anything you might see in the

17 future. It is multifactorial but the occlusions

18 tend to be flush with the aorta. There is

19 neointimal hyperplasia; there is thrombus. First

20 of all, the angiogram does not look like a typical

21 angiogram that you might see with an occluded vein

22 graft; it is completely different. There is also

23 the possibility that the vein graft itself has

24 changed its position on the connector. In

25 addition, that was a connector that had a high

40

1 profile. There is also the possibility that there

2 could be a right angle kink right at the end of the

3 connector.

4 I think in summary, I give credit to the

5 pioneers for being the first ones out there. The

6 first eight patients who received a mitral valve

7 replacement all died. Fortunately, we still do

8 mitral valve replacements and maybe with the first

9 generation connectors we are seeing some of the

10 same things, some of the mistakes. I think many of

11 those have been changed by changes in device and

12 changes in material.

13 DR. YANCY: As you have worked through

14 your clinical trials with these devices, have there

15 been concomitant improvements or changes in medical

16 management because of anticipated problems with

17 these connectors vis-avis antiplatelet therapy,

18 anticoagulation, aspirin, etc.?

19 DR. WOLFE: We do have some data from the

20 E2F Decoy trial. The trial has not opened but we

21 have some demographic data. It has been shown that

22 when patients are followed more closely the chances

23 of them going home on antiplatelet agents are much

24 higher. Although most surgeons say that they send

25 their patients home on aspirin or some antiplatelet

41

1 agent, in fact, many patients do not go home on

2 that but in a careful study situation they do.

3 There is a study bias.

4 DR. YANCY: So, those anticipated events

5 that you thought would be predicted or captured at

6 six months, do you think they are product failures,

7 medical management failures or both?

8 DR. WOLFE: I expect they are product

9 failures and they probably would be in an extreme

10 environment such as a very atherosclerotic aorta,

11 but I am not sure. I am not sure.

12 DR. TRACY: I think we are going to have

13 to move on at this point. There is a number of

14 other speakers. Thanks very much. Dr. Robert

15 Emery?

16 DR. EMERY: While we are setting up my

17 disc here, I am Robert Emery. I am in private

18 practice in Minneapolis-St. Paul, Minnesota. I am

19 not being sponsored by any companies but I have had

20 relationships in terms of research grants by St.

21 Jude Medical, ATS Medical, AtriCure, Congestive

22 Heart Failure Solutions. I have been on research

23 advisory boards for St. Jude Medical, Medtronic,

24 Myocor, Percardia, CardioGenesis, Inc.; data safety

25 monitoring boards for Cardioblate and for Myocor,

42

1 and I have received speaking fees for several of

2 the aforementioned companies.

3 \[Slide\]

4 I would like to address our early

5 experience in the Minneapolis-St. Paul area looking

6 at why vein grafts fail, the new issues with aortic

7 connectors. We have been through the etiology of

8 graft failures so I won\'t go into that, however,

9 there are several new issues that are introduced by

10 the currently used generation of connectors. There

11 can be overloading of the connector, that is, too

12 much vein graft placed below the prongs;

13 double-loading of the connector like putting on

14 your socks where you can invert the graft and load

15 that which inhibits flow through the graft. You

16 can skive the aortic punch and that make take out a

17 complete circle.

18 There are variations in operative

19 technique. For instance, performing your proximals

20 first, as most surgical trainees in the United

21 States perform distals first you are radically

22 changing the way we have been trained in our

23 everyday use in conduct of the operation. Grafts

24 can move. After the patient is closed the lungs

25 can push the grafts to various positions and this

43

1 can cause loss of the 90 degree angle, that has

2 been mentioned here, that is necessary for the

3 current generation St. Jude connector.

4 \[Slide\]

5 Let\'s look at some of these issues that we

6 have seen. Here is a surgical technical error at

7 the distal anastomosis that would lead to graft

8 failure if not completed. I don\'t think that could

9 be blamed on the connector but a connector was

10 utilized.

11 \[Slide\]

12 This is the first case I performed in the

13 United States, the second one done in the United

14 States after FDA approval. You can see two

15 technical errors here that I learned over time and

16 if I had not changed my operative technique one

17 would have a consistent mode of failure that would

18 be uncorrected. That is, these grafts are placed

19 on top of the aorta instead of further down the

20 side toward the pulmonary artery, therefore,

21 maintaining a 90 degree angle. The grafts are also

22 reflected superiorly with some kinking at the

23 anastomotic site, not maintaining that 90 degree

24 angle. As I mentioned, these grafts can move. All

25 grafts should be tacked to keep that important 90

44

1 degree angle. If you lose that you can predict

2 some degree of graft failure.

3 \[Slide\]

4 There can be poor run-off, as shown on

5 this slide, to a patent vein graft but a poor

6 distal vessel.

7 \[Slide\]

8 Another example is shown here. The graft

9 can be too short, as mentioned. Again, it may be a

10 variation in operative technique.

11 \[Slide\]

12 Here a graft is tethered across the

13 pulmonary artery and you can see the narrowing

14 several centimeters distant from the connector

15 device.

16 \[Slide\]

17 And a similar vein here wrapped around the

18 pulmonary artery more tightly than one would like

19 to see.

20 \[Slide\]

21 Improper placement of the graft is also

22 important.

23 \[Slide\]

24 Here is a vein graft that was placed on

25 the right side of the aorta as we traditionally

45

1 place our saphenous vein grafts when we suture

2 them, rather on the anterior surface of the aorta,

3 riding over the right ventricular outflow tract

4 maintaining the 90 degree angle. You can see the

5 acute bend on the right side as this graft reflects

6 against the patient\'s pleural surface.

7 \[Slide\]

8 Aortic disease was mentioned and this can

9 be important. Here is an occluded connector in a

10 diffusely diseased aorta and you can see, as Dr.

11 Wolfe mentioned, the flush occlusion of the aorta.

12 \[Slide\]

13 A combination of factors\--here is a small

14 vein graft and poor run-off.

15 \[Slide\]

16 And here is a very small vein graft that

17 has become atretic over time to a small distal

18 vessel, still patent through the connector but,

19 nonetheless, narrowed.

20 \[Slide\]

21 Then there is the unknown. Here is the

22 occluded connector again flush at the angiographic

23 site.

24 \[Slide\]

25 Here is an occluded vein graft marked by

46

1 the stainless steel ring in the same patient. You

2 can see the connector graft slightly to the left

3 and one or two centimeters down in this example.

4 There are connector related issues that are key.

5 \[Slide\]

6 This is what was addressed a little bit in

7 the prior question, proximal anastomotic problems

8 in the face of appropriate graft and appropriate

9 distal connectors that need to be investigated.

10 \[Slide\]

11 Yet, there are technical issues. Here is

12 another proximal connector with a very good vein

13 graft and a large distal run-off system.

14 \[Slide\]

15 Improved and more extensive training may

16 obviate several of the modes of failure that we

17 have seen. We need to develop indications and

18 contraindications for the use of these devices,

19 particularly as they come out not just general,

20 overall approval. There are technical

21 considerations that need to be mentioned. Many

22 modes of failure are unstudied or unconfirmed.

23 Thus, prospective studies are warranted including

24 operative technical detail, both visual, such as

25 the photograph I showed you and verbal operative

47

1 reports, and improved mentoring may be necessary

2 even for devices that seem intuitively simple.

3 \[Slide\]

4 There are tips for success that I have

5 developed in my own practice based on my

6 experience.

7 \[Slide\]

8 What we do not want to do is throw the

9 baby out with the bath water because these

10 connecting devices offer us a great opportunity to

11 improve our service to our patients. Thank you.

12 DR. TRACY: Thank you. Are there any

13 brief questions from the panel members? I do want

14 to remind you that there are a lot of people who

15 want to present today.

16 DR. KRUCOFF: Just one question. The

17 angiograms you showed us, were they part of a study

18 protocol that required angiography or were these

19 clinical presentations of people who came back

20 sick?

21 DR. EMERY: These were clinical

22 presentations in approximately our first eight

23 months of use, from May, 2001 through the first

24 eight months, and we have seen very few since we

25 have modified our surgical techniques.

48

1 DR. KRUCOFF: And the denominator for

2 these eight months?

3 DR. EMERY: It was about 160, and these

4 are not all of them. These are representative

5 samples of technical errors that are correctable

6 with proper training and changing of your

7 techniques as you learn the process.

8 DR. AZIZ: When you say you tack the

9 grafts, are you putting many anchoring stitches or

10 what do you do?

11 DR. EMERY: Three or four generally on the

12 left side. I put one on the pulmonary artery and,

13 again, depending on the length of the graft,

14 because you are doing proximals first with this

15 device, I will connect it so that it won\'t move

16 with respiration. On the right side I connect it

17 down the body of the right ventricle as the graft

18 goes directly up from the aorta over the right

19 ventricle and down to the right coronary artery,

20 the posterior descending artery, just some 6-0

21 prolene suture tacking.

22 DR. AZIZ: We normally do the regular

23 suturing technique; usually you don\'t have to do

24 that?

25 DR. EMERY: No, I don\'t.

49

1 DR. AZIZ: So, why do you think you need

2 to do it here?

3 DR. EMERY: Because I learned doing this

4 distal first and I think my measurement of the

5 length of the vein graft to the aorta is better on

6 a distal first process in my hands. So, sometimes

7 I would rather make my grafts too long than too

8 short because the shortness of the graft may be one

9 reason for disconnection of these connectors from

10 the aorta. As the pulmonary artery fills, if the

11 graft is too short you can pull these off. I have

12 pulled them off myself in the operating room by

13 tugging a little bit too hard and I had to put my

14 finger over the hole. So, a short graft can lead

15 to connector displacement from the aorta,

16 particularly as the patient moves or the heart

17 fills in the postoperative period.

18 DR. TRACY: Dr. Hirshfeld?

19 DR. HIRSHFELD: I would just like to say

20 as an angiographer who has probably taken pictures

21 of thousands of bypass grafts, I have heard a lot

22 about considerations that I was never aware of

23 before from your brief presentation, and I think it

24 calls for a sharing of information between

25 angiographers and surgeons about many of these

50

1 technical considerations that affect graft

2 performance. So, I would hope that out of this

3 will come that kind of sharing of information.

4 DR. EMERY: I have reviewed all the

5 angiographs of patients that failed in my hands.

6 DR. TRACY: I think we have to move on; we

7 have a number of speakers. I am sorry to cut this

8 short; it is very interesting. To remind you,

9 there will be more time this afternoon to discuss

10 things in detail. Dr. Schoettle?

11 DR. SCHOETTLE: Good morning. My name is

12 Dr. Phillip Schoettle. I am a thoracic and

13 cardiovascular surgeon in practice at Methodist

14 University Hospital in Memphis, Tennessee.

15 I am here this morning to discuss my

16 experience with the Symmetry proximal anastomotic

17 device. I would like to disclose at the outset

18 that I have no financial interest in this matter.

19 I paid my own way to Washington, and I am not

20 employed by anyone, nor intend to be employed by

21 anybody with a financial stake in this issue.

22 In September of 2001 I was trained in the

23 use of the Symmetry proximal anastomotic device,

24 along with two of my scrub assistants, by St. Jude

25 Medical. I was attracted to the device because of

51

1 the reasons mentioned previously which would allow

2 you to do a proximal anastomosis off the aorta

3 without the use of a partial occluding or

4 side-biting clamp with its attendant risk of

5 embolic debris.

6 I rapidly incorporated that device into my

7 practice and used it almost exclusively for the

8 next eleven months. Initially I was very pleased

9 with the results. I had minimal, if any, technical

10 issues with the device and was not aware of any

11 acute or subacute saphenous vein closures.

12 Unfortunately, at approximately ten months we began

13 to see almost a deluge of patients returning to the

14 cardiac catheterization laboratory with vein graft

15 occlusions or high grade stenoses invariably

16 occurring in the connector site.

17 This occurrence was totally incompatible

18 with my previous surgical experience. I reported

19 this to St. Jude Medical and I felt like it

20 warranted a distribution to the surgical community

21 and I began a review of my patients, resulting in

22 the paper that you see here. This paper was

23 entitled, \"Use of an Anastomotic Device in Coronary

24 Bypass Surgery: A Word of Caution.\" It was

25 published in the January edition of the Journal of

52

1 Thoracic and Cardiovascular Surgery.

2 Without going into great detail, I would

3 like to summarize the results of that paper. It

4 was a review of two years of experience. The first

5 year was the year prior to my beginning to use the

6 device, while proximal saphenous vein connections

7 off the aorta were done in the conventional manner,

8 that is, hand-sewn with a partial occlusion clamp.

9 Beginning in September of 2001, for the next eleven

10 months, comprises the next group of patients where

11 almost exclusively all proximal anastomoses were

12 done with the St. Jude Symmetry anastomotic device.

13 I divided the group in group A and group

14 B. Group A was the first group, the prior year

15 with hand-sewn anastomoses. I reviewed all

16 patients who required repeated cardiac

17 catheterization after coronary artery bypass

18 surgery. What we found was that even though the

19 patients in group A had had a year longer of

20 exposure to my cardiology colleagues, less of those

21 required repeated cardiac catheterization, although

22 that number was not significant between the groups.

23 The number of grafts studied between group

24 A and group B was also similar. However, what we

25 did find was that the group A patients, those with

53

1 hand-sewn anastomoses, had an 80 percent patency

2 rate of vein grafts studied. Remember, these were

3 symptomatic, or at least theoretically symptomatic

4 patients. So, 80 percent of the grafts were widely

5 patent in the hand-sewn anastomoses, with no

6 significant stenoses, and 20 percent were

7 occluding.

8 Unfortunately, in the group B patients,

9 those with the Symmetry proximal anastomotic

10 device, only 20 percent of the grafts studied were

11 patent. Fully 80 percent of the grafts were either

12 totally occluded or had high grade stenoses

13 uniformly occurring at the connector site. The

14 significance in p value in favor or patency of the

15 hand-sewn anastomoses was standardly evaluated with

16 a p value of 0.0001.

17 Based on my experience with the Symmetry

18 proximal anastomotic device and review of my own

19 patients, I have several observations and two

20 conclusions I would like to make. The use of the

21 Symmetry St. Jude proximal anastomotic device in

22 its current generation results in a significantly

23 higher saphenous vein closure and occlusion rate

24 when compared to hand-sewn anastomoses.

25 I do not believe that technical issues are

54

1 the major factor. I can show you arteriograms of

2 what appear to be perfectly laid out saphenous vein

3 grafts with a 90 degree angle off the aorta, with

4 no kinking, where the stenosis arises immediately

5 in the connector site off the aorta.

6 In two patients that I reoperated, I was

7 able to harvest the segment of aorta with the

8 connector and the saphenous vein. This was looked

9 at microscopically by the pathologists in my

10 hospital who reported basically a foreign body

11 reaction in the connector site with associated

12 neointimal hyperplasia.

13 I would also point out that these

14 connector stenoses and occlusions are not

15 clinically insignificant. In this group at least

16 six patients have required early reoperation.

17 Thirty patients, over a year ago, required PCI

18 stents and angioplasty. There have been four

19 sudden deaths in these patients, two of which were

20 almost certainly related to myocardial infarction.

21 If I can have the liberty of making a

22 conclusion, I see no clinical indication for the

23 current generation of the St. Jude proximal

24 connector. The use of this connector or any other

25 vascular anastomotic devices must be evaluated by

55

1 scientifically controlled, prospective clinical

2 trials.

3 I do not believe that uneducated surgeons

4 and uninformed patients should be the testing

5 ground for these devices that have not proven to be

6 clinically safe or effective. I clearly am not

7 opposed to technological advances in coronary

8 bypass surgery. I have been an early proponent of

9 off-pump surgery and less invasive coronary

10 surgery. I do not want to throw the baby out with

11 the bath water. I do not believe, however, that

12 the cause of less invasive coronary artery bypass

13 surgery is furthered by the ill-advised use of

14 these unproven devices. Thank you. I would be

15 glad to answer questions if there is time.

16 DR. TRACY: Any brief questions? Dr.

17 White?

18 DR. WHITE: Would you just clarify for me,

19 in the early part of your statement you said

20 something about follow-up at ten months. Was there

21 a ten-month interval that was special to you?

22 DR. SCHOETTLE: No, I believe it just

23 would have become apparent to me, you know, with

24 just the overwhelming evidence of patients. All of

25 a sudden I was getting call after call from these

56

1 patients.

2 DR. WHITE: Would six months not have

3 identified these patients? Would a six-month

4 follow-up, do you think, not have been adequate?

5 DR. SCHOETTLE: I was asked that question

6 last night. I don\'t have that answer. My gut

7 feeling is that six months would probably be

8 appropriate but I don\'t know that answer based on

9 this review.

10 DR. BRIDGES: I have a question. In the

11 brief study that you gave us I didn\'t see the

12 mortality in the two groups. You said that there

13 were no sudden deaths in the hand-sewn group but

14 what was the overall mortality in the two groups

15 and are there any updates since this paper was

16 submitted?

17 DR. SCHOETTLE: The operative mortality

18 was less than three percent but the overall

19 mortality long-term, I don\'t have that; there have

20 been no updates at this point although I intend to

21 do that.

22 DR. BRIDGES: But both groups\--

23 DR. SCHOETTLE: They were very similar.

24 DR. BRIDGES: At least for the graft

25 connector patients, what would be medical therapy

57

1 for these?

2 DR. SCHOETTLE: It is in the paper, but

3 all patients were discharged on aspirin and all

4 patients were discharged on Plavix for two months.

5 DR. AZIZ: But when you had to reoperate

6 on them did you have to redo the whole anastomosis

7 or could you immobilize it and rehook it? How did

8 you do that?

9 DR. SCHOETTLE: In a couple of cases I was

10 able to continue to use that vein segment. Conduit

11 length was an issue. Several of the veins were

12 totally occluded and we just had to sacrifice those

13 veins.

14 DR. AZIZ: So, the orifice was like the

15 whole length?

16 DR. SCHOETTLE: That is correct.

17 DR. AZIZ: So, you probably had intimal

18 hyperplasia proximally and you had full flow and

19 then thrombus\--

20 DR. SCHOETTLE: And then thrombus

21 distally, correct.

22 DR. AZIZ: Obviously most people don\'t,

23 and they probably should use some flow techniques

24 to measure flows.

25 DR. SCHOETTLE: All patients in both

58

1 groups had mediastinal transit time flow evaluation

2 at the time of surgery, and 95 percent of cases

3 were done off-pump.

4 DR. AZIZ: When you did proximal

5 anastomoses with the device did you do any

6 sequential grafts\--

7 DR. SCHOETTLE: No, they were sequential

8 grafts but I don\'t have that number available to

9 me.

10 DR. TRACY: Thank you.

11 DR. SCHOETTLE: Thanks.

12 DR. TRACY: Dr. Frater?

13 DR. FRATER: Let me state immediately I am

14 the Medical Director of St. Jude and, obviously,

15 have that as a conflict of interest.

16 I have a few points to make. I had

17 expected ten minutes so I am going to try and make

18 them quickly. I think we can all agree that the

19 MDR system is a warning light that tells us nothing

20 about incidence and, unless we are very lucky,

21 doesn\'t give us much information on causality, hard

22 as we try to look into every single report that

23 comes in from the field. I shall not elaborate on

24 that. I suspect the FDA feels the same about the

25 MDR\'s utility as we do.

59

1 The question of comparing anastomotic

2 devices to historically published data for sutures

3 is an interesting one. The data that was obtained

4 in the past has been cardiac surgeons who were

5 trying to find out what they were doing 30 years

6 ago when they were making venous anastomoses. The

7 patients were younger. The vessels were better.

8 The extra conditions, such as diabetes, were far

9 less common and it was a different group of

10 patients. Those patients have long since been

11 captured by the interventionalists and the cardiac

12 surgeon today faces a very different patient.

13 We need to know what the patency rates are

14 today with the current set of patients. We also

15 need to know what the difference may be between

16 off-pump and on-pump. There was a paper presented

17 just a few weeks ago at the ACC, the so-called Prog

18 IV Trial, a randomized comparison between off-pump

19 and on-pump surgery with angiography at one year.

20 The patency rate of the cases performed on-pump at

21 one year was 59 percent; the patency rate of those

22 performed off-pump was 49 percent.

23 There is a paper being published in The

24 New England Journal of Medicine by Kahn. It came

25 out of Britain. Again, a randomized study of

60

1 on-pump and off-pump anastomoses studied at three

2 months by angiography, which was performed in 80

3 percent of the patients in the trial. The patency

4 rate of the on-pump cases was exemplary. At three

5 months they had a 98 percent patency rate but the

6 off-pump cases had an 88 percent patency rate at

7 three months.

8 I present this material, which is clearly

9 important in trying to assess what will be the

10 target of patency that we will be looking at in

11 future trials, and a recognition that times have

12 changed and circumstances are clearly very

13 different.

14 We have done a meta-analysis of some 7,000

15 patients in which angiograms were done between 6

16 and 12 months. We chose that 6- and 12-month

17 period for the obvious reason that you have already

18 heard today, that after 12 months atherosclerosis

19 dominates the failure of vein grafts. The mean

20 occlusion rate was 16 percent in this meta-analysis

21 between 6 and 12 months of sewn anastomoses. But

22 the range was from 9.5 to 26.5. There is an

23 immense diversity from different institutions and

24 we can speculate forever, certainly not in five

25 minutes, as to what the reasons for those

61

1 differences are. I am sure that the surgeons in

2 the Prog IV study have not suddenly become

3 incompetent; there are factors that we need to look

4 at.

5 The question of the extent to which

6 clinical utility data is considered to be

7 necessary, I think we have already begun to deal

8 with this. Six months seems to be a period of time

9 that people are reaching, and that is not

10 unreasonable considering that stents are a Class

11 III device which may or may not be identical to

12 anastomotic devices\--that is debatable\--are being

13 evaluated with MACE and target vessel interventions

14 at six months.

15 Certainly, it is reasonable to state that

16 it should not be more than 12 months for the

17 obvious reason that by then atherosclerotic disease

18 dominates. There is intimal damage and technical

19 factors in the first week, neointimal hyperplasia

20 for the next few months, blending finally into

21 atherosclerotic disease.

22 Now, it is essential that the FDA provide

23 clarity on the type of clearance that we need. If

24 the clinical data requirement reaches the point

25 which would normally be required for a PMA, then it

62

1 should be a PMA. If you are required to produce

2 the data for a PMA, then the process should be done

3 under a PMA process. Thank you very much.

4 DR. TRACY: Any questions?

5 DR. WEINBERGER: I have a question for

6 you. You said that you were concerned that the

7 follow-up should be at six months because you

8 thought that atherosclerosis dominates the

9 subsequent natural history of graft failure. I am

10 concerned because we have a pretty good idea that

11 there is distinct biological heterogeneity in

12 different vascular beds in terms of the kinetics of

13 responses to manipulation. For instance, we know

14 that for coronary interventions basically at six to

15 nine months the process is over. But if you look

16 in the periphery, like the iliacs, the usual time

17 is three years. Do you have any data to suggest

18 that the process to response to injury in vein

19 grafts is over at nine months?

20 DR. FRATER: Well, if you look at the data

21 from peripheral vascular intervention where it is

22 far easier to follow the patients, it seems fairly

23 definite that while there is an acute phase, which

24 is partly technical and partly because of the

25 damage we do to the vein by the various things we

63

1 do when we take it out and manipulated it, it

2 starts in the first week. The neointimal

3 hyperplasia seems to blend at 12 months in these

4 peripheral vascular studies with the

5 atherosclerotic process. It would seem reasonable,

6 if there is an atherosclerotic process taking place

7 in veins after 12 months, not to attribute that to

8 how we handled the vein at the time of the initial

9 anastomosis.

10 DR. WEINBERGER: Just one follow-up, if

11 there is any kinking in the vein and you have a

12 jet, that jet wouldn\'t lead to an accelerated

13 atherosclerotic process later on as well?

14 DR. FRATER: It would happen far quicker

15 than that. Usually, if you leave a kink in a vein

16 there is a consequence that is soon and definite.

17 DR. WEINBERGER: Data?

18 DR. FRATER: Data? Clinical experience.

19 I am a cardiac surgeon.

20 DR. TRACY: Dr. Bridges?

21 DR. BRIDGES: Yes, there are two points.

22 One is to echo Dr. Weinberger\'s point that I don\'t

23 think we know exactly. There is nothing to suggest

24 that there can\'t be an interaction between

25 mechanical factors and atherosclerosis that extends

64

1 beyond one year. To say that you can divide these

2 into two discrete processes that are technical,

3 device related and then atherosclerosis I think is

4 unsubstantiated and you can\'t really defend that.

5 Furthermore, I am sure we are going to

6 hear from Dr. Mack but his own data that was

7 presented at the STS meeting, just in January,

8 showed, at least in his series which I am sure he

9 will comment on, that it was not until you got out

10 beyond one year that you started to see a

11 difference in MACE, that is, you know,

12 cardiovascular events. So, that, in and of itself,

13 also suggests that the idea of only looking at a

14 one-year or six-month time period is clearly going

15 to result in us missing failures.

16 DR. FRATER: The obvious issue is how long

17 would you like it to be? Clearly, it becomes

18 extraordinarily difficult if you are suggesting

19 that we should wait five years, or something like

20 that. Dr. Mack can speak for himself but I believe

21 that in diabetes there was a difference and there

22 may well be factors like that that make a

23 difference.

24 DR. BRIDGES: My point is not to suggest

25 how long we need to look, I am simply objecting to

65

1 the concept that we can definitively or

2 declaratively state at this point, based on what

3 evidence we have, that we know that six months or

4 nine months is an acceptable time frame in order to

5 exclude device-related issues.

6 DR. TRACY: Dr. Yancy, and then if there

7 is time Dr. Maisel.

8 DR. YANCY: Just a very short yes/no

9 question. I have not seen the referred to NEJM

10 article comparing on-pump versus off-pump surgery.

11 Were connectors used in the off-pump cases?

12 DR. FRATER: This was absolutely a study

13 of on-pump versus off-pump vein patency.

14 DR. TRACY: Dr. Maisel?

15 DR. MAISEL: You have eloquently stated

16 that times have changed and that historical

17 controls are just that, historical, and you stated

18 data that the patency rates vary greatly from

19 institution to institution. In many respects that

20 is a strong argument for randomized trials but you

21 didn\'t come out and state that. Are you a

22 proponent of randomized clinical trials to assess

23 these devices?

24 DR. FRATER: You know, in the best of all

25 possible worlds, yes. I am speaking as a cardiac

66

1 surgeon now.

2 DR. TRACY: Thank you.

3 DR. EDMUNDS: Did I hear you say that the

4 one-year patency rate for off-pump proximal veins,

5 the occlusion rate was 9-26 percent?

6 DR. FRATER: In the meta-analysis that we

7 did between 6 and 12 months, there was a range from

8 9.5 to 26.5 percent in this meta-analysis of some

9 7,000 cases. In the Prog IV study\--

10 DR. EDMUNDS: For hand-sewn?

11 DR. FRATER: Hand-sewn anastomoses, in the

12 Prog IV study the patency rate was 59 percent

13 patent at one year on pump, 49 percent patent

14 off-pump. It was just presented at the ACC.

15 DR. TRACY: We do have to move on, I am

16 sorry. Dr. Mack?

17 DR. MACK: My name is Michael Mack and I

18 am a cardiac surgeon in Dallas. By way of

19 disclosure, I am not sponsored by anybody today. I

20 paid my own way here. I have served as a

21 consultant in the past at St. Jude, also to

22 Cardica. I have received research grant support

23 from St. Jude regarding anastomotic devices, and I

24 am also on the scientific advisory board for

25 Medtronic and Guidant, both of which have equity

67

1 interests in anastomotic device companies.

2 The thrust of my presentation was to

3 discuss saphenous vein graft patency and not our

4 own St. Jude device paper, which has been

5 presented, in view of the fact that I only have

6 five minutes but I will try and get this done in

7 four and just spend the last minute discussing

8 that.

9 \[Slide\]

10 Specifically, what I would like to discuss

11 is I thought until I looked at all this that I knew

12 what the gold standard for saphenous vein graft

13 patency was. Eeverybody throws around numbers but

14 until I did a meta-analysis of the literature I

15 really didn\'t know, and this is specifically to

16 address the trial design question number one of the

17 FDA, the gold standard of sutured anastomoses had a

18 well-documented history of over the past thirty

19 years, and I would like to go over those thirty

20 years right now\--

21 \[Slide\]

22 \--or the why of saphenous graft failure in

23 five minutes.

24 \[Slide\]

25 Since between 1979 and 2001 there have

68

1 been thirty studies published, analyzing a total of

2 28,081 grafts.

3 \[Slide\]

4 Factors impacting the studies are

5 angiogram survivors. You lose early graft

6 occlusions resulting in death so, therefore, you

7 are automatically losing patency in any angiogram

8 series because you can only angiogram survivors.

9 Studies are impacted by the completeness of

10 follow-up, the percent of patients actually

11 undergoing angiograms, and whether the study was

12 done as a surveillance study or done for cause.

13 \[Slide\]

14 If we look at a meta-analysis of all

15 studies that looked at 30 days or less, there has

16 been a total of 11,000 grafts looked at. If you

17 just skip to the number at the bottom right, the

18 patency rate at 30 days in these 7 studies,

19 comprising 11,000 grafts, is 87.8 percent.

20 \[Slide\]

21 If you now look at 3 to 6 months and look

22 at the 10 studies published here, with a total of

23 2,290 grafts, at 3 to 6 months 84 percent is the

24 saphenous vein graft patency.

