UNITED STATES OF AMERICA

           FOOD AND DRUG ADMINISTRATION

    CENTER FOR DEVICES AND RADIOLOGICAL HEALTH

        MEDICAL DEVICES ADVISORY COMMITTEE

 

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         CIRCULATORY SYSTEM DEVICES PANEL

 

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                      MEETING

 

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                     THURSDAY,

                 JANUARY 13, 2005

 

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            The Panel met at 9:00 a.m. in Salons A, B and C of the Hilton Washington, D.C., North/ Gaithersburg, 620 Perry Parkway, Gaithersburg, Maryland, Dr. William H. Maisel, Acting Chairperson, presiding.

 

PRESENT:

 

WILLIAM H. MAISEL, M.D.             Acting Chairperson

CHARLES R. BRIDGES, M.D.            Consultant

THOMAS B. FERGUSON, M.D.            Consultant

KENNETH W. JOHNSTON, M.D.           Consultant

JOANNE LINDENFELD, M.D.             Consultant

NORMAN S. KATO, M.D.                Consultant

MITCHELL W. KRUCOFF, M.D.           Member

MICHAEL C. MORTON                   Industry Rep.

LINDA A. MOTTLE, M.S.M.R.N.,CCRP    Consumer Rep.

GARY G. NICHOLAS, M.D.              Consultant

SHARON-LISE T. NORMAND, Ph.D.       Member

JOHN C. SOMBERG, M.D.               Consultant

CLYDE YANCY, M.D.                   Consultant

JUDAH Z. WEINBERGER, M.D., Ph.D.    Consultant

CHRISTOPHER J. WHITE, M.D.          Member

GERETTA WOOD                        Exec. Secretary

FDA REPRESENTATIVES:

 

BRAM ZUCKERMAN, M.D.

DOROTHY ABEL

BINITA ASHAR, M.D., MBA

DAVID BUCKLES, Ph.D.

ANDREW FARB, M.D.

GARY L. KAMER

MEGAN MOYNAHAN

 

SPONSOR REPRESENTATIVES:

 

MICHEL S. MAKAROUN, M.D., F.A.C.S.

R. SCOTT MITCHELL, M.D., F.A.C.S.

MICHAEL C. NILSON

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

                    AGENDA ITEM               PAGE

 

WELCOME/OPENING REMARKS:

William Maisel.................................. 5

CONFLICT OF INTEREST:

Geretta Wood.................................... 5

INTRODUCTIONS:.................................. 8

VOTING STATUS STATEMENT:....................... 10

CRITICAL PATH INITIATIVE:

Binita Ashar................................... 11

GUIDANT COMPANION UPDATE and

PHILIPS MEDICAL HEARTSTART HOME OVER-THE-COUNTER AED:

Megan Moynahan.............................. 23/26

LIFELINE REGISTRY:

Rodney White................................... 31

SOCIETY FOR VASCULAR SURGERY:

Greg Sicard.................................... 38

AUDIENCE MEMBER COMMENT:

Bill Tinker.................................... 40

HARVARD MEDICAL SCHOOL:

Richard Cambria................................ 43

LOYOLA UNIVERSITY:

Michael Tuchek................................. 47

HARBORVIEW MEDICAL CENTER:

Riyad Karmy-Jones.............................. 51

QUESTIONS:..................................... 53

SPONSOR PRESENTATION:

GORE TAG THORACIC ENDOPROSTHESIS:

Mike Nilson.................................... 57

ETIOLOGY AND CURRENT THERAPY:

Scott Mitchell................................. 59

TAG DEVICE, HISTORY AND DESIGN:

Mike Nilson.................................... 65

CLINICAL TRIAL PROGRAM RESULTS/DATA:

Michel Makaroun................................ 73

CLOSING REMARKS:

Scott Mitchell................................. 99

Mike Nilson................................... 102

Q&A SESSION:.................................. 103

FDA PRESENTATION:

Dorothy Abel.................................. 121

Andrew Farb................................... 133

Gary Kamer.................................... 146

                 AGENDA CONTINUED             PAGE

 

PANEL QUESTIONS:.............................. 156

PANEL REVIEWS AND SPONSOR QUESTIONS:

Henry Edmunds............................. 182/303

Clyde Yancy............................... 183/299

Judah Weinberger.............................. 194

Ken Johnston.................................. 198

Sharon-Lise Normand........................... 212

Norm Kato..................................... 232

John Somberg.................................. 239

Charles Bridges............................... 245

Gary Nicholas................................. 254

Mitch Krucoff................................. 260

Joanne Lindenfeld............................. 281

Tom Ferguson.................................. 294

William Maisel................................ 301

QUESTIONS TO PANEL:

Question 1 - Assurance of Safety.............. 307

Question 2 - Assurance of Effectiveness....... 313

Question 3 - Control Group Differences........ 320

Question 4 - Indication For Use............... 320

Question 5 - Additional Warnings.............. 326

Question 6 - Labeling Comments................ 328

Question 7 - Physician Training Plan.......... 330

Question 8 - Post-Approval Study/Follow-Up.... 336

Question 9 - Post-Approval Study Plan Adequacy 345

PUBLIC HEARING SESSION:

Riyad Karmy-Jones............................. 346

Gregorio Sicard............................... 350

Rodney White.................................. 352

J. Michael Tuchek............................. 353

ADDITIONAL FDA COMMENTS:

Dave Buckles.................................. 356

MOTION TO APPROVE WITH CONDITIONS:............ 363

CONDITION 1 - POST-APPROVAL STUDY............. 363

VOTE TO APPROVE CONDITION 1:.................. 368

CONDITION 2 - APPROPRIATE TRAINING:........... 371

VOTE TO APPROVE CONDITION 2:.................. 372

CONDITION 3 - INCLUSION/EXCLUSION CRITERIA:... 372

VOTE TO APPROVE CONDITION 3:.................. 373

VOTE TO APPROVE WITH CONDITIONS:.............. 375

ADJOURN:

William Maisel................................ 384

               P-R-O-C-E-E-D-I-N-G-S

                                         9:01 a.m.

            ACTING CHAIR MAISEL:  Good morning.  I would like to call to order this meeting of the Circulatory System Devices Panel.  Today's topic is discussion of a pre-market application for the W.L. Gore and Associates GORE TAG Thoracic Endoprosthesis, P040043.  I would like to ask Geretta Wood to read the Conflict of Interest statement.

            EXEC. SEC. WOOD:  The following announcement addresses Conflict of Interest issues associated with this meeting and is made a part of the record to prevent even the appearance of an impropriety.  To determine if any conflict existed, the Agency reviewed the submitted agenda and all financial interest reported by the Committee participants.  The Conflict of Interest statutes prohibit special Government employees from participating in matters that could affect their or their employer's financial interest.

            However, the Agency has determined that participation of certain members and consultants, the need for whose services outweighs the potential conflict of interest involved is in the best interest of the Government.  Therefore, waivers have been granted for Drs. Charles Bridges, L. Henry Edmunds, Thomas Ferguson, William Maisel, Clyde Yancy and a waiver was previously granted for Dr. Judah Weinberger for their interest in firms that could potentially be affected by the Panel's recommendation.

            The waivers for Drs. Bridges, Edmunds, Ferguson and Maisel involve a grant to their institution for the sponsor's study.  The panelists had no knowledge of the funding and had no involvement in the generation or analysis.  Dr. Ferguson's waiver also involves his affiliation with a nonprofit organization that is the recipient of an unrelated educational grant from a competitor.

            Funding to the organization is between $100,001 and $300,000 per year.  Dr. Yancy's waiver involves unrelated consulting services with a competitor for which his fees have not yet been determined.  Dr. Weinberger's waiver includes a stockholding in a competitor in which the value is between $50,001 and $100,000.  The waivers allow these individuals to participate fully in today's deliberations.

            Copies of these waivers may be obtained from the Agency's Freedom of Information Office, Room 112A-15 of the Parklawn Building.  We would like to note for the record that the Agency took into consideration other matters involving Drs. Mitchell Krucoff, Joanne Lindenfeld and Clyde Yancy.  These panelists reported past or current interest involving firms at issue, but in matters that are not related to today's agenda.  The Agency has determined therefore that these individuals may participate fully in the Panel's deliberations.