25 \[Slide\]

69

1 If we now go to 12 months and look at the

2 13 studies comprising almost 12,000 grafts, the

3 patency rate is 82.7 percent in the literature.

4 \[Slide\]

5 Lastly, if we look at 2 to 5 years, with a

6 total of 3,100 grafts in these 3 studies, the

7 patency rate between 2 and 5 years is 74.3 percent.

8 \[Slide\]

9 If we summarize all this, there is a

10 significant attrition in the literature of about 12

11 percent of vein grafts in the first 30 days.

12 Between 30 days and 3-6 months another 3 percent of

13 grafts are lost at that point. If we go between

14 3-6 months to 12 months another 1.5 percent of

15 grafts are lost. Then there is a slightly greater

16 attrition from 2 to 5 years. If you look at

17 overall graft patency of all 28,000 grafts done at

18 any time, it is 84 percent.

19 \[Slide\]

20 Variables known to impact graft patency

21 include age, gender, diabetes and how well the

22 diabetes is controlled, obesity, which vessel is

23 bypassed, the LAD, the circ. or the right, the

24 target vessel size, the presence of distal disease,

25 the size of the vein graft, harvest injury, whether

70

1 an endarterectomy was done, what the graft flow at

2 time of implant was, individual versus sequential

3 vein grafts, how much myocardium was supplied, what

4 the ventricular function of the patient was,

5 whether lipid management was tightly controlled,

6 whether antiplatelets were used, surgeon

7 experience.

8 \[Slide\]

9 Variables that are not known how they

10 impact on graft patency has been alluded to.

11 Whether it is done on a beating heart or an

12 arrested heart. That recently has been called into

13 question. And whether anastomotic connectors

14 impact positively or negatively on the saphenous

15 vein graft patency.

16 \[Slide\]

17 I think how you design your study you can

18 get 100 percent patency at ten years if you do an

19 LAD, do it as a sequential and a three millimeter

20 target with no distal disease, use a small vein,

21 have a large run-off in a thin male that does not

22 have insulin-dependent diabetes and normal ejection

23 fraction, does not have a hypercoagulable state, is

24 on antiplatelet agents and is well controlled with

25 statins. On the other hand, you can do the

71

1 converse of all those and you will end up with a 10

2 percent patency rate in less than 30 days.

3 \[Slide\]

4 In conclusion, I think that many variables

5 other than anastomotic connectors impact graft

6 patency. Angiography is the only reliable method

7 to determine patency. Meta-analysis reveals an

8 overall saphenous vein graft patency of 80-85

9 percent. There is no significant difference from

10 3-6 months versus 12-16 months or, for that matter,

11 even between 30 days and the latter two endpoints.

12 An angiographically normal graft at the earlier

13 study times is often likely to develop occlusion on

14 later follow-up and, in my opinion, a 6-month

15 angiographic endpoint is adequate to evaluate graft

16 patency with anastomotic devices.

17 Real quickly regarding our experience, it

18 has been published on the St. Jude device. We did

19 find that there were events that happened after six

20 months. These were clinical events. The study

21 that we performed was very similar to Dr.

22 Schoettle\'s. We took a one-year experience with

23 the St. Jude device and compared it to one-year

24 previously with a similar cohort of patients and

25 found that there was a higher incidence of clinical

72

1 events in the St. Jude patients. However, these

2 were all limited to diabetics. We looked at the

3 non-diabetic population and we looked at all

4 possible variable by logistic regression diabetes

5 was the only thing that sorted out. The

6 confounding variable in all this is that all these

7 procedures were also done on a beating heart.

8 Thank you.

9 DR. TRACY: Thank you. Panel, you have 4

10 minutes and 36 seconds to ask questions. Any

11 questions? Dr. Weinberger?

12 DR. WEINBERGER: In surgical literature

13 everyone seems to focus on patency. Are you

14 interested at all in morphology, like quantitative

15 angiography looking at 30 percent stenosis, 40

16 percent stenosis? Is that information valid to

17 surgeons?

18 DR. MACK: Absolutely. Because I do think

19 that that is a precursor of potential total

20 occlusion.

21 DR. WEINBERGER: And if that is the case,

22 are your angiographic colleagues who have looked at

23 these connectors able to assess the morphology

24 right around the metallic connector adequately?

25 DR. MACK: I think the answer is yes.

73

1 DR. KRUCOFF: Not being as familiar with

2 the surgical literature, in this list you sort of

3 ended with do you think there is sufficient data to

4 create a real propensity score in planning a trial?

5 DR. MACK: Yes.

6 DR. KRUCOFF: To actually create risk

7 categories that could be sufficiently evaluated in

8 new populations?

9 DR. MACK: Yes, I do. I think that

10 everything I listed there\--one study or another has

11 listed those factors implicating graft patency and,

12 yes, I think you can develop a propensity score.

13 DR. TRACY: Dr. Edmunds?

14 DR. EDMUNDS: Mike, you said that all of

15 these were off-pump bypasses.

16 DR. MACK: In our St. Jude experience,

17 yes.

18 DR. EDMUNDS: Were they mostly right

19 grafts?

20 DR. MACK: First of all, we did not have

21 any connectors placed to the LAD so they all went

22 to diagonal circumflexes or right, and which vessel

23 it went to, in our experience, did not sort out as

24 a factor.

25 DR. EDMUNDS: But non-LAD?

74

1 DR. MACK: All non-LADs.

2 DR. EDMUNDS: And these were surveillance

3 angiograms, not for symptoms?

4 DR. MACK: No, the surveillance was

5 clinical events only. The only angiograms\--

6 DR. EDMUNDS: So, you have bias towards

7 symptomatic patients.

8 DR. MACK: The endpoint was not

9 angiography. The endpoint of our study was

10 clinical events, major adverse events at now two

11 years of follow-up. We did not do a specific study

12 angiogramming the patients. The only angiograms we

13 had was in patients that were done for cause.

14 DR. EDMUNDS: The 28,000 patients were

15 from 30 studies, weren\'t they?

16 DR MACK: Okay, I am mixing up your

17 question then. Ask again, Hank.

18 DR. EDMUNDS: Well, the cohort of 28,081

19 angiograms was from 30 papers\--

20 DR MACK: Right.

21 DR. EDMUNDS: \--and were those

22 surveillance angiograms or for symptoms?

23 DR. MACK: I am sorry, I thought you were

24 talking about our own experience with the

25 connectors.

75

1 DR. EDMUNDS: No, I am sorry, Mike.

2 DR. EDMUNDS: No, all of those were

3 surveillance. Any that was done for cause and I

4 did not include in that. All those were

5 surveillance studies. Similarly, there were a

6 couple of other studies that looked at just

7 saphenous vein graft, the LAD, I did not include

8 those because those were abnormally high.

9 DR. TRACY: Dr. Bridges, did you have a

10 question?

11 DR. BRIDGES: My question really is that

12 given that in the results you presented recently

13 there was a difference in major adverse

14 cardiovascular events, I guess in the manuscript

15 that I have seen a draft of it was limited to

16 diabetic patients. However, those were non-insulin

17 dependent diabetics, I believe, and I was wondering

18 if you had a hypothesis as to why non-insulin

19 dependent diabetics would be different than insulin

20 dependent diabetics. Given that, should we be then

21 separating diabetics from everyone else in terms of

22 determining the applicability of these devices?

23 DR. MACK: That is an excellent question,

24 and we were a little bit surprised to find that

25 that was the case also because from the stent

76

1 experience you would expect it would be more so in

2 insulin dependent diabetics but such was not the

3 case. We have hypothesized that perhaps it was due

4 to the fact that with non-insulin dependent

5 diabetic oral agents the blood sugar is not as

6 tightly controlled, but we have no proof; it is

7 total hypothesis.

8 I also think that the way that we look at

9 diabetes now, today, is totally blurring the line

10 between insulin dependence and non-insulin

11 dependent diabetics. I think we have a lot of

12 metabolic syndrome patients who are actually Type 2

13 diabetics but are insulin dependent and we are

14 actually categorizing them as insulin dependent

15 when, in fact, they really should not be.

16 DR. TRACY: Thank you. Dr. Slaughter?

17 DR. SLAUGHTER: Thank you. I was asked to

18 speak today on behalf of Converge, and I am a U.S.

19 investigator for their ongoing trial for distal

20 anastomotic studies and they did pay my travel here

21 but I have no other financial relationship with

22 them.

23 \[Slide\]

24 To date so far we have heard predominantly

25 about proximal anastomotic devices and what I would

77

1 like to do is to tell you a little bit about a

2 current and ongoing look at distal anastomotic

3 devices.

4 \[Slide\]

5 Certainly, this comes up in many issues

6 and I don\'t think we need to belabor the fact but

7 perhaps at the end I will comment briefly on some

8 of the other questions asked, but there is still no

9 question, and it is really sort of one of the

10 unspoken issues for any outcome for the patient,

11 and that is, you know, the quality of anastomosis

12 and the overall revascularization and long-term

13 patency. Certainly surgeon skill is very

14 important. There are also the other issues of the

15 anatomy, disease state, access and visibility that

16 would affect these things. But all these things

17 are very important in determining not only acute

18 but long-term graft patency and the overall outcome

19 for the patient.

20 \[Slide\]

21 This has been brought up now several times

22 and I think is very important. This is just

23 another way of presenting it. It is looking at

24 sort of the time scale injury. That is, as was

25 brought up by Dr. Weinberger as well, there is no

78

1 question that there is good information and good

2 data as to the initiation of the injury,

3 inflammation and then subsequently intimal

4 hyperplasia. As a rule of thumb, the idea is that

5 within, say, six to eight weeks the injury has

6 stopped. I don\'t think anybody in their right mind

7 would argue that there is not heterogeneity and

8 certainly there are differences within patients.

9 Certainly that would show up as stenosis and

10 changes in morphology, as you mentioned.

11 But the idea is there is reasonably good

12 science and information to suggest that within

13 about 60 days a vascular anastomosis has healed,

14 particularly within the coronary-arterial tree.

15 So, beyond that time, if there are graft failures,

16 the question is what are they due to, and it is

17 generally due to ongoing atherosclerosis, intrinsic

18 patient factors and/or perhaps a lack of medical

19 therapy such as antiplatelet agents, aspirin and/or

20 Plavix.

21 So, you know, if hand-sewn anastomosis is

22 so perfect, why are we here today? The issue is

23 they are not perfect and there certainly is room

24 for improvement. Certainly, by hand sewing in a

25 bad distal vessel it is calcified in a diabetic.

79

1 They have lateral calcification. By piercing them

2 with needles\--we all had that experience, you end

3 up with plaque rupture. You have hemorrhage within

4 the media. The idea is this is a traumatic event.

5 \[Slide\]

6 The other is reliability. The issue is

7 how can you do it day to day, 20,000 a year. The

8 idea is you want to make it as reliable as

9 possible and it needs to be reproducible between

10 different surgeons at different institutions.

11 The other is it must be reversible. The

12 idea is if you don\'t like it you have to cut the

13 suture, take it out and redo it. You want to be

14 able to do the same thing, perhaps in a less

15 traumatic fashion, with a coupler device.

16 The other is it must be easy to use. The

17 idea is if anybody walks up to the podium and is

18 giving you a talk, they basically should all be

19 able to have the same results without any

20 significant extensive training.

21 The other is I think we do need to realize

22 there are differences between proximals and

23 distals. I don\'t think we need to spend a lot of

24 time on this today but the main two differences are

25 the flow dynamics which clearly are different at

80

1 the proximal and distal ends, as well as tissue

2 characteristics. On the tissue characteristics, on

3 the right it is either going to the aorta or vein

4 aorta or artery depending on which you conduit you

5 use. Certainly for distal anastomoses what you are

6 looking at is vein to coronary artery or an

7 arterial conduit to an artery but it is a very

8 different scenario.

9 Also, with flow dynamics there is no

10 question that the size or the shape of the opening

11 or the angle of the take-off is very important, the

12 pressure differential, as well as the vessel

13 diameter throughout the length.

14 \[Slide\]

15 I think one other issue which hasn\'t been

16 brought up today which does need to be mentioned,

17 at least just to bring it up, is actually the type

18 of material. I think this sort of goes into the

19 heterogeneity or perhaps ongoing injury to intimal

20 hyperplasia. These are not new materials. They

21 have all been used before. They have all been used

22 in intravascular scenarios and the idea is there is

23 good evidence to suggest, whether it is nitinol,

24 stainless steel, titanium, that they are

25 compatible, and I don\'t think that we can sort of

81

1 imply or say that they are intrinsically the source

2 of perhaps later stenoses or some ongoing failures

3 beyond the eight-week time period. Certainly there

4 is the heterogeneity of healing in some patients

5 but it is a relatively small number. It is like a

6 cheloid. Some patients get cheloids but not all.

7 The answer is you see it as it progresses. If you

8 follow them and you look for it you can identify

9 who those patients are.

10 \[Slide\]

11 I would like to just show you a histologic

12 series which I think is interesting in helps people

13 visualize. Really the sort of best description I

14 think for the Converge distal anastomotic device is

15 that of sort of a compression clip. The idea is it

16 is two frames which are expandable. In the upper

17 right it sort of gives you the diagrammatic picture

18 of a graft into the artery. The important thing

19 here is that you now are able to mechanically

20 manipulate flow dynamics as well as other

21 engineering aspects so you get a perfect 30 degree

22 take-off; you get perfect dynamics. You won\'t get

23 turbulence at the site of the anastomosis.

24 The left side shows the bypass graft,

25 which is CABG going down to the circumflex artery.

82

1 I think the important thing here is this was done

2 at 90 days but, once again, the idea is it is

3 completely endothelialized so the idea is if you

4 get an angiogram at six months and you have a

5 normal lumen you have no narrowing. The idea is

6 are you going to have ongoing intimal hyperplasia

7 that would be an unexpected finding? I think the

8 answer is no.

9 DR. TRACY: If you could finish up in the

10 next few sentences.

11 DR. SLAUGHTER: Sure, I can finish up in

12 about 30 seconds.

13 \[Slide\]

14 The idea is you see very clearly that it

15 is a well healed anastomosis and you have the

16 advantages.

17 \[Slide\]

18 This has already been brought up. The

19 idea is are historical controls acceptable? I

20 think the answer is yes.

21 \[Slide\]

22 There is no question there is lots of

23 existing data. We have also lots of information to

24 suggest not only at seven days but at years out

25 that you can evaluate intimal hyperplasia.

83

1 \[Slide\]

2 Certainly angiography\--we know the causes

3 of failure, early failure and what we need to do is

4 differentiate between a device failure and ongoing

5 atherosclerosis.

6 \[Slide\]

7 I will just show\--

8 DR. TRACY: I am sorry, we are just going

9 to have to cut this off if we are going to have

10 time for questions from the panel.

11 DR. SLAUGHTER: I apologize.

12 DR. TRACY: We have three minutes left for

13 questions from the panel. Anybody? Dr. Hirshfeld?

14 DR. HIRSHFELD: I would just point out

15 that in the coronary stent experience if we used a

16 two-month follow-up we never would have discovered

17 restenosis.

18 DR. TRACY: Dr. Krucoff, did you have a

19 comment?

20 DR. KRUCOFF: I would just also say that

21 in the stent experience I think if we started with

22 historical controls based on lung literature, we

23 would have left a lot of important information out.

24 DR. SLAUGHTER: I think the one difference

25 though, and this has come up I think in other

84

1 discussions with the FDA panel, is that although it

2 uses a similar material and it is stent-like, it is

3 not a stent. The idea is it is just the edges that

4 are present along the edges of the coronary artery.

5 It is not compressed plaque and the idea is it is

6 very different. It is really sort of a compression

7 clip that applies the vein graft to the distal

8 coronary artery.

9 DR. TRACY: Dr. White?

10 DR. WHITE: I think there is no evidence

11 for that, and I think everything that we have heard

12 today sounds like it is a stent, although a stent

13 in a graft. So, the question would be if you don\'t

14 believe it is a stent, then you should show us data

15 that suggested that intimal hyperplasia within the

16 tube is not the primary cause of these closures.

17 DR. SLAUGHTER: Sure.

18 DR. YANCY: And because of that, I think

19 it is even more important to state that historical

20 controls would be really problematic I think.

21 DR. TRACY: Any other comments from the

22 panel?

23 \[No response\]

24 Thank you. Is Mr. Lotti here?

25 \[No response\]

85

1 We will move on then to Dr. Martin.

2 DR. MARTIN: Good morning. As so many

3 members of the panel have already suggested,

4 including Dr. White, I can make my comments brief.

5 My name is Dr. Frank Martin. I am Chairman of the

6 Department of Cardiology at Methodist Care in

7 Memphis, one of the largest private hospitals in

8 the country. I have no financial ties with any

9 anastomotic device companies or, for that matter,

10 any stent companies.

11 My historical experience, I trained with

12 John Simpson back in 1985, \'86, and have

13 relationships with many of the members of this

14 panel. I trained with people who are icons today,

15 like Paul Yak, Paul Tierstien, Dean Keriakus, Met

16 Selman, Morris Bookbinder, Rock Califf, Eric Topal

17 and did interventional cardiology until

18 approximately four years ago and made a life style

19 change, and now I do only diagnostic caths and do

20 my chairmanship. Also as discussed earlier, in the

21 late 1980s, with Dr. Chris White, we did brachy

22 therapy because some of the early DCA slides showed

23 needle intimal hyperproliferation similar to

24 cancer.

25 That having been said, I, as many of you

86

1 all, have honed this sixth sense of skill with

2 cardiology over the last 15 years of practice. Dr.

3 Phil Schoettle, who has already presented here

4 today, and I have worked collaboratively for the

5 last 20 years. We basically make a good team

6 because he knows what I do and I know what he does.

7 Our group opened one of the first

8 outpatient cardiac cath labs and it was a labor of

9 trust on his part. Both of us have a sixth sense

10 about when patient is dissected and needs to go to

11 surgery urgently, and have always had that sort of

12 feel. Obviously, in the early days of intervention

13 with PRCA lots of patients went to CABG and, of

14 course, more and more patients went to CABG at that

15 time than do now.

16 So, imagine my chagrin in September of

17 2002 when I cath\'d an ER nurse friend of mine and

18 found one occluded and two stented Symmetry aortic

19 connectors, the first patient I had ever seen.

20 When Dr. Schoettle referred to September, 2002 that

21 was the watershed moment. I walked out of that

22 cath, called him and said, Dr. Schoettle, I don\'t

23 know what this device is but it is a stent and it

24 will act like a stent and it will always be a

25 stent. I said, what is it? What do we know about

87

1 it? And, he basically told me his experience over

2 the last ten months.

3 At that point I found an interventional

4 colleague of mine and said, what are these devices?

5 He said he had been stenting them since April; he

6 didn\'t know much about them. I did an Internet

7 search and found out they were made in nitinol, and

8 realized at that point in time that no

9 cardiologists were involved in either the research,

10 the design, the implementation or the roll-out of

11 this device basically because all the

12 cardiologists, interventional cardiologists,

13 especially know the problems associated with that.

14 It took me about 45 days, almost two

15 months, with multiple interventional colleagues of

16 mine and surgeons in Memphis to have it withdrawn

17 from all the shelves of all three hospitals in

18 Memphis, Tennessee, and that was in the latter part

19 of fall of 2002.

20 As patients have returned to the clinic,

21 dozens, and dozens, and dozens have been found to

22 have virtually total and/or subtotal occlusions of

23 these devices. The first contact I had with St.

24 Jude was in December, 2002 after I had gone to TCT,

25 in September I believe, and HA in November, telling

88

1 them about the problem with these devices and why

2 they acted like stents. Finally, they walked in on

3 me while I was cath\'ing a 70 year-old ob/gyn who

4 had two patently occluded Symmetry aortic

5 connectors. Basically, I said this is the problem.

6 You don\'t understand anginal syndrome because most

7 of these patients won\'t come back with chest pain

8 for multiple reasons\--denervation of the heart;

9 more LV dysfunction problem. You don\'t understand

10 the role of clopidogrel or Plavix in these patients

11 because most of them go to surgery without Plavix

12 on board, and you don\'t understand the fact that in

13 stent pathology, which we obviously cath a lot, you

14 can have one patent graft, for instance the LIMA

15 which most of these patients get, and the other two

16 can subtotally occlude slowly and their only

17 symptom is LV dysfunction.

18 We, as cardiologists, as members of this

19 panel, diagnose ischemia. We send these patients

20 to a surgeon for treatment and continue to reattach

21 and stent these folks. They will come back for

22 years with their LIMAs. An anecdotal experience of

23 one surgeon in Jonesboro, Arkansas, close by

24 Memphis, asked two of the cardiologists in his

25 community, \"so what\'s up with this Symmetry aortic

89

1 connector?\" And the cardiologists response was,

2 \"are you having any problems?\" And he said, \"well,

3 I don\'t know.\" And they said, \"well, don\'t worry

4 about it.\"

5 He wasn\'t satisfied with that, came to

6 Memphis, we cath\'d him and his two connectors were

7 occluded and his lumen was patent. After

8 intervention he told me that as an oral surgeon he

9 uses nitinol every day to induce scar tissue

10 formation and keep bridge reconstruction in place.

11 The fact that you auger a hole in the aorta, hold a

12 finger over it beginning the platelet clotting

13 cascade, implant a metallic device with hooks

14 without the benefit of loading doses of Plavix or

15 predictable absorption is inconceivable.

16 The idea of a connector makes sense for

17 improvement of stroke risk, however, I feel the

18 present device should be withdrawn and should have

19 been withdrawn years ago. Basically, I think the

20 cardiologists need to be involved in any future

21 trials or designs and I think to do otherwise is a

22 violation of our sacred oath to our patients.

23 Thank you.

24 DR. TRACY: Thank you. Any questions from

25 the panel? Comments?

90

1 \[No response\]

2 Thank you. Dr. Hausen?

3 DR. HAUSEN: By way of introduction, my

4 name is Bernard Hausen. I am the present CEO of

5 Cardica. My background, I am a cardiac surgeon by

6 training. My financial conflicts are inherent with

7 my position, otherwise I have none other.

8 \[Slide\]

9 I want to use this opportunity to show you

10 new generation of products that we are developing

11 beyond the pioneers in this field that we have been

12 discussing so far.

13 \[Slide\]

14 We have two products in the pipeline. One

15 is a distal anastomosis system.

16 \[Slide\]

17 It is called C-Port and it is based on the

18 principle of simulating interrupted stitch distal

19 anastomosis by applying a set of eight implantable

20 clips, all simultaneously, and performing

21 arteriotomy with the push of one button. This type

22 of a system results in a minimal amount of metal

23 exposure. It is a applied in distal anastomosis

24 and it is in clinical evaluation as we speak.

25 \[Slide\]

91

1 This is just a video showing how it works.

2 This is a 1.5 mm LAD. You insert the anvil; pull

3 it out and you are basically done; place one stitch

4 to close the anvil insertion hole. This is a 1 mm

5 diagonal cadaver heart and shows how it works.

6 This technology, we believe, will enable

7 beating heart surgery as it is quick and does not

8 require any temporary ischemia of the myocardium

9 during placement.

10 \[Slide\]

11 We have a second device which is called

12 PAS-Port. It stands for proximal anastomosis

13 system, and it is a second generation proximal

14 system. We have the advantage of being a company

15 that is going to be able to take advantage of the

16 knowledge from the predecessors, predicate devices.

17 \[Slide\]

18 So we were able in our design to spend a

19 lot of time on key improvements from things we have

20 learned from the other devices. We have focused on

21 trying to minimize or completely eliminate

22 endothelial trauma of the graft during loading. We

23 wanted to minimize blood-exposed non-endothelial

24 tissue, i.e., metal exposure. We wanted to

25 maximize the orifice area and reduce the incidence

92

1 of kinking by a low profile.

2 \[Slide\]

3 We did that by basically having nothing

4 touch the endothelium of the vein during loading or

5 deployment. This is a cross-section of the

6 implant.

7 \[Slide\]

8 We have a minimal amount of metal exposed

9 with the stainless steel device. It is the same

10 material as is being used for coronary stents. And

11 we wanted to maximize the orifice, especially for

12 small vein grafts, and have a very low profile

13 height.

14 \[Slide\]

15 For all this we have done a clinical

16 trial. We have had a lab cardiologist review our

17 data by QCA and determine what is the amount of

18 narrowing of the implant versus the graft body.

19 They first looked at some hand-sewns that were done

20 concurrently in those patients and, as you can see,

21 the average narrowing of a hand-sewn is about 5

22 percent at discharge and about 18 percent at 6

23 months. This is in agreement with all the

24 published literature.

25 \[Slide\]

93

1 Then we asked them to look at the PAS-Port

2 data. What you find, and you can hardly see this,

3 this is a minus 7 percent narrowing, i.e., the

4 grafts at the anastomosis are larger than they are

5 in the graft body and that is by design. That is

6 how the implant has been designed.

7 Now at 6 months, the most important

8 figure, the average narrowing is 3 percent compared

9 to 18 percent in hand-sewns. I propose that if a

10 device had a problem at discharge or at 6 months

11 you would be seeing that in this quantitative

12 analysis. If you don\'t see it because the

13 injurious event was at the time of surgery, you are

14 very unlikely to see it going forward besides the

15 normal decay of a vein graft, as alluded to by the

16 previous speakers.

17 \[Slide\]

18 So, Cardica\'s regulatory position is we

19 are applying for 510(k) clearance based on

20 prospective multicenter non-randomized trials, and

21 our primary study endpoint for this distal device

22 is vessel patency at discharge and 6 months, and

23 for the proximal device performing a vessel patency

24 study at 6 months with QCA. Thank you very much

25 for your attention.

94

1 DR. TRACY: Thank you. Any questions?

2 Dr. White?

3 DR. WHITE: I just noticed that on the

4 last slide you said you were going to do MRI

5 follow-up on these metal grafts. How are you going

6 to do that?

7 DR. HAUSEN: We have done that on the

8 proximal anastomotic device. Basically, with the

9 gadolinium contrast injection you can see\--the only

10 thing CTs and MRIs allow you to do is determine is

11 the graft patent or not. You cannot evaluate the

12 degree of stenosis at the implant. So, a preferred

13 method is a quantitative angiography.

14 DR. WHITE: Do you have experience with

15 MRI?

16 DR. HAUSEN: We have done five MRIs in the

17 patients in this study.

18 DR. WHITE: And also CT?

19 DR. HAUSEN: And CT too and MDCT.

20 DR. WHITE: And there is no difference in

21 your hands?

22 DR. WHITE: I like the MDCT much better.

23 I think the image is much clearer. The 3-D

24 reconstructions are very impressive.

25 DR. AZIZ: And how does that correlate

95

1 with angiograms?

2 DR. HAUSEN: It depends on what your

3 outcome variable is. If you want to just know if

4 the graft is patent or not, there is a very, very

5 good correlation. That has been shown in the

6 literature. If you need more than that, if you

7 need to know is there a degree of narrowing, that

8 will not suffice.

9 DR. AZIZ: If you do distal anastomosis if

10 you have bleeding, how can you control that? Can

11 you put a regular stitch over that?

12 DR. HAUSEN: Yes, you can. It is the same

13 as a steel device. It is very firm. The pull-out

14 force of this device is very high because stainless

15 steel is three times stiffer than nitinol. So,

16 what you do, you just place the first string around

17 the anastomosis and slowly tighten it. That brings

18 the aorta closer to the implant\--

19 DR. AZIZ: If you do distal anastomosis if

20 you have bleeding, can you do regular stitches?

21 DR. HAUSEN: Yes.

22 DR. AZIZ: You have obviously shown a vein

23 graft. If you had an arterial graft can you use

24 your same distal anastomotic site for that?

25 DR. HAUSEN: This generation of device,

96

1 no; the next generation, yes.

2 DR. TRACY: Dr. Bridges?

3 DR. BRIDGES: You showed differences in

4 percent stenosis of the proximal anastomoses at

5 discharge and at 6 months.

6 DR. HAUSEN: Yes.

7 DR. BRIDGES: What about occlusion or

8 patency at the same time points?

9 DR. HAUSEN: We have 87.9 percent patency

10 rate so we had 6 occlusions in 50 implants, which

11 is 100 percent in agreement with the historical

12 data from the meta-analysis you saw and we did too.

13 DR. BRIDGES: So, how would you interpret

14 the fact that in spite of having a higher orifice

15 area or diameter you have the same patency at the

16 6-month time point?

17 DR. HAUSEN: That is wonderful proof that

18 it has nothing to do with the connector. It is

19 probably your distal run-off or any of the other

20 200 factors that Dr. Mack said.

21 DR. AZIZ: If you had a very thick

22 proximal ascending aorta\--

23 DR. HAUSEN: Yes?

24 DR. AZIZ: \--sometimes you do a hand-sewn

25 vein graft that dunks in and obviously you don\'t

97

1 want that.

2 DR. HAUSEN: Yes.

3 DR. AZIZ: Does your anastomosis

4 technique\--where would that fit in? Would the vein

5 also dunk in?

6 DR HAUSEN: It is inverted over the

7 implant so it is in the lumen but, because it is a

8 stainless steel implant, it props the anastomosis

9 open and you will not have lumen reduction, if that

10 is where you are heading towards. And we have

11 shown that, minus 7 percent widening of the

12 anastomosis is evidence that that is exactly what

13 the implant does and it accommodates the varying

14 thickness of the aortic wall because it is like a

15 paper clip. It can adjust to varying thicknesses.

16 DR. AZIZ: And the angle at which it comes

17 off proximally, is that oblique or head-on?

18 DR. HAUSEN: It is theoretically 90

19 degrees. We asked our core lab to evaluate that

20 too. There are hardly any at 90 degrees. They

21 vary from 10-70 degree take-offs. Because the

22 hinge point is so small, only 1.5 mm, the vein can

23 come off almost at any angle it wants to.

24 DR. AZIZ: So, could you take the proximal

25 along through the transverse sinus and pull it

98

1 through?

2 DR. HAUSEN: You could, yes.

3 DR. AZIZ: You could?

4 DR. HAUSEN: Yes.

5 DR. EDMUNDS: What is the size of the shoe

6 inside the vessel?

7 DR. HAUSEN: The shoe inside the vessel?

8 DR. EDMUNDS: Against which you are

9 putting the clamps down. The part of the device

10 that goes inside the vessel, what are the

11 dimensions of that shoe of the device?

12 DR. HAUSEN: There is really nothing

13 inside the vessel. The vein is pulled through the

14 implant and inverted so there is no metal inside,

15 except for the prongs that penetrated the vein and

16 then go outward. I would be more than happy to sit

17 down afterwards and show you maybe some work. I am

18 kind of limited by the time here.

19 DR. AZIZ: Can you do a sequential of this

20 for the distal anastomosis?

21 DR. HAUSEN: No. Well, you could if you

22 did your side by side by hand, absolutely.

23 DR. TRACY: Thank you very much. Prof.

24 Klima?

25 PROF. KLIMA: Ladies and gentlemen,

99

1 members of the panel, my name is Uwe Klima.

2 \[Slide\]

3 I am a full professor at Hanover Medical

4 School for Cardiac Surgery. The financial

5 disclosure I have to make is that Ventrica paid for

6 my trip here and my lodging, and Ventrica provided

7 us with an unrestricted grant for preclinical

8 testing of an anastomotic device three years ago.

9 \[Slide\]

10 I expected a talking time of ten minutes

11 and I will try to cut that down to five minutes.

12 Basically, what I want to talk about is mechanisms

13 of how wound healing takes place after an

14 anastomosis; give you some of our clinical

15 experience with hand-sewn anastomosis, especially

16 with our MIDCAB series; more update or experience

17 with our anastomotic devices; and I will have a

18 little discussion of appropriate methods and

19 follow-up time frames for CABG surgery.

20 \[Slide\]

21 As background, we all know that hand-sewn

22 anastomoses now are more or less on the market for

23 more than four decades. Everything is pretty much

24 well tested and evaluated. We have a pretty clear

25 understanding of what happens to an anastomosis.

100

1 What happens is a healing response\--at what time

2 frame this will be stable. So, I will go into

3 details with my next slide.

4 \[Slide\]

5 There are several publications out now

6 which tell us exactly what happens after an

7 anastomosis has been performed. We know there is a

8 lot of trauma coming after surgery. Cell

9 proliferation is coming out. And the most

10 important message that comes out of this

11 publication, for example, is that the repair

12 process is about to be completed two months after

13 surgery.

14 \[Slide\]

15 We wanted to know what is happening with

16 anastomotic devices. Is it the same response? Can

17 we expect the same thing to happen? Filsoufi

18 published, from Boston. He tested the Ventrica

19 device and what is happening after implantation two

20 months, three months and six months after surgery,

21 and we could see that there is a single layer of

22 endothelium covering after two months, three months

23 and after six months and there was no sign of any

24 inflammatory response at the site of the

25 anastomosis.

101

1 \[Slide\]

2 As a control group\--I would like to speak

3 a little bit about our MIDCAB experience in

4 Hanover. We have now enrolled more than 700

5 patients. Out of the first 500 patients we did

6 angiographic follow-up in 6-7 percent of these

7 patients. The first group, which was the big one

8 with 297 patients, had a pre-discharge angiogram.

9 What was pretty interesting was that in about 6

10 percent of these patients we had a highly

11 significant problem at the site of the anastomosis,

12 as you can see here. As a Swedish colleague

13 presented his data with the same problem four years

14 ago at the ASCTS and recommended just to wait

15 because this is part of the healing response, we

16 changed our politics, which you will see on the

17 next slide, and just let the whole situation be as

18 it was; waited for 3-6 months, reevaluated these

19 patients and saw that the degree of stenosis or the

20 number of intimal hyperplasia went down without any

21 intervention from 6 percent to 1 percent.

22 \[Slide\]

23 There is another example here and, as you

24 can see again, there is a highly significant

25 stenosis here at the pre-discharge angiogram;

102

1 perfect anastomosis 3-6 months later when we

2 reevaluated the patients. What we learned here is

3 that the healing response is still evolving in the

4 earlier time frame. We changed our angiographic

5 follow-up from pre-discharge to a 6-month follow-up

6 so the remaining 203 patients were evaluated 6

7 months after surgery instead of having a

8 pre-discharge angiographic follow-up.

9 \[Slide\]

10 So, what is the Hanover experience now

11 with anastomotic devices? Just to give you a quick

12 overview, Hanover does approximately 2,000 open

13 heart procedures per year. It is a large teaching

14 institution. We are affiliated with several

15 research centers so we are exposed to new

16 technologies and clinical trials. The studies I

17 have performed were with Ventrica, St. Jude and

18 Converge. In addition, I have a little experience

19 also with Cardica and Coalescent, however, I just

20 want to present you the data where I have

21 angiographic follow-up.

22 \[Slide\]

23 St. Jude\--we had a prospective, randomized

24 trial with 11 patients where every patient received

25 two proximal anastomoses. One was hand-sewn and

103

1 the other one was an automatic anastomosis. This

2 is the strongest study design that you can create.

3 The data that we saw was that in 11 patients who

4 were enrolled in the study and came back after 6

5 months and there were 10 postoperative angiograms

6 showing that only 3 grafts were patent. We had 6

7 occlusions and 1 highly significant stenosis at the

8 site of the anastomosis, with a consequent PTCA and

9 stent after graft. Even though the patients were

10 asymptomatic, the study was stopped because the

11 data did not look the way we wanted to have it.

12 \[Slide\]

13 Even though all patients were

14 asymptomatic, due to several reasons that we can

15 discuss, I think independent of the cause a

16 prospective six-month angiographic evaluation was

17 sufficient in our study to detect performance

18 issues of the device.

19 \[Slide\]

20 Ventrica was part of a multicenter trial

21 that we did with two other centers. We enrolled

22 100 patients, 48 came from Hanover\--

23 DR. TRACY: Can I ask you to start

24 wrapping up?

25 PROF. KLIMA: Yes. The most important

104

1 information I want to give you here is that in the

2 first 48 patients we had a pre-discharge angiogram

3 and a 6-month angiogram to study efficacy of the

4 device and performance of the anastomosis after 6

5 months.

6 \[Slide\]

7 The last study we did was with Converge.

8 It was also a multicenter trial. We had 8 weeks of

9 follow-up with good data. However, I think these

10 data just showed us something about the feasibility

11 of the device. It does not give sufficient

12 information about how good the anastomosis will be

13 at 6 months.

14 \[Slide\]

15 In conclusion, I would say that

16 prospective, multicenter trials should be used to

17 evaluate the performance of anastomotic devices.

18 Retrospective clinical endpoints are not sufficient

19 to give you any information about how good the

20 device really is. A comparison to historical

21 controls should be acceptable. Angiographic

22 follow-up is the gold standard and should be used

23 to evaluate an anastomotic device. I think, as we

24 saw from our experience, a six-month angiographic

25 follow-up is sufficient to address the performance

105

1 of an anastomotic device. Thank you.

2 DR. TRACY: Thank you. Any questions?

3 Dr. Krucoff?

4 DR. KRUCOFF: Doctor, do you feel like

5 your conclusions are equally applicable to a device

6 used for proximal anastomosis as opposed to a

7 device used for distal anastomosis?

8 PROF. KLIMA: Yes, I think so because we

9 used this kind of protocol in proximal and distal

10 anastomotic devices. I know there are different

11 mechanisms causing graft failure, anastomotic

12 failure, but the six-month follow-up is the period

13 where I think wound healing has finished and the

14 problems which can come up are really device

15 related.

16 DR. FERGUSON: I like very much the idea

17 that you used the patient as his own control. The

18 question is did you have some randomized way in

19 which it went to one vessel distally and another?

20 PROF. KLIMA: Yes. Either the patient

21 needed two distal anastomoses or four distal

22 anastomoses so that you had either a single graft

23 with a connector or not a connector or a sequential

24 graft with a connector or not a connector. We

25 preoperatively randomized which graft would be

106

1 connected with the automatic connector or would

2 have hand-sewn anastomosis.

3 DR. TRACY: Dr. Yancy?

4 DR. YANCY: Just to be clear, the limited

5 data you showed us suggested 60 percent occlusion

6 for the Symmetry device in the randomized effort

7 you did. Is that correct?

8 PROF. KLIMA: Yes, with six occlusions out

9 of ten patients after six months and patients were

10 asymptomatic.

11 DR. YANCY: So, how has that affected your

12 clinical use of the Symmetry device?

13 PROF. KLIMA: Well, after 11 patients,

14 that was the last implant of that device.

15 DR. TRACY: No other questions?

16 \[No response\]

17 Thank you. Mr. Foley?

18 MR. FOLEY: Dr. Klima gave our report.

19 DR. TRACY: Thank you. At this point,

20 those are all the people who had specifically

21 requested presentations but I would like to ask the

22 audience if there is anyone else who wishes to

23 address the panel on today\'s topic or any other

24 topic.

25 \[No response\]

107

1 We will then close the open public hearing

2 and we will take a five-minute break.

3 \[Brief recess\]

4 Open Public Discussion

5 DR. TRACY: We will try to start the open

6 committee discussion at this point. We would

7 appreciate it if people who were here this morning

8 speaking would remain for as much of the discussion

9 as possible. Once again, thank you for being here,

10 speakers, and please remain if it is at all

11 possible so that the committee has a chance to ask

12 you any additional questions we didn\'t get to.

13 At this point we will begin the open

14 committee discussion and I would like the panel

15 members to keep in mind the series of questions

16 that were presented to us by the FDA earlier. So,

17 we are trying to discuss things that will be

18 relative to ultimately coming up with answers to

19 these particular questions.

20 At this point, are there any opening

21 questions or comments from the committee? Dr.

22 Aziz?

23 DR. AZIZ: Obviously, when we talk about

24 patency we want to get some idea of what the

25 anastomosis is like in the OR. A number of people

108

1 are using variable Doppler flow related probes or

2 different types to give us some idea. Then,

3 obviously, doing angiograms a week later sometimes

4 with those ultrasonic systems you obviously can\'t

5 get an idea of the patency though you may get some

6 idea of the flow. I mean, ideally, I think

7 obviously one would want to know what the

8 anastomosis looks like at the time you complete it.

9 I believe there are some techniques afoot now that

10 allow you to angiographically evaluate what the

11 anastomosis looks like. Do you any of you know the

12 device I am talking about? Are you guys aware of

13 that? Because I think that is what should be used.

14 DR. TRACY: If you are going to make any

15 comments, just come forward to the podium and

16 please identify yourselves.

17 DR. WOLFE: There is an editorial\--

18 DR. TRACY: Sir, please state your name.

19 DR. WOLFE: My name is Randall Wolfe. I

20 am a cardiothoracic surgeon at the University of

21 Cincinnati. There is published, in The Journal of

22 Thoracic and Cardiovascular Surgery, about two

23 years ago, an article on acute assessment for

24 intraoperative assessment of coronary grafts. I

25 was the author of that editorial. It outlines the

109

1 different techniques.

2 The newest technique, which may be the

3 best, is a 13 MHz probe that can be placed directly

4 over the distal anastomosis and gives data both on

5 the flow and the anatomic construction of the

6 graft.

7 DR. AZIZ: Because, I mean if there is any

8 problem that is intraoperative, then that could be

9 fixed there.

10 DR. WOLFE: That is the idea of the

11 editorial, to ask surgeons to please do

12 intraoperative assessment so we can remove all the

13 technical errors.

14 DR. AZIZ: I mean doing an angiogram a

15 week postop to identify the problem makes it really

16 in a sense difficult to fix at that point. So, in

17 our discussions I think we should really be aware

18 of some of the newer things that are coming down

19 the pike that would allow us to detect and correct

20 it, if at all possible, rather than waiting for a

21 week later.

22 DR. WOLFE: I would be happy to get that

23 to you if you wish.

24 DR. EDMUNDS: Randy, if you are going to

25 use ultrasound won\'t the clips or the metal

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1 confound the signal?

2 DR. WOLFE: Actually, the answer is no.

3 The qualification is there is some degradation of

4 the signal if you have a complete ring but in

5 general you can see quite well. Now, with

6 angiography sometimes there can be a little bit

7 with a ring right at the anastomosis but with the

8 ultrasound you can see the anastomosis.

9 DR. EDMUNDS: Well, I know that when it is

10 hand sutured. We have a paper in the Annals for

11 that. But I thought that any time you have some

12 metal, you know, like looking at a valve, you get

13 reflections.

14 DR. WHITE: We look at stents all the time

15 with IVIS and I think the amount of degradation can

16 be handled. I mean, you can see the lumen pretty

17 well.

18 DR. AZIZ: I think the other thing, you

19 know, some of these, let\'s say, graft failures

20 clearly are related to the site of the anastomosis

21 but I think rheology also obviously plays a role in

22 terms of your competitive flow in the vessel. If

23 you are doing an LAD and the LAD is not that

24 stenotic or appears stenotic, I mean that could be

25 a contributing factor. Do some of these ultrasound

111

1 devices help you detect if you have competitive

2 flow?

3 DR. WOLFE: Yes, the 13 MHz probe

4 information was published. I can also provide the

5 panel with that information if you would like

6 because it gives you physiologic data as well as

7 anatomic data.

8 DR. AZIZ: And if you detect that there is

9 competitive flow, what then?

10 DR. WOLFE: In fact, there have been some

11 studies that have shown\--actually, there was a

12 single center German study that showed that if you

13 remove the patients that have low flow at the time

14 of their bypass graft you can actually get a better

15 handle on patency because those low flow grafts do

16 have a higher incidence of occlusion in the first

17 week.

18 DR. TRACY: I think there are several

19 things if one were trying to design a trial to

20 figure out how these things work. The immediate

21 issue is can you put the thing on in the first

22 place. It seems like the issue that you are

23 addressing is assessing the acute patency issue.

24 Maybe I could ask Dr. Emery a question. It seems

25 as though there were a variety of technical things

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1 that you were describing to overcome an inherent

2 problem with the device, tacking things on, etc.

3 Is that part of the initial assessment of acute

4 patency? Do you look at something, do you know

5 something by looking, and how do you pass on that

6 type of information to another surgeon to deal with

7 this acute issue?

8 DR. EMERY: We address that in several

9 points. First of all, I think the training for the

10 use of these devices was not adequate. It went

11 from deploying three or four of these devices in a

12 pig aorta with artificial pulsations to taking it

13 to off-pump beating heart surgery which involves

14 many other considerations. Just the difference

15 between off-pump beating heart surgery and on-pump

16 beating heart surgery is a whole different mental

17 and physical attitude for the surgeon. I think my

18 other colleagues here would agree. Then you apply

19 a device that changes your operative protocols from

20 distal to proximal, for instance; different ways to

21 measure grafts and the different quality of vein

22 grafts. So, the training I think is important.

23 Then, as you discover technical issues you

24 need to carefully modify what you do to make these

25 work, and tacking of the grafts was one thing. As

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1 I mentioned, I over-measure the grafts specifically

2 because I have more fear of a short graft, which is

3 more dangerous to occlude, than a longer graft that

4 you can lay out in various patterns. The length

5 has very little relation to the total blood flow

6 through the graft. It is a very minor portion of

7 Poiseulle\'s equation for flow. So, you can have

8 your graft a centimeter too long and it can be a

9 very appropriate graft. You just have to be sure

10 it doesn\'t move, flop or kink itself because the

11 place it will kink is at the nearest fixed point,

12 which is either the distal anastomosis or, more

13 commonly, the proximal anastomosis. So, these

14 little technical issues arose over using these

15 things over time and trying to evaluate what I was

16 doing.

17 DR. TRACY: Dr. Krucoff?

18 DR. KRUCOFF: Just scanning the questions

19 the agency has posed to the committee, it seems to

20 me that we are in a technology where it might be

21 worth using stent study design from the time that

22 plain balloon angioplasty first addressed stenting

23 to current drug-eluting stent platforms and think

24 about the array of technical\--there are obviously

25 some structural elements; there are technical

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1 implantation techniques. There is a sort of acute

2 procedural outcome; there is near-term and there is

3 long-term outcome however we have gone about

4 defining that over the years. It seems to me to be

5 quite relevant to the purpose of these devices, to

6 make the surgery faster, easier, off-pump.

7 You know, I think you could design a

8 pretty clear series of targets of what are you

9 after in using these devices and then what would

10 demonstrate safety and efficacy along the way. The

11 one thing that, for instance, to me seems very

12 clear is that I do think the proximal anastomosis

13 issues are very different than the distal

14 anastomosis issues and to separate that would seem

15 to me to be a very obvious place to start.

16 Then, getting descriptors together from

17 the literature\--you know, what is it about age,

18 diabetes, the number of grafts, the diameter of the

19 graft targets the surgical community has found to

20 be predictive, published as predictive, would

21 create a propensity population. Then, depending on

22 what the objective of a give device is I think you

23 could begin to draw down on when do you want to

24 assess it; do you want to assess it; why you are

25 doing the procedure in a way that may help you do a

115

1 better procedure. Do you want to assess it in an

2 initial cohort where you do an angiogram before

3 they are out of the hospital? Do you want a larger

4 trial and get out to six months, ten months, or

5 have a discussion about the location for the

6 specific device what is the timing that makes the

7 sort of best primary endpoint.

8 I think maybe we could find that the range

9 of approaches here sort out into something very

10 similar to what we have done over the past twelve

11 years with stents.

12 DR. TRACY: Dr. White?

13 DR. WHITE: Mitch, I completely agree with

14 you. Particularly for the proximal anastomosis

15 issues we are talking about stent-like designs. As

16 an angiographer, as we have just been talking

17 about, I would also make a plea that we consider

18 non-invasive imaging for these devices and we

19 explore the limits of non-invasive imaging because

20 there is a risk of angiography. There is a finite

21 risk of angiography and if there was a way that we

22 could satisfy ourselves about the patency and about

23 the anatomy, morphology, then I would prefer any

24 non-invasive tool to do this than to actually ask

25 for routine angiography. There may not be a way to

116

1 do that. I don\'t know enough about the

2 non-invasive imaging to be conclusive but that is

3 the reason why I asked about the MR. But I think

4 we shouldn\'t just sit back and say everybody has to

5 have an angiogram at six months if we are trying to

6 do no harm. I think if there was a non-invasive

7 way to get that information I would like to promote

8 that.

9 DR. TRACY: Of course, I agree with some

10 non-invasive way to look at these things in the

11 long run. I am concerned that there are different

12 time periods. There is the acute issue where you

13 are plugging the thing in and then how you assess

14 that intraoperatively, then what are the time

15 frames and what are the correct follow-ups. I

16 think your only tool during angiography with the

17 stents is with IVIS. Is that correct?

18 DR. WHITE: There are tools. There is the

19 intracardiac echo machine that has low frequencies,

20 9 Hz and so forth, that is analogous to TEE in many

21 respects, that can be used to look nicely at the

22 ascending aorta but that is a venous invasive exam

23 which might be preferable to an arterial invasive

24 exam.

25 DR. YANCY: By the same token, you are

117

1 particularly using like a 4 tesla magnet MR and can

2 see the proximal stenosis of grafts pretty well so

3 you can get some structural data.

4 DR. TRACY: Dr. Hirshfeld?

5 DR. HIRSHFELD: I think I would sort of

6 like to echo what Dr. Krucoff and Dr. White said.

7 I think there are two core questions. The first

8 question is do these devices confer an important

9 advantage over traditional hand-sewn anastomoses?

10 The second is do they have any downsides either

11 early or late in terms of how patients are in the

12 long term?

13 So, it seems to me that the way to assess

14 these devices is a combination of documenting early

15 patency, which I think can be done non-invasively

16 with CT angio or MR, and then at some point

17 documenting the morphology of these anastomoses

18 with a technique that has high enough resolution

19 such as selective angiography.

20 DR. TRACY: Dr. Mack, did you have a

21 comment?

22 DR. MACK: Michael Mack. I have three

23 comments regarding the issues that have been raised

24 here. First of all regarding intraoperative

25 patency, I think that is going to be extremely

118

1 problematic in terms of designing any trial. First

2 of all, you could do intraoperative angiography.

3 The problem with that is the image intensifiers

4 that are available in most operating rooms, as well

5 as the experience of most surgeons performing

6 angiography, isn\'t going to make that practical.

7 You could do IVIS. You could do

8 intracardiac echo or you could do epiaortic

9 scanning. Again, the problem is you are using an

10 unproven technique with significant user

11 variability to prove an unproven technology and I

12 just don\'t see that as being a realistic way of

13 evaluating a new device in this situation.

14 Secondly, alternatives to angiography

15 after surgery for follow-up, we have experience

16 with both MRI and EBCT. EBCT is great to show

17 whether the graft is occluded or not occluded but

18 it is not accurate in terms of degree of stenosis,

19 which I think is a harbinger in these grafts of

20 potential occlusion later on so it will not pick

21 that up.

22 MRI, at least with stents in our

23 experience and I assume you could make the jump to

24 anastomotic connectors, creates a flow void in the

25 area where the stent is and you cannot diagnose

119

1 instant restenosis with cardiac MRI.

2 Thirdly, I think what a real problem of

3 this whole trial design is, is that there are a

4 number of devices out there that have been given

5 previous guidance as to this was a 510(k) pathway

6 and that six-month angiographic follow-up would be

7 an appropriate endpoint to determine safety and

8 efficacy. I realize that the function of this

9 panel, first and foremost, is patient safety and

10 secondly efficacy, but there are a whole number of

11 studies that are out there done that have six-month

12 angiographic follow-up and a very real, practical

13 question is what happens to those studies and what

14 happens to those devices? Do they just get thrown

15 away and we start all over again?

16 I would say that if that is the case, I

17 think that a number of these devices will never

18 make it to market and the companies will go under.

19 I realize that that is not your purview but I think

20 it is a very practical consideration of the problem

21 that exists right now. Thank you.

22 DR. TRACY: Dr. Zuckerman?

23 DR. ZUCKERMAN: Dr. Mack has raised some

24 important points. I would indicate to both the

25 industry and the investigators here that the

120

1 ongoing studies are developing important data sets

2 for FDA. The question that may need to be raised

3 for some of these companies that are in the process

4 of doing these studies is, depending on what advice

5 this panel gives us today in addition to what is

6 ongoing now, what might be additionally required.

7 But the agency is by no means saying that what

8 companies and investigators have performed to date

9 needs to be thrown out.

10 DR. TRACY: Dr. Kato?

11 DR. KATO: I have a question for Dr.

12 Martin. Can you comment a little bit about the

13 time frame of when you performed your

14 catheterizations in terms of whether 6 months or 12

15 months, in your experience, was of any value or do

16 you have to take this out further in your

17 experience?

18 DR. MARTIN: Well, I will be honest with

19 you, most of my presentation was obviously

20 anecdotal based on the one patient I saw. My

21 problem is the fact that you are subjecting

22 patients to a metallic device without the benefit

23 of platelet inhibition. We know with recent FDA

24 warnings about subacute thrombosis in drug-eluting

25 stents how important that is, and these are

121

1 patients that don\'t get Plavix usually

2 intraoperatively because of the bleeding

3 consequences, or may not get it for 48 hours

4 because of the absorption issues.

5 So, the damage is already done when you

6 install these devices. Basically, the platelet

7 adhesion and the basis or the nidus for fibril

8 intimal hyperproliferation starts immediately and

9 that is exactly what I postulated when I saw this

10 first patient, first case. Basically, that is what

11 I think the problem is. I mean, you can\'t put

12 metallic devices in an aorta. Like Dr. Weinberger

13 said, it is a different pathology virtually.

14 But the point is you are trying to auger a

15 hole, start some sort of clotting cascade with your

16 thumb while you are getting this device ready to

17 implant so you are hoping it clots, but then you

18 don\'t have anything on board to keep it from

19 over-clotting for instance. I think some of the

20 early cases that had thromboses of the grafts were

21 related to that and I think the nidus begins at the

22 time of implantation with these devices, period,

23 because they are metallic.

24 Now, as far as my experience, I have a

25 very low threshold for cath\'g these patients. I

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1 mean, basically anginal syndromes, thallium\--yes,

2 we are trying to get all these patients back. The

3 problem is that a lot of these patients are taken

4 care by a multitude of cardiologists and, you know,

5 they each have their own individual thresholds for

6 doing non-invasive testing, for instance, in

7 bringing the patients in and, of course, economic

8 considerations as well.

9 But, I mean, my opinion is the same as it

10 was two years ago and now\--as I was talking to Dr.

11 White\--what do we do with these patients? Can we

12 use drug-eluting stents? Well, not really because

13 a lot of these patients, as was shown in the

14 article two months ago in JAC by Cavendish\'s group,

15 have a high propensity for restenosis because of

16 the propensity that we see in a lot of stent

17 patients for instant restenosis.

18 So, I hope I have answered your question

19 but the bottom line is I think the injury starts at

20 the time of surgery whether technical or not

21 technical. Every film I looked at on the screen

22 showed evidence of proximal hyperproliferation or

23 intimal endothelial proliferation, every one of

24 them, every graft that was shown up there, and I

25 think that is part and parcel of this whole

123

1 problem.

2 DR. KATO: Well, my question was really in

3 your experience is it going to be 6 or 12 months

4 for your study.

5 DR. MARTIN: That is a great question but

6 basically we normally treadmill people within six

7 months, use thallium treadmills. Normally most of

8 them are cath\'d within six months. That is when we

9 use sort of a definitive marker. But, as I said

10 before, there are lots of patients that can\'t get

11 back for various reasons and there are patients

12 that have to be done over and over again. Some of

13 these patients have been done six, seven and eight

14 times in various circumstances.

15 DR. TRACY: Dr. Bridges?

16 DR. BRIDGES: I have a question for anyone

17 either on the panel or in the audience. Do we have

18 six-month angiographic data on the Symmetry device?

19 Because one of the key questions here is what is

20 the length of time that it takes to discover a

21 problem with these devices. Is that data available

22 because I haven\'t seen it published and I was

23 wondering if anyone can comment on that.

24 DR. SLAUGHTER: Mark Slaughter. I can\'t

25 specifically answer for Symmetry; I think I know

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1 the answer. But I would like to respectfully

2 disagree with Dr. Martin so it doesn\'t go unspoken.

3 To say, you know, a stent is a stent and metal is

4 metal and these things are all the same is not

5 true. And, there is lots of data for the distal

6 anastomosis and Converge. They do get Plavix

7 starting within 24-48 hours. And, the German

8 experience which he put up is 60 days and they have

9 100 percent angiographic follow-up and it is 97

10 percent patency, and they have morphology. That

11 is, there is no stenosis; there is no narrowing.

12 So, to say that because you have something

13 in the lumen and you didn\'t have Plavix

14 automatically means it has to fail is not true.

15 Within our own experience with now half of our

16 patients back and angiograms 6-7 months, we have no

17 occlusions and we have essentially no stenosis

18 whatsoever. So, to just sort of blanketly say that

19 without, you know, preoperative medical therapy if

20 you have this foreign body it automatically means

21 failures and it will never work is not true.

22 By the same token, there are issues

23 related to that as to material design, where it is

24 placed, and what type of injury occurs are

25 important issues and need to be answered along the

125

1 way. I think the issue of six months, I mean, I

2 think someone needs to step up and answer but the

3 idea is in any other study so far with these

4 devices at six months the majority of all failures

5 are identified, or you have changes in morphology

6 that would subsequently predict later failure.

7 DR. EDMUNDS: To answer your question,

8 Charles, blood never sees the metal. It sees a

9 granular layer of proteins that are adsorbed onto

10 the metal or any foreign body and that is what the

11 reaction is. The mosaic of those proteins is

12 empirically derived but it never sees the metal.

13 DR. TRACY: Prof. Klima?

14 PROF. KLIMA: Uwe Klima, Hanover. As I

15 presented in my talk, yes, we have postop

16 follow-up, angiographic follow-up with the Symmetry

17 device six months after surgery and this was

18 sufficient enough to detect a real, real problem at

19 the site of the anastomosis even those these

20 patients were asymptomatic. I think this is a very

21 clear message to say that even though you have

22 asymptomatic patients you might have a significant

23 problem at the site of the anastomosis and I think

24 the six-month interval from surgery until you put

25 the patient back into a cath is sufficient to

126

1 detect any significant problem at the site of the

2 anastomosis.

3 DR. TRACY: Dr. Zuckerman?

4 DR. ZUCKERMAN: Although you have reported

5 very important six-month angiographic follow-up

6 results, what percent of your cohort had six-month

7 angiography?

8 PROF. KLIMA: My total cohort?

9 DR. ZUCKERMAN: Yes.

10 PROF. KLIMA: Well, 67 percent of our

11 MIDCAB patients, 100 percent of the Ventrica

12 patients, 100 percent of the Converge patients and

13 100 percent of the St. Jude patients.

14 DR. ZUCKERMAN: Right, and so in terms of

15 this advisory panel appreciating some of the

16 problems that we have and whether six months can be

17 the gold standard, our paradigm has usually been at

18 least about 80 percent angiographic follow-up,

19 assessed in an independent core lab, to really make

20 statements about the totality of the data. So, I

21 would ask people to consider Dr. Bridges\' question.

22 Even if certain data have been spoken of here, has

23 the angiographic follow-up been sufficient or is

24 there still a paucity of data, reviewed

25 independently, to make any decision regarding Dr.

127

1 Bridges\' question about what is the length of

2 follow-up.

3 DR. TRACY: Could I ask you, did you have

4 other assessments on those patients, other

5 non-invasive assessments performed before the

6 angiogram or was this just part of the routine

7 follow-up?

8 PROF. KLIMA: Well, intraoperatively we

9 did an ECHO measurement of flow. However, I am not

10 a big believer about the accuracy of how good the

11 ECHO is. It gives information about is the graft

12 patent or is it not patent but it does not give you

13 very good information about is there 50 percent

14 stenosis, yes or no. If we have a situation where

15 we see that there is no flow in the graft by

16 ultrasound, yes, we go back and we do anastomosis

17 again. All the other information you get is yes or

18 no; it is patent or it is not patent, no more than

19 this.

20 DR. WHITE: She was asking about thallium

21 stress tests. Did they detect your asymptomatic

22 occlusions? Did any other non-invasive functional

23 tests detect asymptomatic occlusions?

24 PROF. KLIMA: Well, there was a clinical

25 interview, so to say, when we brought the patients

128

1 back about how they would perform. We put them on

2 an exercise stress test and about half of the

3 patients showed ischemia when they were on the

4 bicycle, so to say. But in the clinical situation

5 of daily living\--you know, how patients move,

6 whatever they do, they were asymptomatic.

7 DR. WHITE: So, the important data then is

8 that the non-invasive test for ischemia did not

9 completely identify the set of patients who had

10 occlusions.

11 PROF. KLIMA: Exactly. That is why I

12 would really recommend to you to have a six-month

13 angiographic follow-up and if your data look very

14 good I think you can go on with the clinical tests

15 a year later, bring back the patients and see how

16 your patients are doing. In case they are having

17 troubles you certainly have to reevaluate those

18 patients. Either you do it with an angiogram,

19 which I would not do because the angiogram itself

20 has some morbidity, so to say, or some problems

21 coming up sometimes with an angiogram. I think

22 valuable information would also be with an MRI or

23 CT scan.

24 DR. TRACY: Dr. Hirshfeld?

25 DR. HIRSHFELD: I wanted to ask Dr. Emery,

129

1 because Dr. Emery spoke quite a bit about the

2 technical aspects of using these devices, we have

3 heard reports from a couple of groups of very

4 experienced surgeons and they believe that they

5 have an excessive device failure rate. You have

6 obviously great experience using this device and I

7 wondered if you could offer an opinion as to

8 whether or not the excessive device failure rates

9 may be attributable to technical considerations in

10 terms of how the device is used, and how you would

11 distinguish between that an inherent

12 characteristics of the device.

13 DR. EMERY: I was just thinking that our

14 experience is very much different from Dr.

15 Schoettle\'s and I would like to get together with

16 him actually and see our differences. On the

17 angiograms, I just reviewed them and there are two

18 out of all the ones I showed. Dr. Martin had had a

19 proximal stenosis; the others were widely open

20 proximally.

21 One of the issues that Ms. Marders dealt

22 with was the dehiscence which was a disastrous

23 event. I think that is a technical problem because

24 the graft is too short and when the patient\'s heart

25 fills or they cough or retch after surgery, they

130

1 can pull on that device and pull it off. It is

2 clearly not as strong a suture or as strong as the

3 device Dr. Hausen described. So, I think you need

4 to establish some in vitro criteria for these

5 valves before implantation, not just animal data

6 but the parameters of their strength, just like you

7 proposed for cardiac valve prostheses before they

8 go into clinical trials. I do think the technical

9 issues need to be dealt with because there is no

10 data as to what surgical techniques contribute to

11 failure and that certainly could be one reason,

12 plus regional differences in patient

13 characteristics. It is clear that there are

14 differences in our regional populations\--incidence

15 of diabetes, obesity, male versus female, quality

16 of the veins, these issues all come up and these

17 are not addressed in any of the trials that were

18 presented, except for Dr. Mack\'s trial which came

19 out with diabetes as a very important issue in

20 these device failures.

21 DR. WHITE: Are you still using this

22 device?

23 DR. EMERY: I do for specific indications,

24 people over 80 and in people that have evidence of

25 calcified aorta. Dr. Jim Harte\'s series is a big

131

1 proponent for epiaortic scanning before coronary

2 surgery. If people have aortic disease, then I

3 will use it. I do not use the smaller size unless

4 it is absolutely necessary for very specific and

5 patient-oriented reasons. It has its indications

6 and contraindications I think, like we try and do

7 with all of our procedures, processes and

8 medication in the field of medicine.

9 DR. TRACY: Dr. Krucoff?

10 DR. KRUCOFF: I just wanted to step back

11 to the notion that the range of devices we are

12 talking about, in addition to their individual

13 differences, extend from some that are approved and

14 on the market, some that are already in the course

15 of clinical trials that were discussed and

16 designed, and then others that I guess are thinking

17 about the future. It seems to me there are some

18 common pieces that we could focus on them.

19 One of them is called informed consent. I

20 think whether a trial is being planned or is

21 already in motion or whether a surgeon is planning

22 to use a device that is on the market in a human

23 being, we could look at the informed consent

24 document and process across the board and make sure

25 that it contains the appropriate information

132

1 reflecting current knowledge about the potential

2 risks or benefits.

3 The other is medication. I think there is

4 no question that while maybe loading people with

5 Plavix preoperatively has some downsides, once a

6 gadget like these goes in and hemorrhage and other

7 circumstances is not an issue, anti-platelet

8 therapy across the board, whether you are already

9 doing a trial, is worth probably making sure that

10 you can do as well as possible.

11 Lastly, in the safety assessment is the

12 use of a data and safety monitoring board. What we

13 again very directly from the stenting world

14 recognize is that angiographically, whatever your

15 time window is, you are going to generate clinical

16 events because if at six months people aren\'t

17 symptomatic but you see 90 percent stenosis, the

18 tendency to do something about that is going to

19 impact the population.

20 So, at least insofar as, for instance,

21 with a good data and safety monitoring board

22 supervision program you could move the angiographic

23 endpoint to a later point and if you have a trial

24 that has done all the paperwork but hasn\'t enrolled

25 a patient it may be a little different than a trial

133

1 that has enrolled 210 out of your 215 planned

2 patients. But I think for anything that is in

3 motion, recognizing that an angiographic

4 endpoint\--and is pretty clear from what we have

5 heard that detailed morphology of how these things

6 heal is probably going to be an angiographic

7 endpoint somewhere along the line. But if we push

8 that time window later clinical events will occur

9 more consistently with the natural history of the

10 intervention and be less driven by a response to an

11 angiogram.

12 So, I think as long as there is a safety

13 board or there is a safety surveillance mechanism

14 that can make sure patients aren\'t being harmed,

15 there is a way to envision using angiographic

16 endpoint but pushing out later to allow clinical

17 events to also tell you how patients really respond

18 to these devices.

19 I think from consent to data safety and

20 where you put your time window, frankly, whether it

21 is for a device that is approved and on the market

22 or for a trial that is already enrolling or for a

23 trial that is being planned, that will at least

24 give a backbone that we have learned a lot with

25 stent-like devices that you could think about

134

1 structuring trials.

2 DR. TRACY: Dr. Edmunds?

3 DR. EDMUNDS: Bob Emery, is it your

4 feeling that the technical limitations of the

5 anastomotic device are much more constrained than

6 they are with the hand-sutured anastomosis

7 proximal, one question; distal for the second? And

8 we are talking just vein grafts.

9 DR. EMERY: Not necessarily, Dr. Edmunds.

10 I think, like anything, we have to learn how to do

11 it and I am sure my first few proximal anastomoses

12 when I was a cardiac surgical fellow were not as

13 good as they are right now after twenty years. I

14 think the same is true with the devices and there

15 may be a need for more mentoring on the first

16 several cases so someone can suggest what is good

17 and what is bad, much as is done with other more

18 complex devices. These devices seem intuitively

19 simple but obviously we are coming to the

20 conclusion here that they are not intuitively

21 simple. They have a lot of subtleties in their use

22 both in terms of healing, deployment and events

23 that occur, and those all need to be addressed, not

24 just the fact that you push a button and you have

25 an anastomosis. That is clearly very simple.

135

1 These things, like any other techniques in our

2 medical profession, we need to learn how to do

3 them.

4 DR. EDMUNDS: But you showed us angiograms

5 in which there were problems, that you needed to

6 put it on the side of the aorta towards the

7 pulmonary artery, which you don\'t need to do for

8 hand-sewn anastomoses. It has to be totally at

9 right angles. It can\'t be at a little bit of a

10 hood. Those are the constraints that seem to be

11 much more confining than would be in a hand-done

12 anastomosis. Is that true or not true?

13 DR. EMERY: Yes, and they have to be

14 defined. That is what I was talking about for some

15 of the in vitro tests and even the in vivo tests

16 before the application to our clinical patients.

17 It is not just patency that is important; it is how

18 you use it and define the limitations of the device

19 as part of the preclinical issues that go into

20 preparation for a clinical trial.

21 DR. EDMUNDS: Therefore, the device

22 anastomosis is less robust than is a hand-sutured

23 anastomosis. It is less tolerant of small error.

24 DR. EMERY: That is possible. You know,

25 it is possible but, on the other hand, sewing an

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1 anastomosis in a diseased aorta is less tolerated

2 by the patient and there is value in these devices

3 even though they may be more complex. Also, on one

4 angiogram I showed side-by-side anastomoses where

5 one was hand-sewn because I was over-aggressive in

6 pulling the vein graft and pulled the connector

7 right off the aorta, which, you know, caused a

8 little bit of a stir in the operating room, of

9 course. The other connector was just fine so I

10 just hand-sewed the other anastomosis. The patient

11 returned at three months with both occluded. I

12 can\'t explain why there was a difference in

13 something like that occurring.

14 DR. TRACY: Dr. Yancy, then Dr.

15 Weinberger, Dr. Kato and then lunch.

16 DR. YANCY: Putting some thought into a

17 clinical trial design and thinking of endpoints

18 that would be evaluated in that design, I have not

19 heard a discussion this morning about the presumed

20 advantages for this device, specifically the time

21 of the proximal anastomosis, decreasing that

22 variable to the extent that that is clinically

23 relevant. The second would be the CNS event

24 circumstances because that was purportedly one of

25 the major reasons for developing the technology.

137

1 Are we to assume that that has been proven or are

2 those issues? Because in my judgment, if we are

3 addressing questions of efficacy with regards to

4 the integrity of coronary perfusion and we have

5 missed the purported benefit, then I think there

6 are some serious questions that have to be

7 addressed that are more global than trial design.

8 Are there people in the audience that can

9 specifically comment on the CNS issues and the

10 timing issues, especially if we follow the most

11 recent discussion that more care and consideration

12 needs to be made in generating these proximal

13 anastomoses?

14 DR. BRIDGES: I don\'t think there is any

15 data other than speculation that I am aware of,

16 unless somebody else knows otherwise, that prove

17 those points that you made. I mean, I think the

18 supposition is that there would be less incidence

19 of stroke and that may very well be true but I

20 don\'t think that that data is available.

21 DR. YANCY: Well, I respect that but there

22 is a comment in our packet that 30,000 of these

23 devices have been implanted and we have any number

24 of events reported to the FDA, and I think if we

25 are dealing with supposition and speculation the

138

1 trial design needs to be a bit more rigorous than

2 we may have thought earlier today.

3 DR. FERGUSON: Can I respond to that?

4 DR. TRACY: Yes.

5 DR. FERGUSON: I think you are mixing a

6 little bit apples and oranges because the genesis

7 for many of these mechanical devices has been

8 MIDCAB and off-pump where putting on an anastomosis

9 by hand is much more difficult, sometimes

10 impossible. It obviates the use of an aortic clamp

11 which is not possible if you are doing it

12 hand-sewn. So, I think that responds to the issue

13 of CNS issues because those issues are due to

14 clamping the aorta so you can do the anastomosis of

15 the hand-sewn.

16 DR. AZIZ: But then they should be able to

17 look at the cases they have done and see what the

18 incidence of neurological problems is in the 30,000

19 cases or so that have been mentioned.

20 Theoretically, it should be less than what was

21 expected. I mean, somebody should have that data.

22 DR. TRACY: Dr. Weinberger?

23 DR. WEINBERGER: I would like to sort of

24 echo and expand a little bit on what Dr. Krucoff

25 said. I think that in the past couple of years the

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1 FDA, together with the cardiology community, has

2 developed a paradigm for analyzing new endovascular

3 stents. If you go back to 2000 or 2001 in the

4 early days of drug-eluted stents, the studies that

5 were designed included both clinical endpoints and

6 angiographic substudies, and the angiographic

7 substudies were done to power angiographic

8 endpoints which are completely different than

9 powering clinical endpoints.

10 I think that both are important. I think

11 the surgeons and a lot of us are focusing on

12 morphological endpoints right now, and I think the

13 study done to get a morphological endpoint when you

14 have a continuous variable could be done with a

15 much smaller number of patients.

16 On the other hand, the FDA standard in the

17 past has always been clinical benefit to patients

18 or at least clinical equivalence to previous

19 devices and I think we need to gather clinical

20 endpoints for those particular pieces of

21 information. So, what we really need is to define

22 what the rates of major adverse cardiac events are

23 in hand-sewn saphenous vein surgery at one year or

24 two years, some time point, and use a clinical

25 endpoint for that piece of the information.

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1 We are all sort of focusing on an

2 angiographic endpoint which, at best, is going to

3 be a surrogate to suggest what is going to be

4 happening clinically and probably should represent

5 only a substudy of an ultimate study that is done

6 to approve this.

7 Now, I am sure that the manufacturers are

8 going to howl and say that we are really subjecting

9 this to PMA standards, but I think that given where

10 we are and the fact that we have introduced what

11 appears to be problems at unexpectedly high

12 frequency the data necessary to at least inform

13 patients that we are not exceeding the previous

14 event rates are necessary.

15 DR. TRACY: Dr. Kato and then we should

16 really break for lunch.

17 DR. KATO: Why don\'t I let Dr. Frater talk

18 and I can reserve my comments until after lunch.

19 DR. TRACY: That is fine.

20 DR. FRATER: I just want to try to respond

21 to a couple of the issues that were raised. You

22 did raise the question of angiographic evidence at

23 6 months on the connector in a miscellaneous group

24 of patients in which angiograms were available.

25 There were 221 of them. The occlusion rate between

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1 6-12 months was 20 percent. The range was 2.3

2 percent to 58.3 percent. That is one of our

3 problems, dealing with a range that wide. How can

4 you possibly account for it?

5 It is perhaps fair just to mention that

6 there are studies already published in abstract

7 form in which the outcomes judged by MACE followed

8 by angiography are nowhere near what you heard this

9 morning. I will just quote one from Brady,

10 University of East Carolina, with 400 patients with

11 650 veins and they found, based on clinical events,

12 3 veins that had problems of occlusion or stenosis.

13 The difference between these various studies is

14 enormous.

15 In terms of neurological episodes, those

16 400 patients studied from 2001 to September 2003

17 had a 1.7 incidence of neurological adverse events

18 in the postoperative period. Dr. Schoettle could

19 tell you about his connector patients and their CNS

20 adverse events but I will leave him to do that if

21 he wishes.

22 So, I won\'t spend more time; we clearly

23 don\'t have time, but there are other similar good

24 series to report that we are faced with

25 extraordinary diversity in results from competent

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1 people.

2 DR. TRACY: Thank you. Why don\'t we break

3 for lunch and let\'s be back here at 1:20.

4 \[Whereupon, at 12:20 p.m., the proceedings

5 were recessed for lunch, to reconvene at 1:20 p.m.\]

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1 A F T E R N O O N P R O C E E D I N G S

2 DR. TRACY: If everybody would please take

3 their seats, I would like to resume the open

4 committee discussion because I know there are a lot

5 of additional issues that need to be addressed this

6 afternoon.

7 Again, I would like to thank presenters

8 for hanging around to help us clarify some issues.

9 It is very helpful to get the input of everybody

10 who has made the time to come here. This is a

11 difficult issue that we are wrestling with because

12 there are an awful lot of variables that are

13 involved in the discussion that we are here to

14 have. At the end of the day we are expected to be

15 able to answer some questions or begin to answer

16 questions that have been posed to us from the FDA.

17 I would just like to at this point sort of

18 summarize what I see as some of the complexities

19 that we are looking at right now. I think there is

20 a variety of variable here that we are discussing.

21 One is what type of devices are we talking about.

22 There is a variety of devices that are out there

23 and there is a variety of devices that are coming

24 down the pike.

25 I think an issue that we have to address

144

1 is, is the analysis of each of these different

2 types of devices going to be the same. My

3 suspicion is that that will not be true but is

4 there some sort of paradigm we can come up with

5 that would help to analyze what type of process

6 should be gone through to look at different types

7 of anastomotic devices?

8 I think one thing that is clear that we

9 have heard so far today is that the target vessel

10 is very important\--whether something is being

11 connected to an LAD, whether it is an aortic

12 anastomosis or artery or vein anastomosis. these

13 are variables that are inherent in this type of

14 device and the analysis or process to look at these

15 things may be different if we are talking about

16 distal or proximal anastomosis, and how do we

17 handle that in a given patient population?

18 I think we have heard an awful lot about

19 operative variables, some of which may be

20 technically overcomable, some of which may not be.

21 Maybe a MIDCAB is very different from a coronary

22 bypass graft placed through a thoracotomy. How do

23 we handle that?

24 So, let\'s focus on some of those things as

25 we think about our trial designs and what

145

1 parameters we can look at both acutely, what is the

2 appropriate mid-term analysis on these patients,

3 and what does long-term analysis and long-term

4 follow-up really mean. Are we looking at an

5 anatomic outcome or are we looking at a functional

6 outcome? And what other outcomes are appropriate

7 to consider?

8 One of the original reasons perhaps for

9 developing any of these anastomotic devices was to

10 avoid some of the neurologic outcomes that come

11 from cross-clamping the aorta. So, what other

12 outcomes do we need? We sort of focused on

13 angiographic but are there other neurologic or

14 other types of outcomes we need to think about?

15 The final area that I would like people to

16 sort of focus in on is that it does seem to be

17 almost a separate cardiovascular surgeon training

18 program to learn how to use these things, and what

19 is it that needs to be done to train appropriately

20 for the use of these devices?

21 So, if you can try to keep in the back of

22 your mind the questions that have been posed to us

23 and let\'s try and focus our way through some of

24 these issues.

25 DR. KRUCOFF: As a point of order, I don\'t

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1 know if this is inappropriate or appropriate but

2 would it be possible to actually go through the

3 afternoon discussion by starting with the questions

4 instead of doing the discussion and then ending

5 with the questions? We are not voting.

6 DR. TRACY: We can do that but I think

7 there may be some additional issues. You have the

8 questions listed here so if there are additional

9 things that you think are relevant before we answer

10 the questions, I want to give plenty of time for

11 discussion and input from the audience on this.

12 Yes?

13 DR. MACK: Michael Mack. Do you want me

14 to start? DR. TRACY: Sure.

15 DR. MACK: I have a couple of comments

16 based upon what you just said. The first alludes

17 to what you said, you need a whole separate

18 training program to implant these devices, and a

19 lot of attention was focused on Bob Emery\'s

20 presentation about the permutations that are

21 necessary for this. I think this addresses the

22 issue that implantation of a medical device by

23 surgery or by a catheter is not a pill and you

24 don\'t just give a pill and a placebo and that is

25 the variable. There are intricacies associated

147

1 with the implantation of a device. It is not that

2 the use of an anastomotic device is necessarily

3 more constraining or that the margin of error is

4 narrower, but it is just different and just because

5 you have been sewing coronaries for twenty years

6 doesn\'t mean you can automatically put in a device

7 the first time.

8 I will go to the analogy of drug-eluting

9 stent devices. There are a whole bunch of adverse

10 events with subacute thromboses that happen

11 immediately upon approval of this. It probably had

12 to do with the fact that it is a device, a

13 particular type of stent that most cardiologists

14 weren\'t implanting. It was just different. It is

15 stiffer. The delivery platform wasn\'t as usable.

16 How high do you inflate the balloon? Do you

17 overlap stents? What is the amount of coverage

18 that you have? All those little intricacies just

19 had to be brought up to speed and were different

20 than cardiologists had been doing before.

21 It is the same thing with anastomotic

22 devices. you find out that you have to put a

23 suture to tack a vein graft to keep it straight

24 coming off, whereas you don\'t with a sutured one,

25 and there are little permutations like that that

148

1 you find when there is broader experience with it.

2 The second has to do\--it was either Chris

3 or Clyde that mentioned this, we talked a lot about

4 adverse events about the procedure. Well, what

5 about the benefit? Well, I think there is benefit

6 potentially both with the device itself but what it

7 is ultimately going to lead to.

8 One is the device itself. Maybe you

9 actually have a more reliable anastomosis. That is

10 not proven. But this is a brick in a wall of less

11 invasive surgery in general and both minimal access

12 surgery and off-pump surgery. The reasons for that

13 are the following: The reason that minimal access

14 surgery is so limited is the most difficult thing

15 to do through a little incision is to sew. If

16 minimal access surgery is every going to get any

17 place, this is a necessary brick in the wall to

18 move that along.

19 Similarly, you can argue whether there is

20 a benefit to off-pump surgery or not. The

21 preponderance of evidence would seem to indicate

22 that there is. But it is stuck at 25 percent of

23 CABG in the United States. Why? Because most

24 surgeons aren\'t comfortable putting the heart on

25 end for 20 minutes to sew on a beating heart. The

149

1 potential benefit of an anastomotic device, if

2 proved to be safe and efficacious, is immediately

3 catalyzing off-pump surgery. If it takes a minute

4 to do the anastomosis most surgeons are going to

5 feel comfortable with that.

6 So, I think the ultimate benefit is that

7 it is a potentially more reliable anastomosis, not

8 clamping the aorta, not having neurological events

9 but ultimately what it allows this whole field to

10 progress to is that it is not going to be the same

11 operation as for the last fifty years.

12 DR. TRACY: Thank you. With that as a

13 jumping point and trying to go along a little bit

14 with the lines Mitch indicated, we have heard the

15 historic comparison to CABG and anastomosis as sort

16 of the gold standard. Is that the right gold

17 standard or is this technique different enough that

18 we don\'t use sutured CABG anastomoses as the gold

19 standard? Dr. Aziz?

20 DR. AZIZ: Just before answering that

21 question, you know, we have a technique which is

22 very safe. It is not perfect; the vein grafts may

23 not last long but I think that is usually related

24 to vein biology. So, I mean, we have a certain

25 standard and if we are going to adapt a new

150

1 technology I think at a minimum it can\'t be worse

2 than what we have, and I think we have to be

3 careful on that. I think we need to sort of keep

4 that in the back of our mind. For example, this

5 particular device that was presented, the St. Jude

6 device\--clearly, the results are worse than what we

7 have with hand-sewn. So, I think, you know, we

8 have to make sure that whatever we do is not worse

9 than what we have. It is not like we are in a

10 void.

11 Regarding the sort of controls, as someone

12 else had also mentioned, using the same patient as

13 his own control would obviate the need to have

14 randomized studies in the sense of, you know,

15 having two different groups of patients. You could

16 do one anastomosis with one of these techniques

17 either for the distal or proximal and one doing it

18 the old-fashioned way or the regular way with a

19 suture technique. When you evaluate by angiogram,

20 that in itself could be its own control.

21 DR. FERGUSON: I have kind of done a 180

22 on this because I was impressed with\--I think it

23 was Bob Emery but others too. I came in with the

24 idea that using the traditional statistics for a

25 control, matched control would be a good thing to

151

1 do. But the more I have listened today, the more I

2 think that the patient population has changed so

3 much in the last twenty years that those historical

4 controls are truly historical and probably not

5 relevant to what is going on today given the kinds

6 of patients that are being operated on today, and

7 so forth. I think, Bob, you mentioned something

8 about that too. So, I would only comment that if

9 we truly need control for experimental devices,

10 then I think that we need to make those controls

11 modern-day standard heart/lung operations.

12 DR. TRACY: Dr. Blumenstein?

13 DR. BLUMENSTEIN: I am really seconding

14 what you are saying and maybe stating a little more

15 explicitly that I don\'t see we can do anything by

16 randomize in some sense. I think that you have to

17 have the power of randomization to give you the

18 stochastic equivalence between those treated with

19 the experimental intervention and some kind of a

20 control group. Whether it is matched or whether it

21 is a two-group study, and so forth, will have to be

22 discussed but there are just too many extraneous

23 factors that cannot be controlled. I am just blown

24 away by the number of them. So, you have to have

25 randomization to control the experimental

152

1 intervention and let those other factors be

2 stochastically controlled with randomization.

3 DR. EDMUNDS: Just to maybe start a little

4 bit of discussion on this issue because this really

5 is the heart of the issue, let\'s just look at the

6 problems of a non-randomized control group and what

7 are the alternatives. Well, propensity matching

8 and univariate and multivariate logistic

9 regression. But a lot of the technical problems

10 are not things that we collect data on, as Bob

11 Emery has brought out. Yet, they are very relevant

12 to the success or failure of patency, let\'s say,

13 and that will confound any kind of propensity

14 matched control group or taking it out of a

15 logistic regression equation because you don\'t have

16 the data in there in the first place. So, I can\'t

17 think of a control group other than a concurrent

18 prospective, randomized control. Maybe somebody

19 else can but I can\'t.

20 DR. TRACY: Mitch?

21 DR. KRUCOFF: Because of the breadth of

22 range we are looking at, we really do have to be

23 careful about babies and bath water. I think if we

24 take this as a new device, then a characteristic

25 first question would be is it safe? The first

153

1 in-man type of experience would be one way to go.

2 I think we have seen at least one elegant

3 illustration of using a patient as their own

4 control where you have even numbers of grafts that

5 can be characterized and randomized and carefully

6 followed angiographically.

7 That is living in the morphologic side of

8 are we hurting people anatomically by putting these

9 things in. That would also be a very good

10 opportunity for a bunch of smart surgeons to look

11 at what are the technical features that we would

12 want to capture in a larger, more definitive trial

13 and explore that a little bit in a small but very

14 intensively designed study. I think the one

15 feature there that certainly stood out for me out

16 of this morning\'s presentations is the potential to

17 use a patient as their own control over a series of

18 non-LAD grafts.

19 I think as you move into a more definitive

20 \"okay, this thing is safe,\" now is it effective,

21 and is it effective for what? Is it effective as a

22 stepping stone toward fully robotic surgery, or is

23 it effective to not have to cross-clamp the aorta

24 in 80 year-old people with crunchy aortas? I mean,

25 it depends on the question which the FDA is very

154

1 particular about; it depends on the label; it

2 depends on the indication.

3 But I think if we do this in steps there

4 are points where patients can serve as their own

5 control, where historical descriptors may be

6 useful, and then I think ultimately there is a

7 point where you are going to have to do real

8 meaningful and probably randomized trials to show

9 that it is effective, building along the way.

10 DR. HAUSEN: Bernard Hausen, Cardica.

11 What is the worry, Dr. Ferguson? That we are over-

12 or underestimating with our historic controls the

13 true incidence of occlusions?

14 DR. FERGUSON: It is a different patient

15 population. That is my point. We had this problem

16 yesterday a little bit about using a group of

17 patients that are 20, 25 years out as our control

18 group. I don\'t think we can do that. Somehow or

19 other, we have to have concurrent. Now, how that

20 is done is up for grabs here I think. Go ahead.

21 DR. HAUSEN: Let\'s say Dr. Frater is right

22 and patients are getting sicker; they are

23 definitely getting older; the veins are getting

24 poorer and all this will result into poorer outcome

25 of vein grafts. You could hypothesize that

155

1 nowadays, if I did a brand-new control group with

2 vein grafts hand-sewn, my results would be worse

3 than what Dr. Mack presented to us.

4 DR. TRACY: I think that you are right but

5 the problem is that we don\'t have a proximal

6 control here. We don\'t have something that we can

7 look at that we feel is comparable.

8 DR. HAUSEN: I understand that but if you

9 are worried that when I am comparing my average

10 patency of a device to a control, the worry would

11 be that it gets approved because it is

12 statistically not worse or similar to control where

13 my control would underestimate the true prevalence

14 of occlusions. I don\'t think that is the real

15 world.

16 DR. FERGUSON: That is not a definition of

17 a control in my world.

18 DR. HAUSEN: I know. I know, but from a

19 regulatory point of view you are trying to prevent

20 products, or the FDA is trying to prevent products

21 from getting onto the market that look better than

22 they really are and that pose a patient risk. So,

23 if you have a control group that is worse than what

24 the real world is showing us right now\--

25 DR. BRIDGES: Can I interrupt? I think we

156

1 got the point. I think part of the problem here

2 though is that one of the safeguards of a

3 randomized trial, or at least a prospective

4 trial\--I mean, yes, perhaps the patients today are

5 \"worse\" than the patients were then but what is to

6 prevent someone from doing a study where they are

7 selecting patients from today who aren\'t worse and

8 applying the technology selectively to groups of

9 patients who are not worse than some group of

10 historical controls? That is the whole reason why

11 prospective trials\--it is just to mitigate against

12 that kind of deficiency.

13 So, to simply stand up and say, well, you

14 know, the patients that we are operating on today

15 are worse than they were before, therefore, we

16 don\'t need prospective trials I think is overly

17 simplistic.

18 DR. TRACY: Dr. Sapirstein?

19 DR. SAPIRSTEIN: Given the template or the

20 sample I provided where we use a 95 percent point

21 estimate of patency and a lower confidence limit of

22 5 percent, 95 percent lower confidence limit of 90

23 percent, how much better can you do on a randomized

24 control? The only reason I bring this up is

25 because of the sample size that you would require

157

1 and the difficulty of subjecting patients to

2 angiography.

3 DR. KRUCOFF: Come on, Ralph, how are you

4 not going to submit patients to angiography? In

5 this status of a new device how are you going to

6 avoid doing angiograms in these patients? You are

7 going to have to do angiograms in these patients.

8 DR. SAPIRSTEIN: Yes, I think so. I think

9 that you have to do angiography on a new device but

10 on standard procedure, a LIMA to LAD, are you

11 justified in doing an angiographic evaluation of

12 the control? Maybe you are. It is a point of

13 discussion.

14 DR. TRACY: Dr. Edmunds?

15 DR. EDMUNDS: Before you stand down,

16 because it is very expensive to do randomized,

17 prospective, controlled trials, you have to decide

18 in a power analysis how much of a difference is it

19 that you want to see, and presumably a composite

20 primary outcome, to be meaningful, and do your

21 power analysis on that basis. Now, if you really

22 want to say that a one percent difference

23 multiplied by 260 million people, not all of whom

24 have coronary-artery disease, is what is needed,

25 therefore, you are going to have to have a very,

158

1 very small difference, like half a percent, nobody

2 can afford that trial.

3 DR. SAPIRSTEIN: Exactly.

4 DR. EDMUNDS: So, that power analysis and

5 what you define as a meaningful difference is

6 critical I think to any kind of regulation that you

7 set up for these companies.

8 DR. SAPIRSTEIN: Absolutely. That is why

9 we put up that template. With 80 percent power, a

10 5 percent alpha, can we do\--

11 DR. EDMUNDS: Well, what difference?

12 DR. ZUCKERMAN: \[Not at microphone;

13 inaudible\]\... the expected observed rate for a

14 venous study would be 95 percent with 80 percent

15 power, alpha 5, and setting a delta of 0.05,

16 meaning that you are projecting a lower rate\--

17 DR. EDMUNDS: I am not sure.

18 DR. ZUCKERMAN: \--you need 150 patients.

19 If we expand that delta to 0.07 it could be a lower

20 rate of 88 percent and you would only need 59

21 patients but perhaps the delta should be tighter

22 \[not at microphone; inaudible\]\...consider this

23 approach given that for having just normal CABG

24 patients come back for follow-up angiography, as

25 Dr. White was alluding to, perhaps can be very

159

1 difficult.

2 DR. EDMUNDS: Well, the five percent

3 difference is probably in the realm of

4 reasonableness.

5 DR. TRACY: Let me be clear what we are

6 talking about. Have we moved away from a

7 randomized trial to a trial where we are using

8 historic 85, 95 percent?

9 DR. WHITE: Can I support that?

10 DR. TRACY: You support moving away and

11 using the historic CABG data?

12 DR. WHITE: Right. The reason I say that

13 is that obviously I am an angioplaster so I am

14 anti-intellectual, but the point is that I do like

15 randomized trials and I won\'t argue with you that

16 that is the best of all worlds, but I think we can

17 gain confidence that we are doing as well or

18 better, and we have such extensive historical data,

19 as Dr. Mack presented to us today and other data

20 that is available, that if the manufacturer chooses

21 a relatively high bar for patency, it could be done

22 as a single arm because we would be sure that they

23 would be 90 percent or better and that would

24 certainly meet historical controls and it would be

25 hard to argue that they were worse than historical

160

1 controls.

2 If the manufacturer, on the other hand,

3 decided that that bar was too high and they wanted

4 a randomized, controlled trial because the control

5 group really was going to perform at a lower rate,

6 then I think that is a decision we ought to leave

7 to the investigators and to the company.

8 DR. TRACY: Dr. Blumenstein?

9 DR. BLUMENSTEIN: I am not sure exactly

10 what this represents. I assume this means a

11 single-arm trial with a criterion of success of,

12 say, 95 percent and precluding the possibility\--it

13 is a sort of non-inferiority situation\--precluding

14 the possibility that the outcome is truly 90

15 percent or worse with a 5 percent delta, or

16 whatever.

17 The danger here for a company undertaking

18 such a trial with such a high bar is that if you

19 take that sample size of, say, 150 and you have

20 guessed wrong about what the success rate is, then

21 you are in trouble.

22 DR. WHITE: And we have been here once

23 before when companies come back to us, missing

24 their bar and asking us to make that exception\--

25 DR. BLUMENSTEIN: Right.

161

1 DR. WHITE: \--and it is up to us not to

2 make that exception if they miss that bar.

3 DR. BLUMENSTEIN: But there are two

4 reasons why this is a real problem. Number one is

5 that if you had started with a lower success rate,

6 supposing it was reasonable to do so and we all

7 accepted that it was reasonable to do so, the

8 sample size goes up as the base reference success

9 rate moves closer to 0.5. So, by putting the

10 success rate close to 1.0, then you are getting a

11 smaller sample size than you would had you put the

12 base rate closer to 0.5. So, by setting the bar

13 high, which is a good thing, you are in fat

14 anti-conservative with respect to the sample size.

15 DR. TRACY: Dr. Zuckerman, you look like

16 you have something to add here.

17 DR. ZUCKERMAN: I just want to state that

18 Dr. Blumenstein has correctly summarized what this

19 trial design is trying to do, say, for a LIMA

20 trial. We are trying to show that the new device

21 has an observed performance rate or patency rate

22 above 0.90. Therefore, as he was\--

23 DR. TRACY: Dr. Zuckerman, stay near the

24 microphone.

25 DR. ZUCKERMAN: \--if the observed rate is

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1 0.93 instead of 0.95 they can do a sample size

2 calculation and it will go up. But the question

3 is, is 0.90 the right bar for this performance

4 goal, Dr. White.

5 DR. WHITE: I would be very happy. Given

6 what we know about the historical controls for

7 hand-sewn grafts, the meta-analysis and data that

8 we have looked at, that if I was confident that the

9 device could do 90 percent or better at one-year

10 patency or six-month patency, I would feel pretty

11 comfortable about that.

12 DR. KRUCOFF: How about 89? How about 88?

13 How about 87? I mean, come on, Chris, the

14 likelihood of creating an ambiguous data set that

15 ultimately then would occupy all of us for a

16 day\--you know, I think we have to recognize that

17 the likelihood for ambiguity if we court certain

18 marginal design structures is so intense\--

19 DR. WHITE: I don\'t have a problem with

20 89.

21 DR. KRUCOFF: What if they don\'t make

22 their endpoint? What about that they find out that

23 in 50 year-old women, as a retrospective subgroup,

24 it was 100 percent? You know, the vulnerability to

25 starting in the wrong place to then, in this venue,

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1 having a long discussion about completely ambiguous

2 data is huge and I think the key is don\'t start in

3 the wrong place.

4 DR. TRACY: I think the problem that will

5 come up is that there may be times where it would

6 be inappropriate to have a historic control, but it

7 may be just as inappropriate to have the patient

8 serve as their own control\--a single vessel study.

9 There are all kinds of reasons why either one of

10 these is going to be not optimal fit for any given

11 device that is being tested. So, I think there has

12 to be a little bit of breadth. I think that gets

13 back to the idea that you cannot possibly have an

14 exact study that has to be done by each one of

15 these different devices because they are different

16 devices. So, the patients that are going to be

17 enrolled are going to be different from one study

18 to another. I don\'t know how to get around that

19 except to accept different controls in different

20 studies.

21 DR. EDMUNDS: But a Type 2 error is just

22 as bad as a Type 1 error.

23 DR. TRACY: Dr. Emery?

24 DR. EMERY: I think two issues come to

25 mind. One is that patients serving as their own

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1 control will likely only be utile in proximal

2 anastomotic studies and this would separate the

3 distals from the proximals.

4 The second thing is that, on the side of

5 patients as their one control, you have to be sure

6 you are asking the proper question from the study.

7 For instance, there may be biology of aging. We

8 know from prosthetic valves that a bioprosthesis in

9 an elderly patient will last a lot longer than a

10 bioprosthetic valve in a younger patient. The same

11 may be true for connectors because of the biology

12 of wound healing and inflammation. We don\'t know

13 that. So patients serving as their own control

14 would be a good means of separating out the

15 patients at risk and the patients not at risk based

16 on their individual biology.

17 In our paper published in Circulation, the

18 younger patients that had the aggressive restenosis

19 were at risk for the connectors. On the other

20 hand, if you are looking at stroke risk, which has

21 been brought up, that is not a good study for

22 patients as their own control because, perforce,

23 you have to put a clamp on the aorta for all

24 patients in the study to randomize them and that is

25 one of the highest risk things that we are trying

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1 to avoid with connectors, particularly in the aged.

2 So, it is important to address the

3 question before the study is designed to examine

4 what answer you are looking for, the value to the

5 patient population or the patency and effectiveness

6 of the connector itself.

7 DR. BRIDGES: I have a question related to

8 what Wolf Sapirstein said, which is that one

9 question the panel should consider is, if we are

10 advocating a randomized trial, how do we feel about

11 the risk to control patients being

12 subjected\--assuming that the patient can\'t serve as

13 his own control for example, how would we feel

14 about control patients being cath\'d at six months

15 or one year?

16 DR. TRACY: I think that was Dr. White\'s

17 point, that it is hard to get patients back. We

18 have historic data on those patients regarding

19 long-term patency.

20 DR. FERGUSON: Some of the hardest data we

21 have seen today is from Dr. Klima, at Hanover, and

22 they don\'t seem to have a problem over there when

23 they set up a design trial for any of these issues.

24 I am not quite sure why we do.

25 DR. YANCY: Well, just to take some

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1 exception to that, any study design that comes up

2 has to clear local IRBs that are under increasing

3 scrutiny with regards to what they will subject

4 particularly control individuals to. So, I think

5 that Chris\' point is not an inconsequential

6 consideration. Certainly from the stent era we do

7 use MACE as an endpoint and I wonder how that

8 compromises this study design if we use MACE.

9 DR. TRACY: So, we have the scenario of a

10 historic control. We know what the patency rates

11 are. We have the scenario of the patients serving

12 as their own control, which will limit the type of

13 device that can be studied. There will be limits

14 there. And, we have a scenario of a randomized,

15 controlled study group that would be brought back

16 for intervention. I think each of these has some

17 problems. Dr. White?

18 DR. WHITE: I think that we need very hard

19 endpoints. I think hard endpoints make for

20 smaller, more firm studies. So, I really think we

21 want patency. I think we know already that

22 asymptomatic patients show up this way. We have

23 heard that perhaps non-invasive testing isn\'t an

24 adequate screen so we want the hard endpoint. If

25 we ask for patency at whatever interval, six

167

1 months, one year, then I think we take care of Dr.

2 Edmunds\' concern about the procedural issue because

3 if you are having closure at procedure you will see

4 the closure at six months as well, and you can then

5 backtrack that.

6 I think if you do single-arm studies with

7 objective criteria, which has its own problems with

8 a slippery slope, at least you can subject those

9 patients to a hard endpoint of patency, and I think

10 that minimizes the number of patients who are

11 studied. It gives you the hardest endpoint for the

12 follow-up. And, I think it really puts the

13 patients who are at risk for this problem as the

14 subjects of the study as opposed to the control

15 population.

16 DR. TRACY: Dr. Hirshfeld?

17 DR. HIRSCHFELD: I think there are really

18 two questions. The first question is do the

19 devices perform equivalently to standard hand

20 suturing? That, it seems to me, can be answered in

21 a study with a relatively small population of

22 patients and a study design analogous to what the

23 Hanover people presented. That has a very hard

24 endpoint and has a great deal of statistical power,

25 and that could settle this question with a

168

1 relatively modest number of patients, I would

2 think.

3 The second question is the question of

4 what global benefit does the patient derive from

5 this, and those are all surrogate endpoints. They

6 are neurological endpoints and they are MACE

7 endpoints. That could be addressed with a larger

8 randomized trial in which all the endpoints that

9 were collected were the surrogate endpoints in

10 terms of perioperative neurologic events and

11 long-term cardiovascular MACE and wouldn\'t really

12 require angiographic follow-up.

13 So, it would seem to me that one possible

14 approach to this issue and I think Dr. Mack\'s

15 comment about the importance of continuing

16 development in this field, independently of how the

17 current generation devices actually sort out, is a

18 very important point. But the issue of whether or

19 not we are hurting patients in terms of graft

20 patency can be answered with a relatively small

21 trial, and then the issue of whether or not

22 patients are deriving benefit in terms of surrogate

23 endpoints could be answered with a larger but less

24 complicated trial.

25 DR. TRACY: Dr. Blumenstein, do you have

169

1 any comments on that type of a design?

2 DR. BLUMENSTEIN: I am sorry, I wasn\'t

3 paying attention. I am doing some trial size

4 computations.

5 DR. HIRSHFELD: I am sure that if you try

6 to do a trial size computation there is no way you

7 can concentrate on anything else. But what I was

8 thinking was that if you did a study design

9 analogous to the study that was described from

10 Hanover in which each patient serves as their own

11 control for the performance of the device in terms

12 of graft occlusion, that is a study that has all of

13 the variables controlled through the randomization

14 process and has the highest possible degree of

15 precision in terms of the outcome event, and should

16 be able to be completed with a relatively modest

17 sample size.

18 DR. BLUMENSTEIN: That is exactly what I

19 am trying to compute.

20 DR. HIRSHFELD: But that doesn\'t answer

21 the other question which is are patients better off

22 in terms of events because of the use of the

23 device, or are they equivalently off, or are they

24 worse off. That would require a larger trial in

25 which patients are randomized between the device or

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1 not the device and the endpoints are all the

2 clinical endpoint events, neurological events and

3 cardiac MACE.

4 DR. BLUMENSTEIN: Well, we can discuss

5 this later I suppose but when designing the trial,

6 in order to size the trial you have to pick a

7 primary endpoint. Basically, I think what we are

8 stuck with here in this discussion, without getting

9 into a great amount of detail, is the dichotomous

10 outcome or either success or failure assessed at,

11 say, seven, eight months down the road, giving a

12 window for six-month angiography or something like

13 that.

14 The secondary endpoints or the other

15 benefits that might accrue then have to be assessed

16 in the context of the sample size computed for that

17 structure of the study and within the framework of

18 that study.

19 I think what you are asking is, if you

20 were to do a two group study, then you would have a

21 much better idea of the overall impact of the

22 benefit of this and a two group study might be

23 something like a treatment failure-free survival

24 study where you are using a time-to-event endpoint

25 and you randomize into two groups. In that case,

171

1 what you gain is that the patients in each group

2 are assessed with respect to all the outcomes and

3 are not muddied by having one vessel randomized to

4 the experimental procedure and one vessel

5 randomized to the control procedure. Maybe that is

6 a good follow-on study, a postmarketing type study.

7 But it seems to me that if you can achieve

8 the matched vessel type of study where each patient

9 is serving as their own control. If that study is

10 doable administratively, if you feel that you can

11 do the quality control, implement the intervention,

12 the randomization, etc., then I think that gets at

13 the answer about whether there is success with

14 respect to the vessels and a comparison to a

15 control which would take away the host factors.

16 DR. SAPIRSTEIN: \[Not at microphone;

17 inaudible\]\...safety together with effectiveness,

18 and much of the effectiveness of these devices has

19 yet to be determined by virtue of facilitating

20 other changes to the performance of CABG which

21 haven\'t in themselves been determined. For

22 instance, off-pump, beating heart, MIDCAB and all

23 those sort of things. One of our most important

24 considerations is patency right now. We are

25 interested in safety and MACE events but right

172

1 now\--well, not right now but at this stage of the

2 questions we are really interested in

3 effectiveness.

4 DR. TRACY: I think that is really very

5 important because it doesn\'t matter how safely you

6 can do something that doesn\'t work.

7 DR. SAPIRSTEIN: That is right.

8 DR. TRACY: So, I think that a definition

9 or determination of patency is critical to this.

10 DR. HIRSHFELD: To put this in context, we

11 have a currently approved, marketed device about

12 which some data has surfaced that raises the

13 question that its performance may actually be

14 inferior to conventional techniques. The data to

15 date are inconclusive but there is enough of a

16 cloud that that question has arisen. So, I think

17 our first obligation is to answer the question as

18 to whether or not it is equivalent or not to

19 conventional hand-suturing techniques. That, I

20 think, is something that can be answered with a

21 highly focused trial. Because if it turns out that

22 it is inferior, then all the other questions, all

23 of a sudden, are moved way to the background. If

24 the trial can demonstrate that it is equivalent or

25 superior to conventional techniques, then the next

173

1 question arises which is, well, does that benefit

2 in performance translate into clinical outcomes.

3 DR. TRACY: Dr. Maisel?

4 DR. MAISEL: In my view, I don\'t think

5 that one size fits all. I think there is more than

6 one way that we could feel comfortable with the

7 efficacy, and certainly a randomized clinical trial

8 would meet that standard. But I certainly can

9 imagine an observational trial with 10,000 patients

10 and no events or, you know, 1,000 patients and 5

11 events. There certainly could be an observational

12 trial, a one-arm trial that I think would meet that

13 standard. So, you know, the challenge of drawing a

14 line in the sand is a big challenge but I don\'t

15 think it is impossible.

16 DR. TRACY: Dr. Yancy?

17 DR. YANCY: This is tangential and I am

18 happy to table this item at the Chair\'s

19 prerogative, but Dr. Hirshfeld\'s reference

20 resonates clearly with the concern that has been

21 building in my mind over the last several hours,

22 and that is that there is a device on the market

23 about which questions have been raised. Part of

24 the questions perhaps have to do with the umbrella

25 under which it received approval. Part of the

174

1 questions may have to do with the very issue we are

2 discussing right now in terms of trial design. It

3 is hard to know the denominator. We know there are

4 a number of events that have come to the FDA.

5 It is also incumbent upon us to support

6 the development of the minimally invasive surgical

7 procedures. So, I think the analogy of babies and

8 bath water is correct. But I am beginning to

9 wonder if it is anywhere within our purview to

10 address this one specific device, or maybe it has

11 to be set aside to another entity, but it seems as

12 if it is not unprecedented to make statements about

13 concerns regarding the safety of a device that is

14 already marketed, not necessarily to withdraw it

15 but indicate that we have seen a signal that raises

16 questions. I am not saying it is a bad device

17 because, again, the statistics of looking at this

18 are difficult. If this is inappropriate, then I

19 will withdraw this and beg apology, but it is a

20 question that I would like to pursue.

21 DR. TRACY: If we could let the FDA speak

22 to that.

23 MS. FLEISHER: Dina Fleisher, from the

24 FDA. This issue has been addressed by the FDA.

25 There was a whole team here from our Office of

175

1 Surveillance that has been taking care of this and

2 addressing it in the purview of the limits that we

3 have at FDA. For the interest of this panel

4 meeting, that really isn\'t probably relevant to

5 this particular discussion of what future designs

6 we would like to have.

7 DR. YANCY: One follow-up question?

8 DR. TRACY: Yes?

9 DR. YANCY: Are there activities you plan

10 to do, without compromising your deliberations,

11 that you can tell us? I mean, is there a time

12 sequence or is there a statement to be prepared?

13 Is there anything that you can say in that regard

14 or is that an inappropriate question?

15 MS. FLEISHER: We could probably do a

16 one-minute summary if that is helpful to you.

17 DR. YANCY: I am happy to do that off-line

18 since I may be the only person who has this

19 concern.

20 \[Several members reply, \"no, you\'re not.\"\]

21 Then I think it would be important to us.

22 MS. FLEISHER: I will let the lead

23 reviewer from that office actually address that.

24 MS. HOANG: I am Quynh Hoang, from the

25 Office of Surveillance and Biometrics. As Dina

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1 Fleisher has indicated, the FDA is aware of a

2 number of MDR reports regarding the Symmetry device

3 and we have convened a committee, a cross-center

4 committee, to look at the issue. Your question is

5 specific to what FDA plans to do about the adverse

6 events that we have seen with the Symmetry, and the

7 only thing I can say is that we are working with

8 the company.

9 DR. TRACY: Thank you. Dr. Slaughter?

10 DR. SLAUGHTER: Dr. Slaughter. Just two

11 issues, using a patient as their own control and

12 trying to identify two arteries has been done

13 before, and that was the ARIA trial using a

14 synthetic conduit. Although it seems appealing, it

15 is extremely difficult to administer. The issue

16 that comes up is that even preoperatively you can

17 identify two vessels that you think are similar.

18 The problem is you are doing that on a preoperative

19 angiogram for which the stenosis may be different

20 in each, and the question is were they under-filled

21 because the dye is not getting there or are they

22 really that small? So, you are really using a very

23 crude comparison of external diameter. Then, when

24 you get there you sort of flip a coin and pick one.

25 You open it; you can size it; you open the other

177

1 one and it turns out it is different.

2 The other issue is still that although

3 they may look the same size, you know, before you

4 start there are other issues as to the size of the

5 bed they supply and things like that. It becomes

6 very difficult technically to administer and it can

7 prolong the operation significantly when you are

8 trying to randomize them intraoperatively. So,

9 although it seems appealing, and certainly to use

10 the patient as their own control just in general,

11 and if you do complete angiography as opposed to

12 selective angiography it is more doable, but to

13 truly try and randomize two what you think are

14 matched vessels in an individual patient is

15 technically very difficult.

16 DR. BRIDGES: I don\'t think you need to

17 necessarily match the vessels in each patient. I

18 think that the randomization will take care of

19 that. I mean, you don\'t match patients that are

20 randomized. You don\'t say, well, I am going to

21 randomize these two patients and I think they are

22 equivalent. The randomization itself\--it could

23 very well be that the first patient will have one

24 OM that has a tight stenosis and one that doesn\'t

25 and then in the next patient the converse will be

178

1 true. So, as long as you are randomizing the

2 technique that you use within the patients as you

3 go along, that should be a valid study design,

4 unless I am missing something.

5 DR. SLAUGHTER: Then you are back to where

6 you have a control that is not getting the device

7 and you have to have follow-up with invasive

8 monitoring and you are subjecting a control to an

9 invasive test.

10 DR. BRIDGES: No, what I am suggesting is

11 the same design that the group in Hanover used. In

12 that case, unless I misunderstood it, each patient

13 either had two or four anastomoses performed. If

14 they had two, then a random decision was made as to

15 which of those two would be done with one

16 technique, hand-sewn versus the device and each

17 patient was randomized in that fashion so that

18 there was no control group that was angiogrammed.

19 These are all patients who had an anastomotic

20 device used that served as their own control. So,

21 within those patients it is not relevant whether

22 the two arteries that were randomized were

23 equivalent. That is not the question.

24 DR. SLAUGHTER: I understand. I think

25 they are close but I think it does make a

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1 difference because there is a difference in

2 distals. Unless you quantify the information when

3 you start to review it, it is very difficult to

4 assess patency.

5 DR. BRIDGES: Sure.

6 DR. EDMUNDS: Well, to show off the

7 culture at the University of Pennsylvania, I am

8 going to disagree with my colleague, Dr. Bridges,

9 and agree with Dr. Slaughter. There is plenty of

10 data to show that the degree of proximal stenosis

11 in a native artery influences patency. Moreover,

12 there is a difference in patency rate between

13 target arteries\--circumflex, right, LAD\--well, LAD

14 is not in this equation. And, it will be a

15 logistic nightmare, Charles, to try to get patients

16 in which you can randomize the arteries. You just

17 won\'t be able to get enough patients without

18 getting into a whole lot of institutions, I don\'t

19 think.

20 DR. BRIDGES: Sure. I am not trying to

21 say it would be easy or simple to interpret, but I

22 am simply making the point that I think what has

23 been suggested is following the design of the

24 Hanover study and, as I understand it, that is the

25 way they conducted the study and that is my point.

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1 My point is to say that their study did not involve

2 trying to match arteries. They simply randomized

3 technique selection within patients who had an even

4 number of arteries. I certainly acknowledge that

5 that is not the same question as to whether the

6 degree of stenosis or the circumflex versus the

7 LAD, or whatever, will have different patency

8 rates. Hopefully, that would be taken care of by

9 enrolling enough patients but there still would be

10 challenges with that kind of a study. I am not

11 advocating it; I am simply trying to confirm what

12 the design of that study was.

13 DR. TRACY: I am going to try and move us

14 on to some of the next points, but just to briefly

15 summarize, the clear message is that not having

16 some type of control or some comparative basis is

17 not acceptable. Just having a study where the

18 device alone is being analyzed and then hoping that

19 something will be picked up at a later point is not

20 an adequate endpoint. There needs to be some type

21 of control built into the study but we are having a

22 hard time grappling with what that control should

23 be. Should it be intra-patient; should it be

24 patient-to-patient; or should be looking at a hard

25 outcome compared to historic control, patency

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1 outcome compared to historic control plus

2 randomization on surrogate endpoints such as

3 neurologic events.

4 I think that we would need, and I don\'t

5 think we can do that sitting here, a statistical

6 analysis to figure out what size would be needed

7 for each of these different models\--unless he is

8 very good and very fast. I would like to move on

9 to some of the other issues and maybe, when Dr.

10 Blumenstein is read, to come back to that if we

11 can.

12 DR. KRUCOFF: Cindy, just before you leave

13 that, let me make one comment about size. The

14 other side of what we have heard a lot of wisdom on

15 today is that you can drive the density of

16 endpoints into a higher direction to do a smaller

17 trial. So, if you know that actually arteries that

18 have greater plaque burden are more likely to fail,

19 or if you have diabetics they are more likely to

20 have problems, you can use propensity scores to

21 actually target a higher risk population and do a

22 smaller trial. So, you get into the conundrum of

23 you have to find those patients\--

24 DR. TRACY: I think we have had some

25 disagreement that a propensity score would be

182

1 effective in comparing at least to historic

2 controls so\--

3 DR. KRUCOFF: I am not talking about

4 historic controls. I am talking about how

5 frequently you can anticipate a failure endpoint in

6 a population to do a prospective study and do 100

7 patients and have an answer rather than 500 or

8 1,000 and have an answer.

9 DR. TRACY: Right. Well, we will leave it

10 there for the moment. Let us know when you have

11 finished your analysis, Dr. Blumenstein.

12 The second set of questions, with regard

13 to device placement and device design, please

14 address the following: Given the considerable

15 differences between the proximal and distal CABG

16 anastomoses, what, if any, differences in study

17 criteria should be required?

18 My observation would be you can\'t do a

19 proximal without doing a distal. I am not clear,

20 Dr. Sapirstein, on exactly what the question is

21 here.

22 DR. SAPIRSTEIN: There has been a lot of

23 discussion about the connector device which is

24 strictly for the proximal anastomosis of a venous

25 conduit to the aorta and doesn\'t involve anything

183

1 about suturing to the distal coronary. Now, there

2 are a lot of devices which specifically address the

3 distal anastomosis to the coronary artery and not

4 to the aorta, and other devices which are just

5 going to anastomose an artery, the LIMA to the LAD

6 or something of that nature. So, there is a lot of

7 variation in the indications for a participant

8 device.

9 DR. WHITE: Well, I would say that the

10 first criteria, the primary criteria has to be

11 patency, and patency whether it is proximal or

12 distal doesn\'t matter to me. I want to know that

13 the graft and the device is patent and I am not

14 confident that we have non-invasive ways to screen

15 these patients for patency. So, that brings us

16 back to a hard endpoint, patency. So, I am in

17 favor of applying the same criteria to the distal

18 as I would to the proximal anastomosis.

19 DR. TRACY: John?

20 DR. HIRSHFELD: I am saying this with some

21 fear that I will subsequently be exposed as being

22 simplistic, but I think that the issues are the

23 same and I think that the trial design, whether we

24 are examining proximal or distal anastomoses,

25 should be able to be the same, with the same

184

1 departments.

2 DR. WHITE: No, they are not the same.

3 DR. HIRSHFELD: Okay, I knew somebody

4 would bring that up.

5 DR. TRACY: Dr. Edmunds, do you want to

6 make some comments?

7 DR. EDMUNDS: I would suggest for starters

8 that for proximal saphenous vein, aortal saphenous

9 vein anastomosis the following for endpoints: An

10 aortic complication, changes in neurocognitive

11 state or stroke, patency whether it is an occlusion

12 or stenosis, hemorrhage, and acute revision, you do

13 it at the table or just after you closed, and any

14 device-related death as endpoints. I have left out

15 myocardial infarction.

16 DR. TRACY: I think those were the reasons

17 for wanting the MIDCAB in the first place, to

18 reduce some of those neurologic types of outcomes.

19 The one thing that is in there though that is

20 similar to distal would be patency. But I agree,

21 those are additional concerns for the proximal

22 anastomosis. Dr. Ferguson?

23 DR. FERGUSON: I think we can have the

24 same endpoints but the devices themselves are so

25 dissimilar and used for such different reasons that

185

1 we have to be cognizant of that.

2 DR. KRUCOFF: I agree with Tom. I think

3 it has been made very clear that even the technique

4 of putting something into a beating heart where you

5 are doing a distal anastomosis may be totally

6 different than the technique of connecting

7 something to an aorta. There may be some overlap

8 in the endpoints but these are separate trials.

9 DR. SAPIRSTEIN: A question that comes up,

10 Hank, is, for instance, do you require a six-month

11 patency evaluation for a proximal and a six-month

12 for a distal, or would you require different rigor

13 of evaluation for a proximal, which is a large

14 vessel, a large anastomosis, relatively crude?

15 That is one of the questions that sort of

16 distinguishes the two areas.

17 DR. EDMUNDS: Wolf, I am going to defer to

18 the collective wisdom in the room.

19 DR. AZIZ: From the data that we saw with

20 the other device, by six months we were seeing

21 problems so I think even though the time period may

22 be different I think six months should be at least

23 the minimum time frame.

24 DR. TRACY: Dr. Kato?

25 DR. KATO: I would agree with Dr. Aziz

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1 that six months should determine patency both for

2 proximal and distal anastomoses. The only

3 difference with the distal is that the criteria of

4 any aortic complication or stroke won\'t be there.

5 DR. TRACY: Dr. Yancy?

6 DR. YANCY: Going back to the question of

7 being simple, I think simple is good, John, and the

8 study design is quite similar, in my judgment. It

9 is just the endpoints and surrogates and the

10 variables that we follow are different, some

11 referable to the aortic anastomosis, others

12 referable to the technical concerns. But

13 ultimately the study designs are not terribly

14 different. It is just the length of follow-up and

15 what we follow.

16 DR. TRACY: Yes?

17 PROF. KLIMA: Uwe Klima, from Hanover. I

18 think the myocardium does not care whether the

19 blood flows through a proximal anastomotic device

20 or through a distal device anastomotic device so

21 the endpoint really should be patency rate after

22 six months and does the anastomosis look good

23 whether it is running through a proximal or through

24 a distal anastomosis.

25 DR. TRACY: Dr. Weinberger?

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1 DR. WEINBERGER: Yes, I am sitting here

2 and I am wondering whether people are beginning to

3 blur the difference between graft patency and graft

4 stenosis. I think that the numbers that people are

5 talking about, looking at six months, makes sense

6 in the context of stenosis. If you are talking

7 about patency, the numbers sound to me like looking

8 just at six months you are not going to have enough

9 events. Maybe we can get the surgeons to comment

10 on that. You care ultimately about how the graft

11 feels when it has done healing. The failure rates

12 that we are talking about really are complete

13 occlusions. If you look at six months, is the

14 acute response to the surgical process, given these

15 new connectors, completely finished by that point?

16 DR. AZIZ: You may not get complete

17 adhesion but you may even get severe stenosis so

18 even that is bad.

19 DR. WEINBERGER: I agree that it is bad,

20 but we are talking about endpoints being graft

21 failure. Is that right?

22 DR. EDMUNDS: Well, let\'s just stay with

23 the aortic saphenous vein proximal anastomosis and

24 then deal separately with distal. Okay? The

25 reason is that I think that you can\'t say when

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1 healing ends, except when you change your address

2 permanently. So, I think you just pick a period in

3 time and you say that is our endpoint. If we see

4 25 percent stenosis in 50 percent of the device

5 applications and we see 3 percent stenosis in the

6 control group, that probably would work out, if we

7 got enough power, to significance. Now, how

8 important that is, that is not the question. That

9 is not the outcome either. It is the stenosis.

10 That is what I am advocating.

11 DR. WEINBERGER: So, just to concretize

12 this, we are talking about a continuous variable at

13 six months and we are talking about not measuring

14 graft patency rate, although that might be a

15 secondary endpoint. We are talking about the

16 difference in the distribution of patients with

17 respect how tight the stenosis is proximally. Is

18 that right?

19 DR. EDMUNDS: The question you are asking

20 is the same as what is the patency rate of the

21 rapamycin stent at five years? No one knows. We

22 haven\'t been five years. It could be 50 percent.

23 DR. TRACY: So, I guess the answer here is

24 that you find a time, a period of time where you

25 look and that becomes the data point that you have.

189

1 DR. KRUCOFF: Well, there is an issue with

2 a biomarker. In fact, what you are describing is

3 minimal luminal diameter so as a continuous

4 variable you take your point, six months for the

5 proximal anastomosis in the device group. The

6 minimal luminal diameter is smaller than for the

7 non-device group. That may be a statistically

8 significant difference. Then a separate question

9 becomes is it so small that they are having angina,

10 infarctions or deaths? And, that is a trial design

11 that is, again, pretty well established but it is a

12 biomarker where the statistical significant

13 difference is not one and the same as the

14 clinically meaningful endpoint.

15 DR. TRACY: Let me skip ahead to part b),

16 are there certain aspects of the clinical study

17 design, example, length of follow-up and endpoints,

18 that should be required for all devices

19 irrespective of device form and function? for

20 example, the U-clip performance closely duplicates

21 that of a suture, whereas the Symmetry has greater

22 similarity to a stent.

23 So, where we are I believe is that there

24 would be specific aspects of a clinical trial

25 design that would be different whether you are

190

1 talking about proximal or distal, but there has to

2 be some concrete endpoint, and probably you could

3 come up with a generic time frame\--six months, nine

4 months, whatever you choose\--whereby the patency or

5 the percent stenosis would be analyzed. The other

6 endpoints might be more appropriately analyzed, of

7 course, at different times\--neurologic events

8 acutely or catastrophic events, obviously, would be

9 analyzed acutely.

10 DR. BRIDGES: I think to answer this

11 question, 2.b, my opinion would be that these

12 devices are so different and so protean in their

13 designs that I think it would be difficult for us

14 to prospectively or a priori try to figure out what

15 we expect the differences to be. So, I would think

16 that the design of a study for all distal devices

17 ought to be the same, at least as a starting point.

18 I mean, you might look at a device and say, well,

19 that looks like a suture and, therefore, we don\'t

20 need maybe as large a study group. But I think the

21 most straightforward approach would be to have the

22 same endpoint irrespective of what our opinion

23 about how we think the device will function is.

24 DR. KATO: But the implication really is,

25 is one device similar to another one, which is a

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1 discussion, as Dr. Frater who I guess is not here

2 anymore brought up before about, you know, is this

3 device definitely going to be a PMA or is it going

4 to be a 510(k)?

5 DR. TRACY: It is not in the purview of

6 this group to change whether something is a 510(k)

7 or PMA. That is completely off the table even as a

8 question to this group. The question really is

9 study design. I think that you have to design a

10 study that is going to capture important endpoints

11 with it is a 510(k), PMA, or whatever you call it.

12 A concrete point in time to say let\'s look and see

13 what the anatomy looks like, with it is a

14 continuous variable like stenosis or absolute

15 patency/occlusion, that is a time you choose that

16 makes biologically some sense\--six months, nine

17 months, and the other variables appropriate to

18 those types of outcomes. Does that seem to make

19 sense?

20 DR. YANCY: So, in that context I would

21 like to support what Dr. Bridges said, that there

22 is sufficient variability and sufficient degree of

23 unknown that the answer to the proposed question is

24 that there should be some consistency in the time

25 of follow-up\--

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1 DR. TRACY: Right.

2 DR. YANCY: \--irrespective of the

3 mechanism of action.

4 DR. TRACY: Right. I think that is a good

5 point. Part c) to that question, it is rarely

6 possible to determine the cause of conduit failure.

7 Can you suggest criteria to determine whether a

8 failure is device related? Dr. Yancy?

9 DR. YANCY: That is the essence of a

10 clinical trial design. You have to have a clinical

11 trial that rules out the confounders, or at least

12 equilibrates them between the intervention and

13 reference group so that you can have only one

14 remaining variable and presume that it is, in fact,

15 the device. I mean, that is the whole purpose for

16 a clinical trial.

17 DR. ZUCKERMAN: That is perhaps the first

18 part of the equation, but FDA was also wondering

19 whether the panel agreed with some of Dr. Krucoff\'s

20 earlier comments. For example, should some of the

21 methodologies from the stent trials be adapted to

22 these CABG trials, meaning should there be an

23 independent clinical events committee looking at

24 these events to try to determine cause of graft

25 failure. Two, is it worthwhile to, for example,

193

1 have an independent core angiographic laboratory

2 look at the angiograms, at least in a percentage of

3 patients, to confirm what the sites are calling

4 device versus non-device related?

5 DR. EDMUNDS: Bram, do you have the

6 criteria for the stent trial? I am not sure that I

7 know what those were.

8 DR. ZUCKERMAN: A set of criteria has been

9 developed over the last ten years in order to

10 minimize potential sources of bias and to make sure

11 that we are comparing apples with apples, and they

12 include randomization, use of an independent

13 clinical events committee and, because of the

14 importance of correct angiographic analysis and the

15 known ability of site investigators to look at

16 angiograms and develop measurements that can\'t be

17 confirmed, the use of independent core labs. Those

18 are the main ones.

19 DR. MAISEL: I think an independent core

20 lab is obviously going to be a critical part of any

21 assessment of graft stenosis. I do think that an

22 independent data and safety monitoring board or

23 clinical events committee is also a critical

24 component. I think getting at the issue of cause

25 of device failure or cause of failure of graft

194

1 patency, whether it is due to the device or not, is

2 going to be extremely difficult based on

3 angiographic or clinical criteria, and I think, you

4 know, the trial designs we talked about are really

5 the only way to get at that.

6 DR. AZIZ: I think the cause of graft

7 patency or failure sometimes may be clear-cut. For

8 example, if you are doing an angiogram and you see

9 90 percent stenosis at the proximal end, that may

10 be okay but if you do the angiogram at six months

11 and the graft was stenosing at three months and the

12 flow was slowing by six months, it may be occluded.

13 So, you know, I don\'t think it will always be

14 clear-cut but sometimes I think it will be but

15 sometimes it may not be. All you would say is that

16 the graft is occluded and you may not be able to

17 say if it was, let\'s say, a rheology type problem

18 or whether it was because of stenosis. So,

19 hopefully, by doing a randomized study that might,

20 you know, become clearer.

21 DR. KATO: But one question for you, from

22 what I hear from the angiographers, when you get

23 stenosis or an occlusion from one of these devices,

24 the clot or the platelets go right up to the edge

25 of the aortal-vein junction. Correct? Because

195

1 that is relatively atypical for a hand-sewn graft

2 with a good cobra head which is usually open and

3 then there is clot distal to that, which suggests

4 that it is not a proximal anastomosis problem.

5 DR. WHITE: I think that when you close a

6 graft\--I was interested in some of the images that

7 were shown today, and I think John was too, about

8 some of the stenoses in the middle of the graft.

9 What I think you are saying is that you don\'t know

10 if it is intimal hyperplasia from within the stent

11 part of the device or whether it is the middle part

12 of the graft that actually goes down because as

13 soon as the graft goes, then the thrombus

14 propagates. In the hand-sewn stuff you have to

15 make that hood and we always have a little nipple.

16 These devices seem to go right up flush. But I

17 don\'t know if you can tell where the problem

18 started angiographically after the occlusion has

19 occurred. It could be with the device or it could

20 be in the middle of the graft.

21 DR. KATO: But don\'t you think if the clot

22 or the platelet plug goes right up to the end of

23 the graft, you know, to occlude the device that

24 most likely that is where it started? In the

25 standard hand-sewn anastomosis\--you are right, you

196

1 still have that little nipple there.

2 DR. TRACY: Are we struggling with the

3 fact, exactly what the FDA is saying, that it is

4 difficult to determine the cause of conduit

5 failure? I am not sure that anything we have

6 discussed so far has really gotten us any closer,

7 except to say that having an independent DSMB and

8 core lab to look at it. I am not sure what they

9 are looking at though. I mean, we don\'t understand

10 the pathology, as far as I am hearing from this

11 discussion. Unless, Dr. Emery, you have something

12 that would clarify this.

13 DR. EMERY: I don\'t think so. I agree

14 that when you get either a proximal or distal

15 stenosis, thrombosis propagates to the next major

16 branching which in vein grafts is either the

17 proximal or distal anastomosis.

18 What I was going to address here was the

19 issue of distal anastomoses because you need to

20 remember that the conduits are different. Of all

21 the data we have seen today that is variable, the

22 data that is least and almost invariable is the

23 early and one-year patency of internal mammary

24 artery grafts. As Michael Mack has said, we need

25 to think like cardiologists where we solve problems

197

1 rather than fight about them. The problem of the

2 LIMA to the LAD is fairly straightforward.

3 Historical data is new. It is done on

4 MIDCAB and done on off-pump surgeries. There are

5 multiple papers and very recent literature and it

6 is very solid data, and you are evaluating an

7 artery to an artery anastomosis with a

8 stent-like\--I don\'t want to say a stent, a

9 stent-like process there so interventional

10 angiography could be applied to a mammary to the

11 LAD. In saphenous vein grafts that is not true

12 because the conduit is variable for various

13 individuals. So the criteria for establishing

14 patency leans more towards randomization and, as

15 Dr. Edmunds has addressed, there are different

16 patencies for different systems, different run-offs

17 and different degrees of stenosis with the vein

18 graft in particular. That does not appear to be

19 true with mammary artery grafts. So, you may have

20 to vary your study criteria for the conduit that is

21 being utilized in a particular study.

22 DR. TRACY: John?

23 DR. HIRSHFELD: Thinking ahead to what the

24 data will be, the first endpoint is going to be

25 patent versus not patent and that is going to tell

198

1 us whether there is a performance difference

2 between the device and the traditional technique.

3 Patent versus not patent is not going to say

4 anything about the etiology of the loss of patency.

5 There likely will be a group of grafts that are

6 patent but stenotic and in those grafts the

7 location of the stenosis will probably give us some

8 insight as to what the etiology of the impending

9 failure of that graft would be, and we would

10 probably be able to tease out the answer to the

11 etiology of increased overall graft failure from

12 that data.

13 DR. TRACY: So, it really becomes

14 observational, once again emphasizing the need to

15 have angiographic follow-up so we can over time

16 figure out what these failures are related to. Dr.

17 Yancy?

18 DR. YANCY: I think there is just one

19 other variable referable to the question that Dr.

20 Zuckerman has on the table that captures everything

21 we have been dealing with. The one concept we

22 haven\'t addressed is that of bias. There is no way

23 that this can be a blinded protocol because the

24 surgeon knows what he or she has done. And one of

25 the strengths of having adjudication committees,

199

1 DSMBs and core labs is that it really mitigates

2 that whole variable. So, I think the answer to

3 what you have raised, Bram, is an emphatic yes, we

4 do need to populate that study with the usual

5 complement of oversight committees, maybe even more

6 so because of concerns we might have.

7 DR. BRIDGES: I agree with that and the

8 point that Dr. Hirshfeld made. I think it might be

9 important to make sure as we go through this

10 evaluation process that some attention is paid not

11 just to patency versus non-patency, stenosis versus

12 non-stenosis, but that a deliberate attempt be made

13 to indicate the distribution of stenoses within

14 grafts and that might provide additional useful

15 information. I mean, typically that information is

16 not available when we read studies of this nature

17 but, you know, if you found a different

18 distribution of stenoses that might provide the

19 clues as to whether it was device related.

20 DR. WHITE: I would like to say that I

21 think we can fulfill two out of three of Bram\'s

22 criteria, that is the core objective criteria, the

23 core lab and DSMB. I would still like to leave the

24 door open for a trial that is a single-arm

25 objective performance criteria trial. That would

200

1 still lend itself to DSMB oversight, high rate of

2 angiographic follow-up and independent assessment

3 of the angiographic endpoints, and worry about the

4 slippery slope issues that are real that will come

5 up if you come close but don\'t make the endpoint.

6 DR. SAPIRSTEIN: We have used the

7 generally applied criteria for conduit patency as

8 greater than 50 percent, not more than 50 percent

9 stenosis. If there is stenosis greater than 50

10 percent, we have considered that an obstructive

11 lesion, a failure. Is this an acceptable endpoint?

12 DR. FERGUSON: I am no angiographer by a

13 long shot, but I think we know from the rheology

14 that 50 percent is a flow-limiting lesion\--

15 DR. SAPIRSTEIN: Yes.

16 DR. FERGUSON: \--so I think that is a good

17 place to start.

18 DR. WHITE: I would like to start at the

19 place where intervention is contemplated, and I

20 think that failure would be defined as the level at

21 which you would be willing to reintervene either

22 with reoperation, angioplasty or stent. I think

23 that either 50 or 70 percent is going to be that

24 threshold.

25 DR. KRUCOFF: I think as a true continuous

201

1 variable, minimal luminal diameter at the actual,

2 let\'s say, proximal anastomosis site might be a

3 useful observation, whether it is a primary

4 endpoint or not.

5 DR. EDMUNDS: One more would be symptoms

6 from the region at risk.

7 DR. WHITE: That is absolutely true,

8 except we heard today that many of these vein

9 grafts fail without symptoms or even very good

10 objective measurements. So, that is the problem.

11 DR. EDMUNDS: That can\'t be the only

12 criteria.

13 DR. TRACY: Dr. Zuckerman?

14 DR. ZUCKERMAN: The points that Dr.

15 Krucoff made about use of MLD instead of the

16 dichotomous endpoint of greater or less than 50

17 percent are very interesting, and also Dr. Bridges\'

18 point about looking at the distribution of intimal

19 hyperplasia, etc. because potentially those

20 endpoints can decrease your sample size, but the

21 challenge that we have right now, until we learn

22 more about what that means, is to choose a patency

23 endpoint that is clinically relevant and that is

24 why we, at the FDA, like Dr. White\'s idea of the 50

25 percent benchmark right now. But, Dr. White, can

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1 you explain that the actual determination of that

2 50 percent benchmark is very dependent with vein

3 graft disease on how you measure it, and do you

4 have any qualifying factors here?

5 DR. WHITE: Yes, I would like to be the

6 core lab!

7 \[Laughter\]

8 Bram is referring to the problem of what

9 is the reference object and what is the reference

10 segment from which you take the 50 percent diameter

11 in a vein graft. There are obviously differences

12 in the proximal and distal diameter of that graft

13 and that would have to be codified. I think you

14 would maybe even have to divide the graft into

15 thirds, as we used to talk about, proximal,

16 mid-body and distal regions of the graft, and we

17 could codify the nearest normal segment of that

18 graft to be the 50 percent measurement. The

19 problem with that is the ostium and then you would

20 have to take the nearest distal segment, which is

21 obviously a different standard.

22 DR. EDMUNDS: Why do you seek a single

23 outcome? My car fails in lots of ways\--flat tire,

24 motor stops, clutch falls off, all kinds of ways.

25 So, if this proximal anastomosis blows off the

203

1 aorta, that is a failure as far as I am concerned.

2 DR. ZUCKERMAN: Right. If I were to

3 summarize your comments before, I think we agree

4 that all the endpoints that you noted must be

5 measured and observed on the case report forms.

6 One could generalize them into acute procedure

7 success composite variable and chronic success

8 composite variable measured perhaps at six months,

9 and the six-month variable would include that

10 measurement of greater than 50 percent patency plus

11 perhaps B or C, but I think the 50 percent patency

12 that Dr. White is referring to is a very important

13 part of that chronic composite endpoint due to its

14 clinical implications. It is where he would

15 reintervene if it was greater than that, which is

16 what we are interested in.

17 DR. BRIDGES: The other reason for the 50

18 percent is that the Fitz-Gibbon criteria are based

19 on 50 percent and there is a large literature so to

20 compare the data to that, obviously that would be a

21 useful endpoint and several recent studies have

22 used that classification system. So, clearly, it

23 would be important to have that particular cut-off

24 point.

25 DR. KRUCOFF: The only pitfall I would be

204

1 wary of then is if a 45 percent stenosis at 6

2 months is a harbinger of a 95 percent stenosis at

3 18 months, the dichotomous approach, if your

4 angiographic endpoint is too early, might create a

5 pitfall. I would just be thoughtful about

6 combining the timing of your angiogram\--if a

7 primary endpoint is dichotomous at a clinical

8 level, to make that the timing of your angiogram is

9 sufficiently latent in natural history that it is

10 appropriate.

11 DR. ZUCKERMAN: Again, Dr. Krucoff, you

12 have given an analogy of the stent trials and you

13 mentioned first in man. Does part and parcel of

14 this need to be to show chronic stability in a

15 smaller subset between one and two years, which was

16 the first in man stent analogy? Another technique

17 that we used in the stent trials is to ask for an

18 IVIS subset study in order to show actual healing

19 at the site of implantation. Would you like to

20 comment?

21 DR. KRUCOFF: I think that is a little

22 tougher only because now you are really

23 instrumenting this. I think there has already been

24 expression of concern about how far you are going

25 to go with invasive procedures. I think it is

205

1 pretty compelling in this arena. You are going to

2 have to go at least to an angiogram. That is my

3 personal opinion.

4 I feel a little differently when it gets

5 to full anticoagulation in order to put an

6 interventional catheter, you know, a guide wire

7 through the vessel and bring a device down where

8 you are not actually planning therapeutic for the

9 vessel. It is possible that at a later time you

10 might eventuate a specific question to ask, Bram,

11 but I would be concerned about

12 over-instrumentation.

13 DR. HIRSHFELD: To follow-up on what Mitch

14 just said, the more I listen to this the more I am

15 concerned about the challenge of recruiting

16 subjects to participate in this trial. I am not

17 backing away from the importance of doing the

18 trial, but I think the challenge to the sponsors

19 and to the investigators will be to recruit a

20 patient who is going to receive two saphenous vein

21 grafts, and tell the patient that one of those two

22 grafts will be treated with this new device and, as

23 a reward for participating in this study, they get

24 to have a cath at six months. So, it may be that

25 there will be relatively limited incentive in the

206

1 part of patients to actually sign up for this, and

2 it might be a real challenge to recruit for this.

3 I think we have to weigh that consideration in

4 addition to everything else.

5 DR. AZIZ: We could ask the professor from

6 Germany, he could probably give us some insight as

7 to how difficult it was to recruit patients. Could

8 you give us some insight on that?

9 PROF. KLIMA: Could you just repeat the

10 question for me?

11 DR. AZIZ: You know, there has been some

12 concern raised that if we stay with the strict

13 criteria and the patients need to have an angiogram

14 that they may not want to come into the study. Did

15 you have difficulty in recruiting patients into the

16 trial?

17 PROF. KLIMA: Not at all. I think you

18 have to real give the patient the information that

19 you are using a new system, and even though all

20 these devices had a CE certificate in Europe which,

21 you know, is some kind of approval from the

22 European governments, you have to make the point

23 clear that this is that we do not know how it will

24 react within the next six months, twelve months, or

25 whatever. So, we talk to the patients before we do

207

1 the surgery and I would say that 99 percent of the

2 patients agreed to be a part of the study.

3 DR. AZIZ: Also, were they sort of

4 favorably disposed to the angiogram?

5 PROF. KLIMA: Well, I think that really

6 depends on your study coordinator. I would say

7 more than 80 percent would say yes, they will come

8 back for an angiogram.

9 DR. TRACY: I think we have a lot of

10 history of having protocols where we have had to

11 ask patients to come back and do procedures that

12 clinically otherwise wouldn\'t have been indicated.

13 Either you can do it with a good coordinator or you

14 can\'t. If you can\'t, then you are not going to

15 have the patients enrolled in the study. I don\'t

16 think that that is our concern here. I mean, we

17 are trying to decide what the best design is.

18 DR. AZIZ: I think that question has been

19 raised a number of times as to whether if you told

20 a patient they are going to have an angiogram at

21 six months how easy to would be to recruit the

22 patients.

23 DR. TRACY: Well, if you can\'t, you can\'t.

24 DR. WHITE: I think that is a cultural

25 issue. Having practiced in a European country, I

208

1 can tell you that the American population reacts

2 differently than they do in Scotland and I am sure

3 that the German population, in their relationships

4 to their physicians, is distinct from the

5 relationship that we have in the United States and

6 I don\'t know that that translates very well.

7 DR. BRIDGES: I have one quick question on

8 the study design by the professor from Hanover.

9 Given that you hand-sewed half of the anastomoses

10 and you used the anastomotic device for the other

11 half, and your patients were all done on bypass I

12 believe.

13 PROF. KLIMA: Yes.

14 DR. BRIDGES: How did you decide which

15 graft to do first? Did you use side-biting clamp

16 for your proximal anastomosis for the hand-sewn and

17 then remove it and then do the Symmetry device, or

18 did you use the Symmetry device in the presence of

19 a cross-clam? I just wanted to know if at some

20 point you could provide those details because those

21 would be important details in terms of figuring

22 out\--if the committee decided to follow that sort

23 of study design, those would be important details.

24 PROF. KLIMA: Yes, we did both proximal

25 anastomosis first under the side-clamping condition

209

1 because there are several techniques out there

2 which allow you to make a proximal anastomosis

3 without side clamping. However, this is pretty

4 difficult because you would have another device

5 which you need to make a proximal anastomosis. So,

6 we just side-clamped, made the proximal anastomosis

7 first and then, as a consequence, we did the distal

8 anastomosis depending on the target artery which

9 was selected for the Symmetry device or the

10 hand-sewn anastomosis.

11 DR. BRIDGES: You applied the Symmetry

12 device with a side-biting clamp in place?

13 PROF. KLIMA: Yes, we did.

14 DR. BRIDGES: Which is a little bit

15 different than the typical application in beating

16 heart surgery.

17 PROF. KLIMA: Yes, that is correct but you

18 can use the system also in an arrested heart

19 situation where you make your cross-clamp, for

20 example, and still have the opportunity to make a

21 shot with this device. The side-clamp technique

22 allows you to have a pretty similar situation at

23 least for your first shot when you are doing the

24 Symmetry anastomosis because the aorta is still

25 filled with blood so you are able to bring the

210

1 system in, in a very similar way as you would do

2 without side-biting or without cross-clamping the

3 aorta.

4 DR. AZIZ: Did any of the patients have a

5 stroke?

6 PROF. KLIMA: No.

7 DR. TRACY: Dr. Hausen?

8 PROF. KLIMA: May I just make one final

9 comment because there was a lot of discussion going

10 on about this Hanover model I presented today, and

11 a lot of discussion going on with respect with

12 should we use historical controls, yes or no. I

13 think we cannot exclude historical controls because

14 if we just look at the Hanover data with hand-sewn

15 anastomosis compared with an automatic anastomosis

16 and if our hand-sewn anastomosis would have been as

17 bad as the Symmetry anastomosis, we would have

18 concluded that the Symmetry device is as good as

19 the hand-sewn anastomosis, which is absolutely not

20 comparable with this data of the atrial

21 vascularization. So, you have to have a historical

22 control in order to see whether your results really

23 compare to the data of the atrial vascularization

24 out there.

25 DR. TRACY: Thank you. Dr. Hausen?

211

1 DR. HAUSEN: Bernard Hausen. I share Dr.

2 Hirshfeld\'s concerns. If you look at all these

3 trials that are happening with these devices, 90

4 percent are done in Europe for a good reason,

5 because you can\'t recruit American patients to come

6 back and have their angiograms performed at six

7 months or, if you do, you get completion of

8 follow-up of less than 50 percent which Dr.

9 Zuckerman told us is not acceptable. I mean,

10 almost all these trials for American products for

11 American approval are done overseas. I think that

12 is an ethical concern, especially now that there is

13 a class action suit against one of the major valve

14 companies because one of the valves didn\'t work

15 well and the patients didn\'t fare well, and now the

16 lawyers in Europe are saying you are putting our

17 patients through all this for the benefit of

18 Americans because we think of all these wonderful

19 trials that involve lots of controls and follow-up.

20 So, I think that is just something we have to put

21 in context here.

22 DR. WHITE: That is not true. That is

23 absolutely not true. I mean, the European trials

24 clearly precede the American trials, that I won\'t

25 argue, but we do randomized trials; we do

212

1 angiographic follow-up at a very high percentage

2 rate for stent trials for example. So, we do the

3 same thing in the American population that we do in

4 the European population. It just usually lags

5 because of regulatory issues.

6 MR. MORTON: To echo Dr. Klima\'s very good

7 point, he has been conducting studies against

8 devices which are CE marked, that is, cleared for

9 marketing, and what we are wrestling with on the

10 panel today is what sort of information do we need

11 before going to 510(k) clearance and that very much

12 affects the sponsors.

13 MR. LOTTI: My name is Richard Lotti. I

14 am the CEO of Converge Medical. I have some

15 inherent conflicts, of course.

16 I just want to comment on the last

17 statement regarding trials in the U.S. We are one

18 of the companies that actually did attempt an IDE

19 trial in the United States. We have been

20 successful with it. I will tell you that we had 17

21 IRB sites approved in the U.S. Over a 12-month

22 period we were able to get 6 sites to enroll

23 patients. During a 3-month period in Germany we

24 were able to get 3 sites to enroll the same amount

25 of patients. So, there clearly are differences in

213

1 the two marketplaces, but we believe we have been

2 able to accomplish patients from both geographic

3 centers.

4 DR. TRACY: Dr. Blumenstein, I think you

5 have some analysis for us.

6 DR. EMERY: May I make one comment while

7 he is coming up? Dr. Klima raised a very important

8 point in technique because he put the Symmetry

9 device on while a partially occluding clamp was on.

10 I think that is a technical mistake and I am sorry

11 respectfully to do that, but you have to

12 depressurize the system to punch it. You apply the

13 device and then you repressurize the system to

14 aortic pressure and that can disrupt the seating of

15 the device and cause device failure. I think the

16 device was made to be applied in a pressurized

17 system, and varying from that developmental

18 indication can cause problems with the device. So,

19 it may not be a device failure that he suffered

20 through in his bad results but a technical

21 application of the device which alters the way it

22 is implanted.

23 DR. BLUMENSTEIN: Please keep in mind

24 these are very preliminary, cone by the seat of my

25 pants as I was sitting there.

214

1 \[Slide\]

2 So, one of the designs we discussed was a

3 paired comparison with a dichotomous outcome. Of

4 course, in any trial one must always identify a

5 primary outcome and in this structure one would

6 define a primary outcome for each vessel graft in

7 each patient and that would be a success or

8 failure. The success, for the purposes of this

9 presentation, is that the graft is okay at the

10 specific follow-up time, say six months. And, you

11 have to define what \"okay\" is somehow or another

12 and that, of course, is never simple. Failure is

13 not success and that is a way to try to get around

14 missing data but there are still some things I want

15 to say about that.

16 Within each patient you would randomize

17 two vessels or I suppose four if you could. If you

18 did that, then you have to consider whether you are

19 counting the patient as two units or one. It may

20 require special statistical techniques to handle

21 that situation but for the moment let\'s assume that

22 we are doing two vessels per patient. One would

23 get usual care, whatever that is, the other would

24 get the experimental intervention.

25 We have to decide also what to do about

215

1 inevaluable patients, that is, patients who don\'t

2 return for their, say, six-month evaluation. That

3 may not be so bad since you are missing both

4 endpoints but you would, of course, have to assess

5 the reasons the patients didn\'t come back.

6 There are lots of complications here. I

7 think I tried to communicate that before. This is

8 a very complicated design. It would be very

9 difficult to administer the randomization, and so

10 forth, and I think we already heard some other

11 people commenting on that. Nonetheless, it might

12 be worth trying.

13 \[Slide\]

14 The basic data structure is a 2 X 2 table.

15 What we would be recruiting would be N pairs of

16 vessels. For each pair of vessels there is an

17 outcome that is either failure-failure,

18 success-success, failure-success or

19 success-failure. So, each of these Ns represents a

20 number of pairs of vessels for which there is both

21 fail, both succeed, etc.

22 The outcome measure of interest is this

23 number here over this N and this number here over

24 this N, and specifically the difference between

25 those two proportions, that is, this over N and

216

1 this over N.

2 \[Slide\]

3 So, these two proportions estimate

4 proportion of success and control vessels and

5 experimental vessels respectively. The statistical

6 test one uses for this is called the McNemar test

7 for testing the difference in these proportions.

8 The required study size depends greatly on the sum

9 of N failed-success and N success-failed, in other

10 words, the discordant cases. If we go back, it is

11 these cases here that represent the difference in

12 outcome within the same patient. Specifically, a

13 smaller proportion of discordant cases leads to a

14 smaller study size.

15 \[Slide\]

16 Now I want to say a word about

17 non-inferiority because that is really I think what

18 we are aiming to test here. We would be testing a

19 null hypothesis of a specified difference. In

20 other words, we would beforehand decide what

21 represented non-inferiority. The alternative

22 hypothesis would be equal or better than

23 inferiority. Rejection of the null hypothesis

24 provides evidence of non-inferiority. I don\'t

25 happen to have software for planning a

217

1 non-inferiority trial for the McNemar test but we

2 can come close to that.

3 \[Slide\]

4 I want to say a word about data monitoring

5 in a non-inferiority trial. A data monitoring

6 committee watches for evidence of rejection of the

7 null and would also look for futility. But early

8 evidence of rejection of the null is easy if the

9 experimental intervention is superior. So, one

10 would put a non-inferiority trial under very tight

11 monitoring if one suspected that there was a

12 possibility of superiority.

13 \[Slide\]

14 The study size computed here is computed

15 for a specified difference of superiority. The

16 non-inferiority study size would be slightly

17 larger. I am sorry, I don\'t have the software for

18 that. I have assumed an alpha of 0.025 one-sided

19 and a beta of 1.0 or 90 percent power. That is

20 pretty rigorous. I decided to put in the delta,

21 that is, the difference that represented the

22 clinically consequential difference here, of 5

23 percent.

24 Now, these are different levels of

25 discordance. That is, this is the proportion of

218

1 total patients that are discordant at the end of

2 the trial. So, if we had 20 percent discordant

3 patients the total number of pairs of vessels would

4 be 845. If the discordance was only 10 percent,

5 you are down to a trial size of 420. I personally

6 don\'t know where in here you would be, or if you

7 were higher or even lower. That is something that

8 would have to be gotten from some other data.

9 \[Slide\]

10 I also did a two-group trial. Being

11 basically a refugee from cancer, I like failure

12 time endpoints so I designed this for a failure

13 time endpoint. Specifically here I said

14 intervention failure-free survival. I just called

15 this AOK. That is alive and okay. You would

16 assess this event continuously or as often as the

17 patient is evaluated immediately post surgery up to

18 whatever is decided to be a reasonable follow-up

19 time.

20 In particular, you might specifically have

21 time to evaluation, say, at six months as a major

22 evaluation. But the event is a reintervention or

23 death, whichever comes first. Hopefully, you

24 wouldn\'t reintervene after death. Anyway, this

25 requires a very careful definition of failure.

219

1 And, we are designing this again as a

2 non-inferiority trial. I am using an alpha of

3 0.025 one-sided, beta of 0.9.

4 \[Slide\]

5 If I assume that the proportion of

6 patients in the alive and okay at six months is 75

7 percent, and just from the data I saw before here

8 in the room that seems like that might be a little

9 low but perhaps not unreasonable considering that

10 we are talking about all kinds of failures, not

11 just failure of the patency of the vessel or

12 occlusion, whatever. So, this is what our control

13 arm would have.

14 Then we are going to assume that what

15 represents inferiority is a hazard rate, that is a

16 rate of failure that is 20 percent higher than in

17 the control arm. What I get when I do my

18 computation is 1,800 total patients required,

19 randomized in two groups.

20 \[Slide\]

21 Just to give you an idea of what this

22 looks like, this is patients\--

23 DR. WHITE: Are those patients or vessels?

24 DR. BLUMENSTEIN: Paired

25 vessels\--patients.

220

1 DR. TRACY: Patients or vessels?

2 DR. BLUMENSTEIN: Patients, each patient

3 contributing two vessels. So, assuming an

4 exponential distribution, which isn\'t quite right

5 because I doubt that your failure at two years is

6 this high so if I were going to do this outside the

7 context of this meeting I would probably use a

8 different distribution that would have a plateau

9 here. But we are focusing on this area here, not

10 out here. So, it is going to make a little

11 difference.

12 The black line represents the control arm.

13 The blue line represents what we consider to be

14 inferiority. The red line represents the critical

15 outcome, assuming the black line is true, of what

16 we would reject and where we would reject given

17 that outcome. So, that gives you an idea of what

18 the inferiority trial would like. You would be

19 looking at this definition between the black and

20 the blue line as representing the criterion for

21 inferiority, but the red line would be the critical

22 outcome assuming the control arm was actually

23 realized. That is it.

24 DR. HIRSHFELD: Dr. Blumenstein, one

25 generic question about this, for your AOK 75

221

1 percent rate I assume that you are looking at a

2 composite rather than a single endpoint. In other

3 words, any one of these trials to generate a 75

4 percent AOK rate as opposed to a 90 percent AOK

5 rate, we would be looking at a composite endpoint.

6 As a statistician, how do you feel about the use of

7 a composite endpoint as opposed to a single

8 endpoint for analysis?

9 DR. BLUMENSTEIN: Well, I think it makes a

10 lot of sense in this case because you don\'t know

11 all the reasons why you would want to discount the

12 experimental intervention. In other words, there

13 could be things happening that you did not

14 anticipate as a result of side effects, and so

15 forth. So, by using a composite endpoint of

16 failure, just simply failure, then you sop up all

17 those bad things that happen that you didn\'t

18 anticipate. In fact, if you think about it, this

19 is what counts to the patient also. So, the

20 two-group trial has the advantage of pulling

21 together all of those things. It focuses on

22 differences between the groups, whereas the matched

23 study is focused on success with respect to the

24 outcome in the vessels.

25 DR. HIRSHFELD: Right, although in the

222

1 interventional world a composite endpoint has been

2 criticized because some of the components of the

3 endpoint are subject and involve clinical decisions

4 and there is varying of actual clinical

5 significance, and this has led to a great deal of

6 consternation in the interventional arena in terms

7 of the meaning of the composite endpoint that gets

8 virtually into all the interventional device

9 trials.

10 DR. BLUMENSTEIN: Yes, I mean this is the

11 reality. One would think about setting up an

12 endpoint committee to review the declaration of the

13 endpoints, the timing of them and so forth. I

14 mean, this is not uncommon throughout all of

15 clinical medicine to be discussing endpoints that

16 require some kind of judgment. At least with

17 time-to-event, given that you don\'t have a lot of

18 issues with respect to interval censoring, that is,

19 frequency of follow-up and so forth, I think you

20 have a gain in precision of using it as a

21 time-to-event rather than as a binary outcome.

22 DR. BRIDGES: One other study design that

23 you didn\'t show us is what if we didn\'t have each

24 patient as their own control but you had two

25 separate groups of patients where, in each case,

223

1 all of the proximal anastomoses for example were

2 done with one device, and in the other case all of

3 them were done in the conventional manner, assuming

4 that you typically had two grafts per patient.

5 Would that result in fewer patients being required

6 or a greater number of patients being required,

7 particularly in view of the concerns that have been

8 raised by Dr. Emery regarding the Hanover study

9 design? If we backed up and went to a control

10 group that just had hand-sewn anastomoses and an

11 experimental group that had device implemented

12 anastomoses, how would those numbers work out in

13 that case?

14 DR. BLUMENSTEIN: Well, that was the

15 second design that I showed you. It would be

16 randomization to a group of patients treated by

17 usual care\--

18 DR. BRIDGES: Sure.

19 DR. BLUMENSTEIN: \--but I used an

20 outcome\--

21 DR. BRIDGES: But you used a single

22 outcome.

23 DR. BLUMENSTEIN: Yes, I used an outcome

24 that represented time to failure in essence.

25 DR. BRIDGES: Right, but in this case what

224

1 I am suggesting is that you would actually have two

2 outcomes in each patient, the patency of each of

3 the grafts, which would I think decrease the number

4 of patients necessary. In other words, the total

5 number of data points would be twice the total

6 number of patients in that case, whereas, in your

7 study proposed the number of data points is equal

8 to the number of patients, that is, AOK or not AOK.

9 DR. BLUMENSTEIN: What you are talking

10 about is using a different endpoint than this

11 failure time endpoint, and using an endpoint where

12 you can have multiple observations of that endpoint

13 for each patient. That is a possibility but you

14 then get into issues about what happens if you have

15 missing on one and not the other, or if you have

16 three vessels in one patient and two in the other.

17 You get into some issues like that. They are not

18 difficult terribly but they do cause some kinds of

19 complications. One of the first things that

20 happens is you wonder if the patients who

21 contribute more vessels aren\'t the ones that were

22 sicker to begin with. So, you have a lot of those

23 kinds of issues. I mean, there are many, many

24 other trial designs that we can talk about.

25 I thought you were going to ask me about

225

1 whether there could be a trial design that had

2 multiple endpoints, for example not only occlusion

3 but also patency and other things of that nature.

4 There are trials that are designed to allow for

5 multiple endpoints, success being defined, say you

6 had five endpoints, meeting three of five. That is

7 a whole other ball game that is very complicated

8 and difficult to get into.

9 DR. EDMUNDS: That is what I was thinking

10 about, leaving out death because that trumps all

11 endpoints, but a composite endpoint of all of those

12 things that I listed. Is that feasible at all?

13 DR. BLUMENSTEIN: Well\--

14 DR. EDMUNDS: And mapping that endpoint

15 meets every outcome within the composite having a

16 normal distribution, doesn\'t it?

17 DR. BLUMENSTEIN: Well, no, it depends on

18 what you are measuring. You are talking about

19 multiple things contributing to the definition of

20 failure where any one of them can cause a patient

21 to be declared a failure at that moment in time.

22 There is that, plus there is the multiple

23 measurements that one could do. You know, all of

24 these variations lead to different trial designs

25 and different considerations.

226

1 The problem that you have when you define

2 multiple endpoints, multiple distinct endpoints is

3 that then you have the weighting issue. Which

4 endpoint is more important than others? For

5 example, in arthritis trials they may have multiple

6 measurements of outcome and they always have the

7 issue of how you weight those things, what is more

8 important.

9 DR. EDMUNDS: But these cardiology trials

10 usually have death, myocardial infarction and

11 reintervention, or something like that, as a triple

12 composite endpoint. I have always wondered whether

13 that is statistically sound.

14 DR. BLUMENSTEIN: Oh, I think it is

15 statistically sound. It is statistically sound to

16 consider failure without death. The problem is

17 that you have a hard time making a Kaplan-Meier

18 curve in that case because the Kaplan-Meier curve

19 is them\--

20 DR. EDMUNDS: But death trumps. I would

21 much rather have a myocardial infarction than die.

22 So, they are not equal endpoints and, yet, they are

23 rolled together as a single outcome.

24 DR. BLUMENSTEIN: Yes, but they make sense

25 to the patient. That is, the patient wants to live

227

1 without reintervention so that endpoint as a

2 composite makes sense as a definition of patient

3 benefit. Usually in a trial where you have a

4 composite endpoint you feature as secondary

5 endpoints subsets of events that make up the

6 composite.

7 DR. EDMUNDS: Well, if it works for

8 cardiologists why doesn\'t it work for surgeons?

9 DR. BLUMENSTEIN: Well, I don\'t know why

10 it wouldn\'t. I think it would.

11 DR. TRACY: I think we are sort of

12 addressing question number four, which is should

13 the primary effectiveness endpoint be graft patency

14 alone, or include both graft patency and myocardial

15 perfusion? I think we are looking at trials that

16 are quite large at this point, with a minimum of

17 420 and a maximum of 1,800 patients, looking at

18 very hard endpoint. I think we would need to try

19 to fine-tune that and see if there really are

20 additional effectiveness endpoints that make some

21 sense in this context so we are not studying

22 devices ad nauseam. Chris?

23 DR. WHITE: I thought that was great.

24 That was one of the few times I could understand

25 what a statistician has to say, and I think those

228

1 numbers are way too big\--way too big. I think they

2 are not realistic. I think that is not what this

3 field is used to. I think I would be happy with

4 smaller studies that would satisfy the need and I

5 think we need to come up with ways to make these

6 trials doable in order to provide us with useful

7 information.

8 DR. BLUMENSTEIN: You are the first

9 physician who has ever said to me that they prefer

10 a smaller trial. I am amazed.

11 \[Laughter\]

12 We statisticians are always in the role of

13 trying to get you to do more than you want to do.

14 DR. WHITE: I just think that when you

15 look at 400 patients in a trial like this, that is

16 bigger than any trial I can think of, perhaps not

17 drug trials but when you talk about device trials

18 and surgery trials a couple of hundred patients is

19 huge. So, 1,800 is out of the question; 400\--I

20 heard four people hit the floor over there; they

21 passed out.

22 MR. MORTON: It is not so much that anyone

23 wants smaller numbers, we would love to bring

24 larger numbers to the FDA but it is the

25 affordability of the trial.

229

1 DR. WEINBERGER: Just one comment, that is

2 something on your slide about the exponential

3 drop-off rate. That is, the earlier you look after

4 the time of implantation, the larger the sample

5 size you will need to show a small difference. As

6 time develops from the original implantation the

7 two curves should splay apart further and one

8 should be able to do the trial with smaller

9 populations to show a meaningful difference. Is

10 that correct?

11 DR. BLUMENSTEIN: If you are talking about

12 the same difference but at a later point in time,

13 you actually need more patients. The other aspect

14 of this is that there are other causes of graft

15 failure than failure of the proximal connector, and

16 the longer you wait the more those causes come into

17 play and become essentially noise in the data set.

18 DR. BRIDGES: So, do I interpret Dr.

19 Blumenstein\'s analysis to suggest that a randomized

20 trial to look at either a composite endpoint or

21 graft patency, certainly in the paradigm of the

22 patient serving as his own control, would require a

23 larger number of patients than we think is

24 appropriate? Then, does that imply that we should

25 take a step back and go to the historical control

230

1 issue? Also, as an aside, do you agree with Wolfe

2 Sapirstein\'s calculations about the number of

3 patients, which is considerably less, that would be

4 required if we use the historical measures such as

5 80 percent patency for vein grafts and 95 percent

6 patency for mammary grafts?

7 DR. BLUMENSTEIN: I mean there is nothing

8 wrong\--I didn\'t redo the computations. I assume

9 that the computations were done correctly.

10 DR. ZUCKERMAN: They were done several

11 times.

12 \[Laughter\]

13 DR. BLUMENSTEIN: But we are using

14 completely different methodologies, different

15 criteria and so forth. They are not completely

16 comparable. But I think the main difference is

17 that the computations shown earlier were based on a

18 single group non-inferiority assessment which

19 suffers from all of the things that one would

20 suffer from by using retrospective data,

21 non-concurrent, randomized controls that is.

22 So, I think it is very important to first

23 decide whether it is essential, and I think it is

24 personally, to have randomized to control for all

25 of these factors that you can\'t control and can\'t

231

1 measure and then go on from there. I also want you

2 to remember, and I tried to point this out as I was

3 showing those slides\--I was trying to give you an

4 upper bound on the sample sizes. I was using 90

5 percent power, and so forth, and it is possible

6 that you can trim the sample sizes some. Also, I

7 chose criteria, you know, based on the things that

8 I have seen here today and my best guess at it. It

9 may be that I am using criteria that are too tight.

10 I don\'t know but this is a beginning.

11 DR. TRACY: Dr. Edmunds?

12 DR. EDMUNDS: Would it be irrational to

13 consider any of this list an adverse event and then

14 calculate the number of adverse events for each of

15 the two groups randomized prospectively, and do a

16 power calculation for the occurrence of any one of

17 several adverse events, one per patient maximum,

18 and compare the two at a certain time point? Could

19 that get our N down, and a 5 percent difference

20 rather than 10 or 20? Because we are trying to

21 show equivalency.

22 DR. BLUMENSTEIN: Well, that is the reason

23 I showed you the two-group non-inferiority trial.

24 In point of fact, the things that went into the

25 definition of what I called AOK could be adverse

232

1 events, that is, things that I

2 said\--reintervention, that was just a suggestion.

3 You could say that the definition of failure is

4 anything bad that happens, in which case it becomes

5 time to first bad thing. But, you see, in order to

6 preclude the kind of inferiority that I used in

7 those computations, it requires a fairly large

8 trial size.

9 DR. EDMUNDS: So, the first model was just

10 chi square, wasn\'t it?

11 DR. BLUMENSTEIN: It is a McNemar\--yes, it

12 is a chi square.

13 DR. TRACY: I think if you really have an

14 inferior product, by one of these methods you are

15 going to pick it up quicker but if you have

16 something that is not inferior it is going to take

17 longer and it is going to require larger patient

18 populations, and I think there really is an issue

19 here of what is feasible to do; how many patients

20 is it reasonable to include? These are massive

21 trials that we are talking about. I think we

22 either have to come up with a better answer to

23 number four, looking at primary effectiveness, or

24 we have to readdress the idea of historic controls.

25 DR. BLUMENSTEIN: I want to emphasize that

233

1 the two trials that I presented are really quite

2 different in terms of their objectives.

3 DR. TRACY: Right.

4 DR. BLUMENSTEIN: They are quite

5 different.

6 DR. TRACY: Right. I don\'t think we got

7 an answer here but I think we see what the problems

8 are.

9 DR. HIRSHFELD: We can answer this

10 question though, can\'t we?

11 DR. TRACY: Number four?

12 DR. HIRSHFELD: Yes. I mean, it is

13 patency, period, isn\'t it?

14 DR. TRACY: Number four is should the

15 primary effectiveness endpoint be graft patency

16 alone, or include both patency and myocardial

17 perfusion? I think we have heard that myocardial

18 perfusion doesn\'t necessarily predict patency. I

19 think patency is a definite primary endpoint. I

20 would think that primary effectiveness is going to

21 in part depend on how large the trial has to be.

22 If your trial has to be enormous, they you accept

23 other pieces of primary effectiveness.

24 But I think that patency as the

25 dichotomous thing\--it is either open or it is

234

1 not\--is a very important endpoint but the other

2 criteria, such as aortic complications, neurologic

3 changes, hemorrhagic problems, acute revision, all

4 those are other primary effectiveness endpoints in

5 particular for the proximal anastomoses. So, I

6 think you look at your specific device and decide

7 whether there are specific primary effectiveness

8 endpoints that you need to reach. If you are

9 having a 30 percent aortic dissection rate with

10 this particular device, then it is a real problem.

11 DR. EDMUNDS: I would argue for any

12 adverse event compared between the two groups, and

13 if we find that the adverse events are similar

14 between the two groups then the new device is no

15 worse than what we are doing now, and that really

16 is the question.

17 DR. WHITE: I disagree. I mean, I

18 understand what you mean but I disagree. I think

19 the endpoint is patency. In fact, the primary

20 endpoint has to be patency; the secondary endpoints

21 can be other issues. But I think the trial,

22 whatever we look at, has to be powered at patency

23 because the experimental device has a direct effect

24 on patency of the graft and that is what we care

25 about.

235

1 DR. HIRSHFELD: After all, we are going to

2 measure patency by a fairly sophisticated

3 technique, i.e., angiography. These others are

4 going to require endless hours because they are a

5 continuum. You know, you have good flow; you have

6 bad flow.

7 DR. EDMUNDS: Yes, but nobody learns

8 anything if the trial is not done because it is so

9 large.

10 DR. TRACY: If we can move on to number

11 five.

12 DR. ZUCKERMAN: I think we forgot question

13 number three.

14 DR. TRACY: Oh, I am sorry. That is true,

15 we did skip that. Number three, do you believe

16 that the significant differences between an

17 arterial conduit and a venous conduit warrant

18 distinct study criteria and assessment for each?

19 If so, please identify these criteria and analyses.

20 I think the essence was yes, they are

21 different. They are distinctly different, however,

22 the endpoints of patency remain the same whether it

23 is a venous or an arterial structure we are talking

24 about.

25 DR. ZUCKERMAN: Well, then this helps both

236

1 the agency and the industry develop a paradigm.

2 You are saying that a specific indication could be

3 developed for a device intended for the internal

4 mammary and a specific indication could be

5 developed for an SVG device, whether it is proximal

6 or distal, and they are two separate trials.

7 DR. TRACY: Yes.

8 DR. ZUCKERMAN: Then, the next question is

9 suppose we are talking hypothetically about an SVG

10 device, the circumflex vessels may behave

11 differently than right-coronary artery. So, what

12 type of distribution or other advice can you give

13 to allow us to have confidence that we don\'t have

14 to keep slicing and dicing, that we have enough

15 data. Should we have 50 percent RCA, 50 percent

16 circ, or is that too proscriptive, etc.?

17 DR. WHITE: I think that is too

18 proscriptive. Why doesn\'t it work to do what we do

19 for stents, and that is that you get data from a

20 stent trial that you then retrospectively look at

21 LAD, circumflex and right because you know there

22 will be a distribution of those? We know from

23 those large trials what the distribution would be.

24 So, I don\'t know if there is a priori any reason to

25 consider a difference between circumflex and a

237

1 right graft. I am not aware that there are

2 differences in patency there. But I would simply

3 do that in a retrospective way, assuming that there

4 would be a good population of patients having both

5 of those grafts done.

6 DR. EDMUNDS: If you are insisting on

7 patency as the only primary endpoint, you are

8 trying to make this a stent trial and not a

9 surgical trial of an anastomotic connector. And,

10 this is a surgical trial of how to make a

11 connection. It isn\'t a stent trial and the analogy

12 is not very good. That is why I think there are

13 multiple adverse outcomes and I don\'t think you can

14 ignore the others just to concentrate on 50 percent

15 or greater patency.

16 DR. ZUCKERMAN: In general I think the

17 agency would agree with that viewpoint. Even if

18 the sponsor wins on patency but the aortic

19 dissection rate or neurological complication rate

20 is unacceptable, then it is an unacceptable device.

21 We would ask the sponsor up front, even though one

22 of the key sample size calculations would be for

23 the patency hypothesis, to show with what

24 confidence they can rule out some of these other

25 problems because we are looking at multiple key

238

1 endpoints. But I guess the question that I have

2 for number three is, is there a big difference

3 between plugging in these grafts with devices to

4 the circ and RCA territories up front that we

5 should be very proscriptive in terms of number of

6 vessels or, as Dr. White has suggested, if you get

7 a fair distribution and then retrospectively it

8 looks like the results are homogeneous, then that

9 is okay?

10 DR. MAISEL: I think it is one of the

11 factors that goes in with all the other preclinical

12 factors\--presence or absence of diabetes, the

13 distal outflow of the graft. I think which vessel

14 it is attached to is equivalent to one of those

15 other factors.

16 DR. HIRSHFELD: I agree with that. I

17 think that path is an endless path and if you have

18 a hard data point\--I agree with Chris, if you have

19 a hard data point that is our goal you can pick up

20 all those other things on an analysis of the data.

21 DR. EDMUNDS: I think we need to remember

22 that these surgeons are not using these vein grafts

23 to go to the LAD, and there are plenty of people

24 walking around asymptomatic with a patent LAD and

25 nothing else. It is the most important they are

239

1 grafting the right and the circ with occasional

2 diagonal branches. We need to consider this in the

3 trial and I think you have to consider multiple

4 endpoints because we have multiple complications

5 which are unique to this device, or so it is

6 alleged.

7 DR. ZUCKERMAN: Right, and I think we

8 would like other panel members to respond. I think

9 we are in agreement that we are going to consider

10 multiple endpoints but I like your other point that

11 you just made about the importance of LIMA patency

12 for prognosis and survival. Then the implication

13 is if we are looking at separate trials for the

14 LIMA devices versus the SVG devices, are you

15 implying that our delta for non-inferiority for the

16 LIMA trials should be much tighter, say, than for

17 the SVG trials?

18 DR. HIRSHFELD: I would like to respond to

19 that. I would like to find out first who in the

20 room would have the intestinal fortitude to do a

21 mechanical device LIMA to LAD? I mean, that is the

22 gold standard. I agree with him that there are

23 people running around, myself included, that have

24 LAD grafts that have been patent for 20 years. To

25 say that somebody is going to put a device in there

240

1 I think is absolutely wrong. I mean, I would make

2 a condition of the instruments that they exclude

3 the LAD-LIMA.

4 DR. TRACY: We will take a comment but we

5 are rapidly going to be losing panel members here

6 so if we can try to move along here.

7 MR. FOLEY: I will try and address that

8 question. I am Mark Foley. I am CEO of Ventrica.

9 Actually, in the trial that we just completed,

10 which was a 100 patient trial with six-month

11 angiographic follow-up, core lab-assessed data and

12 a clinical events committee looking at the MACE

13 endpoints in the trial, we did do LIMA-LADs. We

14 had a 94 percent patency rate in LIMA-LAD. We also

15 did one-year clinical follow-up on the same group

16 of patients. In that group of patients that we

17 followed 46 of 48 were contacted; two were not able

18 to be reached. We had no additional events, no

19 admission to hospital for chest pain, no

20 reoperation, no additional caths in that group.

21 DR. HIRSHFELD: I think that is terrific

22 but I think you have to follow those people 20

23 years because the gold standard, as you well know,

24 is LIMA to LAD hand-sewn.

25 DR. KRUCOFF: Did you have any trouble

241

1 enrolling patients?

2 MR. FOLEY: We didn\'t. Our trial was done

3 completely in Europe so we were able to enroll

4 patients in the trial. But I would like to ask one

5 more question to Dr. Zuckerman\'s point, with

6 mammary graft patency will we need to do a separate

7 trial for vein grafts?

8 DR. TRACY: I am not sure what the answer

9 to that is. I think we are struggling here because

10 the behavior of the vessels is different and the

11 LIMA to LAD is considered the best patency rate

12 that we have. Dr. Aziz, do you have any answer for

13 us?

14 DR. AZIZ: I think you have said it. I

15 think the biology\--you know, the arterial grafts

16 produce prostacyclin and there are a lot of other

17 factors that keep pushing down there so I think at

18 this early stage you should consider them

19 differently. Once you have the data, then I think

20 maybe in the future we may not need to. But at

21 this stage we don\'t know how the reaction to injury

22 is going to be with some of these new devices.

23 Even though you have shown it is good in the

24 arterial circulation and anastomosis I still think

25 you need to look at it differently.

242

1 MS. WOOD: I think I am going to have to

2 insist that we move on to the next question because

3 we are going to lose panel members. We have two

4 more questions to discuss. Let\'s please make them

5 as brief and to the point as possible for comments,

6 please.

7 DR. TRACY: Number five, with regard to

8 device safety what criteria, i.e., acceptable

9 adverse event rate, as compared to that for suture

10 should be applied to the evaluation of device

11 safety as distinguished from device effectiveness,

12 for example, myocardial infarction, reoperation,

13 neurologic events and incidence of aortic

14 complications?

15 DR. EDMUNDS: What is the difference to

16 the patient from a huge stroke? I mean, I don\'t

17 see the distinction between safety and

18 effectiveness here. Effectiveness, you could

19 argue, is patency but safety is just about

20 everything else.

21 DR. TRACY: I think safety is, for

22 example, the device ripping off the aorta as the

23 patient stands up the first day postoperatively

24 versus effectiveness, finding a vessel six months

25 out to be patent. So, I think there are some

243

1 different safety versus effectiveness endpoints but

2 I think that they should be basically the same

3 safety and effectiveness endpoints as a suture

4 anastomosis would be expected to have. So, I don\'t

5 think there is a difference between those two

6 safety and effectiveness endpoints.

7 DR. KRUCOFF: Again, another way to

8 approach this is to start with what is the primary

9 question and what is that going to power to versus

10 what are all the other key concerns about lower

11 incidence events that could happen, and how broad a

12 boundary around those events also would influence

13 thinking about power. You can separate out for a

14 given question a primary endpoint that is

15 effectiveness versus an adequate assessment of

16 safety.

17 DR. YANCY: And it could be that the

18 better way to do this so we don\'t struggle is use

19 it as a time-related function, so have group safety

20 and efficacy in one bundle and look at early and

21 then intermediate. That would probably suffice to

22 capture the spirit of the question.

23 DR. SAPIRSTEIN: Can I just make one

24 point? We make a distinction between safety and

25 effectiveness and it may not be a very hard

244

1 distinction, but if we have to re-explore a patient

2 for bleeding and put an extra little stitch in,

3 that is a safety event. If the patient develops a

4 peripheral embolus from the device which still has

5 good patency and the patient gets an infarction in

6 the bed, we call that an adverse event that occurs.

7 Maybe this is not a realistic approach but from the

8 point of view of evaluating these devices we do

9 have to make a distinction between effectiveness

10 and safety.

11 DR. TRACY: It also becomes difficult to

12 use the patient as their own control because if a

13 patient goes back for a re-bleed for one thing

14 versus another thing, it doesn\'t matter to that

15 patient, they are still going back for a re-bleed.

16 So, that argues in a way for using historic

17 controls or randomization between a control group

18 and an experimental group but we are seeing that

19 that experimental group might be prohibitively

20 large.

21 DR. EDMUNDS: You know, if a device comes

22 loose from the aorta, is that effectiveness

23 failure? Is the device not effective? Absolutely.

24 Is it safe? Hell, no.

25 DR. TRACY: Right. We will move on to

245

1 number six, with regard to appropriate patient

2 follow-up, part a), in view of the possible

3 persisting risk of failure of some mechanical

4 anastomosis sites, distinct from progression of

5 native vessel disease, what duration of follow-up

6 is advisable for premarket evaluation?

7 I think we have sort of addressed these

8 issues. We don\'t know the biologic activity of

9 some of these things or exactly what the time frame

10 to healing is but we do have to come up with some

11 arbitrary point at which a look is taken, and that

12 might be six months, nine months, something that

13 could be concretely determined as the point at

14 which experience so far tells us that most of the

15 failures would have occurred in the devices that

16 are currently on the market. So, I think we can

17 look at that and decide what that time frame would

18 be for the repeat angio, which seems to be the

19 standard that we are leaning towards for a concrete

20 output.

21 DR. KRUCOFF: Again, beware of the pitfall

22 that if you look earlier you may see a sign that

23 may or may not be clinically relevant yet. So, if

24 you use a continuous measurement of lumen diameter

25 earlier, that will probably work. If you use a

246

1 cut-off, is this a flow-limiting lesion earlier, it

2 may not work and you may really miss something that

3 blossoms later.

4 The other option to wait until later, you

5 then have more clinical events that will accrue

6 before you look. So, I think you just have to be,

7 again, thoughtful about what is the intention of

8 the trial design as to where you put that and what

9 endpoint you are using, dichotomous or continuous.

10 DR. TRACY: But, again, in terms of study

11 design it does become difficult to ask a person to

12 come back in a year after an intervention. By that

13 time they have forgotten what you did in the first

14 place so they are not too likely to want to come

15 back. We are already wrestling with a pretty, you

16 know, task-full study.

17 DR. ZUCKERMAN: Dr. Tracy, I think you

18 have outlined the tensions in this question, but

19 the real question then is, is the stent model

20 applicable, as Dr. Krucoff just said, where

21 routinely there is six-month angiographic follow-up

22 but clinically the patients are followed for

23 another three months to make sure that something

24 seen on the angiogram which may not look

25 significant doesn\'t portend something down the

247

1 road. You know, is there a role for later clinical

2 follow-up?

3 DR. TRACY: I think we have heard from

4 some of the members that came to speak today that

5 further follow-up is warranted, whether that be by

6 phone follow-up or clinic visit. That probably is

7 appropriate at some point past the angiographic

8 follow-up.

9 Part b), should postmarket follow-up be

10 required to assess long-term device effectiveness?

11 If so, please define the appropriate length of

12 follow-up after primary patency evaluation.

13 I don\'t have a specific time but I do

14 think that out to a minimum of a year with some

15 type of clinical follow-up, whether that is phone

16 contact or office contact.

17 Number seven, can non-invasive measuring

18 instruments, example, echocardiography, ultrafast

19 spiral CT, MRA, EBT, etc., be used for primary

20 assessment of graph patency or is angiographic

21 follow-up necessary? And, at what time points

22 should patency be assessed? John?

23 DR. HIRSHFELD: I would like to throw out

24 a suggestion and to get the group to react to it.

25 I think there are three patency variables, acute

248

1 patency which is was the graft patent at the time

2 of hospital discharge and the major determinants of

3 that are likely technical. Then there is

4 intermediate patency, which is probably somewhere

5 between three and six months. Then there is late

6 patency, which is six months and beyond.

7 I would submit that non-invasive imaging,

8 either MR or CT angio, can answer the patency

9 question, and that we should reserve angiography

10 for the time at which we want a morphologic

11 assessment of the actual appearance of the graft.

12 So, one possible paradigm would be to obtain a CT

13 angio or an MR at the time of hospital discharge

14 which would establish the patency of the graft at

15 that point and we probably take technical and acute

16 thrombosis issues off the table at that point.

17 Then, intermediate patency at three to six months

18 could be assessed by another non-invasive imaging

19 study and that might identify candidates for an

20 early angiogram to try to delineate the etiology of

21 the graft failure when graft failure is observed.

22 Then, the late patency would be at six months and

23 that would be an angiographic study.

24 DR. KRUCOFF: One historical lesson

25 learned just to keep in mind, whenever your

249

1 angiographic endpoint is, we have certainly seen

2 that the threshold to reoperate is going to be very

3 high but the threshold to dilate or stent a 75

4 percent lesion in a completely asymptomatic person

5 once you are in the cath lab, judging by our own

6 history, is going to be very tempting. So,

7 recognize that if you put the angiogram early and

8 don\'t let people have events you are going to

9 generate events that go with the angiogram. I

10 would suggest that what you do for already

11 enrolling studies maybe we have to take another

12 half step back, but certainly for planning future

13 studies or until we understand the biology of these

14 things in the proximal and the distal locations,

15 which are different, I would suggest pushing out to

16 at least nine months and possibly even a year if

17 the investigators felt it was feasible to get

18 patients back.

19 DR. TRACY: Chris?

20 DR. WHITE: I agree with John. My only

21 reservation is that we are asking the non-invasive

22 technology to really step up here. I think that

23 probably those of us around the table who are not

24 absolutely confident that CT or MR is going to give

25 us\--at least in our own hands and probably in our

250

1 own hospitals, we don\'t understand the same

2 reliability. But I think the early tests and the

3 screening that we are talking about, it is fine to

4 do it that way as long as the hard endpoint is done

5 with angiography. I think that Mitch is right that

6 late is better but if I was the investigator six

7 months would be where I would really be wanting to

8 do this because I think there is enough activity

9 there. I think we have heard today that the suture

10 lesions in the mammary had calmed down by six

11 months so those sort of things aren\'t going to be

12 there. And, I think that immediacy to the patient

13 is important. So, I would suggest the six-month

14 angiogram would be okay.

15 DR. YANCY: I think especially for the use

16 of a non-invasive variable early on, a core lab or

17 a central reading environment really is critical

18 since there is so much more subjectivity about that

19 interpretation.

20 DR. BRIDGES: Since we are talking about

21 analogies to the percutaneous coronary intervention

22 literature, what is the precedent for the use of

23 non-invasive imaging to assess not graft patency

24 but angiographic patency?

25 DR. WHITE: Well, in the coronary

251

1 circulation it is very early on, as you know. In

2 the peripheral circulation it is an acceptable tool

3 for looking at patency of non-coronary vessels.

4 DR. BRIDGES: But in the coronary because

5 that is what we are talking about?

6 DR. WHITE: If we are looking at grafts, I

7 think there is quite a literature about looking at

8 graft patency. I don\'t think it is unrealistic. I

9 just think that in your hospital you are not going

10 to say that your sensitivity and specificity is 94

11 percent because you haven\'t looked at that, and

12 most of us haven\'t in our own hospitals.

13 DR. TRACY: I don\'t think it is most of us

14 in our hospitals, I think nobody has. I just don\'t

15 think those are established techniques but I think

16 that they do have merit in a trial like this and as

17 an intermediate endpoint I think they are

18 appropriate. Dr. Sapirstein, is there something

19 else that we should be talking about here?

20 DR. SAPIRSTEIN: No, I think you have

21 helped us considerably and we appreciate that very

22 much. I know there are still a lot of

23 argumentative principles and debate but I think you

24 have given us considerable help.

25 DR. TRACY: Thank you.

252

1 MR. MORTON: Dr. Tracy, one quick comment,

2 back to 6 b), what we would be looking at in 6 b)

3 would be a postmarket\--what the panel indicated was

4 that, yes, there would be some further information

5 that you would be interested in at, say, one year.

6 Postmarket surveillance usually is not done on a

7 510(k) device and what I would suggest is that

8 there could be some creative way of getting the

9 information that you would be interested in perhaps

10 by writing into the clinical protocol that there

11 would be telephonic follow-up, say, at one year,

12 but at the follow-up time of the study the data

13 could be compiled and submitted to the FDA with

14 that phone follow-up to follow. That way we stay

15 out of that unfamiliar regulatory field of

16 postmarket surveillance with a 510(k).

17 DR. TRACY: I think the spirit of what we

18 want to know is because the biologic activity of

19 these devices is not known, Dr. Krucoff and others

20 have indicated that the six-month look may be

21 premature in terms of finding the true failure rate

22 of these devices. Therefore, some additional

23 follow-up at some later point is appropriate. Now,

24 exactly where in the regulatory process that takes

25 place I am not clear, but I think you need to ask

253

1 the patient, \"hi, how are you doing? Have you had

2 any chest pain?\"

3 DR. ZUCKERMAN: Dr. Tracy, we are going to

4 clarify that regulatory process for you right now.

5 DR. HOANG: This is Quynh Hoang, from the

6 Office of Surveillance and Biometrics. I am from

7 the side that does the postmarket. To answer your

8 question, yes, it is possible to request a

9 postmarket surveillance study on even a 510(k)

10 device. The question that we would need is what is

11 the postmarket public health question that you have

12 for the device. It is not limited to the premarket

13 side of how the device was cleared or approved or

14 entered the market. So, I have to stress the

15 adjective or the qualifier of it being a postmarket

16 question, it should not be a question that is

17 required to be answered for the device to be

18 considered acceptable to enter the market. It is a

19 postmarket public health question.

20 DR. TRACY: I think we are looking for

21 late failures, late clinical failures. So, you are

22 asking the patient how they are; have they had

23 chest pain; have they required reintervention; are

24 they alive or dead.

25 MS. HOANG: With the question defined,

254

1 what we would do would be to go out and it is an

2 order from the FDA to the company to perform a

3 postmarket surveillance study. The one caveat for

4 such a study is that, by law, it is not typically

5 longer than three years. The other one is that the

6 company can come back\--we pos the question but the

7 company can come back and offer us different ways.

8 It could be a registry; it could be continued

9 follow-up of the patients that were studied for the

10 premarket application. We would not be

11 prescriptive. We would not identify what study

12 needs to be done. It would be the role of the firm

13 to come back and say this is how we plan to do

14 address the postmarket public health question.

15 DR. MAISEL: I think that one-year

16 clinical follow-up prior to device approval is not

17 a huge burden given that we are doing a six- or

18 nine-month angiogram.

19 MS. HOANG: When you put in the statement

20 before device approval you have already cut out the

21 postmarket. This is a question that needs to be

22 addressed after the device already enters the

23 market.

24 DR. TRACY: But the spirit of why you are

25 doing it at any point, whether it is premarket or

255

1 postmarket\--and I agree postmarket is appropriate

2 for these devices\--is to find out whether there is

3 something you didn\'t anticipate. I think it is

4 certainly in the company\'s best interest to adhere

5 to that spirit of finding out whether their product

6 needs improvement. So, I don\'t see where they

7 would have any objection to a full type of

8 follow-up with very specific questions that really

9 deal with any unanticipated later outcomes.

10 MS. HOANG: Yes, the only caveat again is

11 that it should not be something that you would need

12 to know before you clear the device because it is a

13 postmarket study.

14 DR. TRACY: Right, and I think that is why

15 we have to be careful in making sure that our

16 concrete endpoint is at a point where we are

17 comfortable. Even though there is biologic

18 variability, I think we have to just say, given the

19 difficulty in getting patients to come back, we

20 have to accept a six-month invasive follow-up

21 point. Then the postmarket surveillance would be

22 for other unanticipated things to be caught at that

23 point.

24 DR. BRIDGES: Just a point of

25 clarification, I thought that if a device is

256

1 approved under the 510(k) it is either approved or

2 not approved. It can\'t be approved with a

3 condition based on a postmarket survey. Is that

4 correct?

5 DR. ZUCKERMAN: I think what you heard is

6 that there should be sufficient data in the

7 application to be able to make a clearance

8 decision. In other words, the major data should be

9 in the application. But then, if there are certain

10 persisting questions or a chronic nature that can

11 be defined, there is a mechanism.

12 MS. HOANG: That is correct, what Bram

13 just said. it is not a condition of approval. The

14 510(k) process, Bran can speak to that. I don\'t

15 believe it allows for conditional approval. But

16 this is a postmarket process that allows for

17 questions that would arise after the device has

18 been out in the market, if there are certain things

19 that occur that cause the agency to wonder whether

20 we should have further studies.

21 DR. TRACY: I think that the data that we

22 heard at the beginning of the day today indicates

23 that the companies are being very responsive and 90

24 percent-plus of the problems that we heard about

25 earlier were brought forth by the company. The

257

1 companies do not want bad products out there. They

2 are going to do this. I think we are belaboring

3 the point here because there is no company in the

4 world that I can think of that would want to close

5 their eyes if their product is having problems.

6 So, I think it is a moot point, frankly.

7 DR. YANCY: Dr. Tracy, prior to my

8 departure I just want to make one entry into our

9 record that has to do with a somewhat dissenting

10 opinion about sample size. It seems as if there

11 was a sense of agreement amongst the panel that the

12 sample sizes that were discussed were too large,

13 and it seems to me that with refinement of the

14 protocols we could achieve a sample size in the

15 400, 500 range. If, indeed, we are talking about

16 350,000 bypass procedures done per year, we are

17 talking about less than a tenth of a percent to try

18 to get into a study design, and I think that if we

19 are going to be free of these kinds of

20 deliberations in the future the appropriate study

21 design up front is necessary and I, for one, would

22 say what is required is a larger sample size. I

23 would like for it to go on the record that one

24 panel member thinks we should insist on that. I

25 think compromising now sets us up for problems

258

1 later.

2 DR. WHITE: Dr. Tracy?

3 DR. TRACY: Yes, Dr. White?

4 DR. WHITE: I think that we all agree with

5 Dr. Yancy as scientists and I think the

6 statisticians say the same thing. The problem is

7 reality and where your cut point is. I think we

8 need to make a decision or we need to make a

9 recommendation that it is not something we are

10 unhappy with and I personally feel very comfortable

11 with a lower bound of 90 percent patency rate. I

12 feel very comfortable that that would be a

13 reasonable device for my father and my grandfather

14 to get for a vein graft anastomosis, and if that

15 can be done with 125 patients, then I think that is

16 not an unreasonable thing. I anticipate currently

17 in many trials the benefit from this OPC criteria

18 that are not randomized and it allows more

19 investigations to be done. It allows more data to

20 be collected, and I think we ought to not put it

21 off just out of hand because it isn\'t randomized or

22 doesn\'t meet the highest standards. I acknowledge

23 that but I think there is some compromise that we

24 perhaps can make without compromising data. If we

25 can\'t do that without compromising data, then I

259

1 think Dr. Yancy is absolutely right and we should

2 insist on what we need to answer the questions.

3 DR. TRACY: I think those are both very

4 fair statements. One more comment and then we will

5 have to move on to the open public hearing. Dr.

6 Bridges?

7 DR. BRIDGES: My only comment, Chris, is

8 would you be comfortable if your anastomotic device

9 for an internal mammary had a 90 percent patency?

10 Would you be comfortable having someone use that

11 device for your internal mammary artery graft?

12 DR. WHITE: No, and I think we have all

13 agreed that we have to have two standards for

14 mammary and vein graft.

15 DR. ZUCKERMAN: But, Dr. White, the

16 calculation that Dr. Sapirstein showed was that the

17 lower confidence limit should be 0.90 for the

18 mammary example. You are now agreeing with Dr.

19 Bridges that that needs to be tightened.

20 DR. WHITE: I think the mammary needs to

21 be tightened. I think for vein graft patency that

22 would be excellent\--

23 DR. BRIDGES: Right, but that is not on

24 the table. I mean, the issue was that with veins

25 we are talking 80 percent and with mammaries we are

260

1 talking 95 percent with a 5 percent delta. So, no

2 one is really talking about a 90 percent vein graft

3 patency. Everybody would be happy with that I

4 think. The issue is with mammaries, is 95 percent

5 the gold standard historically accepting a delta of

6 0.5; with veins is 0.8 or 0.75 or 0.85, whatever

7 you decide\--I don\'t remember what it was he had put

8 up, it was either 0.85 or 0.8, is it acceptable?

9 So, 0.9 for a vein is really not one of the

10 questions that we were asked to look at.

11 DR. WHITE: But we get to pick. You get

12 to say what you think would make you happy. These

13 numbers that were put up were simply hypothesis. I

14 mean, they were hypothesis generating. So, we get

15 to say. What I am saying is that I am willing to

16 have a less rigorous scientific design in terms of

17 giving up randomization for vein graft patency of

18 0.9. Now, perhaps I want patency of 0.98 for a

19 mammary. Again, we get to say what the level of

20 confidence we have is if we are willing to settle

21 for a less severe scientific design.

22 DR. TRACY: Dr. Ferguson?

23 DR. FERGUSON: Further than that, we can

24 make the recommendation we want to make but it

25 sounds to me like if we are going to do an

261

1 extensive randomized trial on devices that have

2 already been put out there rather than \"me too\"

3 comparisons we are going back to a PMA format. I

4 am not sure that that is the proper direction. You

5 might want to comment on that.

6 DR. ZUCKERMAN: Everything that we

7 discussed today can be done through the 510(k)

8 clearance process. There is nothing unusual about

9 doing clinical trials for 510(k)s of this variety.

10 DR. FERGUSON: Of this magnitude? This

11 size and so on?

12 DR. ZUCKERMAN: Correct, in the coronary

13 tree. That is correct.

14 DR. TRACY: At this point I would like to

15 open the afternoon open public hearing. Is there

16 any member of the audience who wishes to address

17 the panel on today\'s topic? If not, we will close

18 the open public hearing.

19 I have a serious question for the FDA. It

20 says here on my script that I am supposed to

21 summarize the discussions.

22 \[Laughter\]

23 Do you really want me to do that?

24 DR. ZUCKERMAN: I know you can do it very

25 well. I will help you if you get into trouble but

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1 I think it would be helpful for us.

2 Summary

3 DR. TRACY: I will give it a shot. The

4 first part we discussed, which is obviously

5 difficult thing to grapple with, was the trial

6 design. I think Dr. Blumenstein put together some

7 very nice but very quick analyses of what would be

8 entailed in doing studies with the patients serving

9 as their own controls versus randomized, controlled

10 studies.

11 The panel expressed concern over the size

12 of the trials that would be required with those

13 designs but does not want to throw out the

14 scientific rigor entirely, but also does not want

15 to throw out the historic information that we have

16 regarding 95 percent patency on the LIMA to LAD.

17 We think that there may be different study designs

18 appropriate if we are dealing with a LIMA versus a

19 saphenous vein graft trial.

20 We think that the endpoints, particularly

21 dealing with part c) of the first

22 question\--surrogate endpoints are not adequate as

23 primary endpoints. The primary endpoint that we

24 think is most reliable is patency. We agree though

25 that there are other design issues that will come

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1 up in some of the later questions. Have I

2 summarized the trial design part adequately?

3 Moving on to question number two with

4 regard to device placement and device design,

5 please address the following: given considerable

6 differences between the proximal and distal CABG

7 anastomoses, what, if any, differences in study

8 criteria should be required? Again, with the

9 proximal anastomoses devices there are peculiar

10 issues that come up, such as stroke, aortic

11 dissection, etc., that need to be taken into

12 account in the study design, yet the critical

13 endpoint is patency at some point based on the

14 biologic behavior of the anastomoses, and we think

15 that probably six months is an appropriate time

16 frame for that.

17 We don\'t think that the endpoint for a

18 proximal anastomosis study versus distal

19 anastomosis study would be different enough to

20 warrant totally different study designs. For

21 example, one shouldn\'t be studied at 6 months and

22 the other at 12 months. We think that there should

23 be an appropriate failure rate or success rate

24 definable at, we think, 6 months that should be

25 adequately captured with an invasive assessment at

264

1 that point.

2 In terms of determining conduit failure,

3 we recognize that that is difficult to understand,

4 especially since the biology of these devices isn\'t

5 clearly understood, and we think that a DSMB and

6 core lab would be very helpful in determining these

7 outcomes and analyzing data on a prospective basis.

8 Question number three, do you believe

9 significant differences between an arterial conduit

10 and a venous conduit warrant distinct study

11 criteria and assessment for each? If so, please

12 identify these criteria. Again, with think that

13 they certainly are biologically very different.

14 The study designs have to take into account, again,

15 the biology of the tissue but also the site of

16 anastomosis but, once again, that patency is the

17 critical outcome that we will be looking for

18 angiographically.

19 Question four, should the primary

20 effectiveness endpoint be graft patency alone, or

21 include both graft patency and myocardial

22 perfusion? We think that myocardial perfusion may

23 be misleading and we believe primary effectiveness

24 for patency is angiographic follow-up. Other

25 issues, such as aortic disruption have been

265

1 mentioned previously. CT and MRI, yes, those

2 endpoints that Dr. Hirshfeld brought up of looking

3 acutely and at intermediate points with CT and MR

4 would probably be appropriate acute and

5 intermediate steps to take.

6 Number five, with regard to device safety,

7 what criteria, i.e., acceptable adverse events

8 rates as compared to that for suture, should be

9 applied to the evaluation of device safety as

10 distinguished from device effectiveness, example,

11 myocardial infarction, reoperation, neurologic

12 events, we think that the same safety and

13 effectiveness endpoints that pertain to suture

14 should be applied to these devices. We do agree

15 that there is a difference between safety and

16 effectiveness, although there is some overlap in

17 terms of effectiveness but certainly safety issues,

18 such as acute aortic disruption, are safety issues

19 that should, hopefully, be seen only fairly early.

20 Endpoint evaluation with regard to

21 appropriate patient follow-up, in view of the

22 possible persisting risk of failure of some

23 mechanical anastomosis sites, distinct from

24 progression of native vessel disease, what duration

25 of follow-up is advisable for premarket evaluation?

266

1 Dealing specifically with premarket

2 evaluation, we think that that point of

3 angiographic intervention is the endpoint probably

4 for premarket evaluation, and we think that that

5 time point should be somewhere around the six-month

6 time.

7 Should postmarket follow-up be required to

8 assess long-term device effectiveness? If so,

9 please define the appropriate length of follow-up

10 after primary patency evaluation.

11 We believe that the answer is yes, there

12 should be some postmarket follow-up. It is in

13 everybody\'s best interest, in particular the

14 patients. And, that does not have to be a

15 prohibitively complex follow-up process. It could

16 be handled by a phone follow-up.

17 Number seven, can non-invasive measuring

18 instruments, echo, ultrafast spiral ST, etc., be

19 used for primary assessment of graft patency or is

20 angiographic follow-up necessary? And, at what

21 point should patency be assessed?

22 I think Dr. Hirshfeld\'s suggestion that

23 some form of non-invasive assessment acutely and

24 them compared with an intermediate time frame, such

25 as a three- to six-month time frame, would be

267

1 appropriate and that could be CT or MR. The late

2 follow-up, however, should be angiographic and that

3 should take place probably at a minimum of six

4 months of follow-up. How is that?

5 DR. ZUCKERMAN: Fantastic!

6 DR. HIRSHFELD: Question, Cindy. I didn\'t

7 hear the final panel recommendation on the study

8 design. I mean, we talked about several of those.

9 Is that something we should talk about or do you

10 know what you want?

11 DR. ZUCKERMAN: Right, well, what we heard

12 were the pluses and minuses of several different

13 study designs. It is an extremely difficult

14 problem. If there is consensus, we would like to

15 hear about it.

16 DR. HIRSHFELD: Well, I would just like to

17 mention that the more I think about it\--I was

18 initially attracted to it but the more I think

19 about it, the more I would come down on the side

20 against the patients being their own control. We

21 just heard about a trap that it would be too easy

22 to fall into and there must be others, you know, in

23 terms of how the grafts are put on the aorta. So,

24 I don\'t know if you want to talk about that

25 anymore.

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1 DR. TRACY: Dr. Blumenstein?

2 DR. BLUMENSTEIN: And another thing about

3 the study design is that I think that anything we

4 do today, at least we have the advantage of

5 hindsight, and any study design considered should

6 be looked at in light of whether it would have

7 detected the problems that you see in the device

8 being marketed. And, I think that is a reasonable

9 standard to apply for future designs.

10 DR. EDMUNDS: Dr. Blumenstein, is there

11 any way you could use Bayesian statistical models

12 to deal with this? Because I am really concerned

13 that this panel was convened because of concerns

14 about safety and it is more akin to concerns about

15 patency which is, of course, related to safety.

16 But to ignore the fact that, you know, 23 of them

17 popped off and the patients died, and so on, is I

18 think missing the point.

19 DR. BLUMENSTEIN: Well, I must say this

20 very carefully, when it comes to clinical trials I

21 do not worship at the altar of Bayes.

22 DR. EDMUNDS: Which altar to you worship

23 at?

24 DR. BLUMENSTEIN: The altar of

25 randomization, which aren\'t necessarily completely

269

1 disjoint but they are pretty much.

2 DR. ZUCKERMAN: Okay, but the Center for

3 Devices does also accept Bayesian randomized trials

4 or single-arm trials when appropriately designed up

5 front with our Bayesian statisticians. I am

6 wondering given Dr. Edmunds\' suggestion, a lot of

7 times companies come in with European data that

8 perhaps could be used as a prior given that they

9 are going to need to potentially also supply us

10 with U.S. IDE cohort data and it would be an

11 interesting issue to further pursue given that

12 sometimes the Bayesian methodology, if correctly

13 applied, can produce smaller sample sizes. On the

14 other hand, if the prior estimates from Europe are

15 incorrect, the nice thing about Bayesian

16 methodology is that it can produce even larger

17 sample sizes.

18 DR. EDMUNDS: My concern is that we can

19 shut down a promising innovation by a lot of

20 different people and engineers, and so on, that can

21 actually make an improvement in patient care with

22 advanced coronary-artery disease, particularly if

23 they have advanced aortic disease, atherosclerotic

24 aortic disease, and it is the baby and the bath

25 water.

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1 DR. BRIDGES: I am going to echo Dr.

2 Ferguson\'s point about the patient serving as his

3 own control. After getting more details on the

4 methodology used in the study in Hanover and

5 thinking about the logistic issues with the

6 sequence of graft placement on the ascending aorta,

7 it seems to me that no matter how you design that

8 study, it would be potentially flawed. So,

9 although I initially thought it sounded like a good

10 idea, now that I understand the details I don\'t

11 recommend that particular study design.

12 DR. HIRSHFELD: Since I was the bad guy

13 who initially recommended that, I would just like

14 to go on the record that I agree. I think the

15 advantage of doing the study with that architecture

16 was that you perfectly controlled for most of the

17 within patient variables. However, if doing it

18 perturbs the surgical technique from what would

19 otherwise be practiced, then that is perturbing the

20 entire study.

21 DR. TRACY: Dr. Zuckerman, were there any

22 additional comments or questions from the FDA?

23 DR. ZUCKERMAN: The agency greatly

24 appreciates the amount of time put in today by the

25 panel on what has become a very difficult issue,

271

1 and I am sure that the agency and industry will

2 benefit from this panel session.

3 DR. TRACY: Ms. Wells, Mr. Morton, do you

4 have any comments you would like to make at this

5 time?

6 MR. MORTON: Just congratulations to you.

7 We are ahead of time and covered a lot of

8 territory.

9 DR. TRACY: All right, at this point we

10 will adjourn the meeting and this concludes the

11 recommendations of the panel regarding the type of

12 data and study required to effectively evaluate

13 performance of aortic anastomotic devices for

14 marketing. Thank you.

15 \[Whereupon, at 4:10 p.m., the proceedings

16 were adjourned.\]