            The Agency also would like to note that in the event that the discussion involves any other products or firms not already on the agenda for which an FDA participant has a financial interest, the participant should excuse him or herself from such involvement and the exclusion will be noted for the record.  With respect to all other participants, we ask in the interest of fairness that all persons making statements or presentations disclose any current or previous financial involvement with any firm whose products they may wish to comment on.

            ACTING CHAIR MAISEL:  Thank you, Geretta.  My name is Dr. William Maisel.  I'm a cardiologist at Brigham and Women's Hospital and I would like to invite the Panel Members to introduce themselves starting on my left with Dr. Zuckerman.

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

            DR. FERGUSON:  Tom Ferguson, Professor Emeritus, Washington University, Saint Louis.

            DR. LINDENFELD:  Joanne Lindenfeld.  I'm a Cardiologist at the University of Colorado.

            DR. KRUCOFF:  Mitch Krucoff.  I'm a Cardiologist at Duke University Medical Center and the Director of the Cardiovascular Devices Unit at the Duke Clinical Research Institute.

            DR. NICHOLAS:  Gary Nicholas, a vascular surgeon, Professor of Surgery, Penn State University, Lehigh Valley Hospital.

            DR. BRIDGES:  Charles Bridges, Cardiothoracic Surgeon, University of Pennsylvania.

            EXEC. SEC. WOOD:  Geretta Wood, Executive Secretary for the Advisory Panel.

            DR. SOMBERG:  I'm John Somberg.  I'm a Professor of Medicine and Pharmacology at Rush University in Chicago, Illinois.

            DR. KATO:  Norman Kato, Cardiothoracic Surgery, private practice, Encino, California.

            DR. NORMAND:  Sharon-Lise Norman, Professor of Health Care Policy and Biostatistics at Harvard Medical School and Harvard School of Public Health.

            DR. JOHNSTON:  Wayne Johnston, Vascular Surgeon, Professor of Surgery at University of Toronto.

            DR. WEINBERGER:  Judah Weinberger, Interventional Cardiologist at Columbia University.

            MR. MORTON:  Michael Morton.  I'm the industry representative.  I'm employed by Medtronics.

            MS. MOTTLE:  Linda Mottle, Director and Faculty of the Clinical Research Program at Gateway Community College.

            ACTING CHAIR MAISEL:  Thank you.  Geretta, if you would read the voting status statement, please?

            EXEC. SEC. WOOD:  Pursuant to the authority granted under the Medical Devices Advisory Committee Charter dated October 27, 1990 and as amended August 18, 1999, I appoint the following individuals as voting members of the Circulatory System Devices Panel for this meeting on January 13, 2005:  Charles R. Bridges, M.D., L. Henry Edmunds, Jr., M.D., Thomas B. Ferguson, M.D., Kenneth W. Johnston, M.D., Joanne Lindenfeld, M.D., Norman S. Kato, M.D., Gary G. Nicholas, M.D., John C. Somberg, M.D., Clyde Yancy, M.D., Judah Z. Weinberger, M.D., Ph.D.

            For the record, these individuals are special Government employees and are consultants to this Panel under the Medical Devices Advisory Committee.  They have undergone the customary Conflict of Interest review and have reviewed the material to be considered at this meeting.  The Agency would also like to note that Dr. William Maisel has consented to serve as Chair for the duration of this meeting.  This is signed by Daniel G. Schultz, M.D., Director, Center for Devices and Radiological Health and signed January 11, 2005.

            ACTING CHAIR MAISEL:  Thank you.  Before we begin this morning's discussion on this application, the FDA has two brief presentations.  I would like to invite Dr. Binita Ashar, Acting Clinical Director, of the CDRH to talk about the Critical Path Initiative.

            DR. ASHAR:  Great.  Thank you and good morning.  I appreciate this opportunity to discuss with you the Agency's Critical Path Initiative from the CDRH perspective.  Basically, what I'm going to do this morning is I'm going to identify some of the challenges in medical product development.  Then I will define for you what the Critical Path Initiative is and then describe what our future efforts are for bringing this initiative further.

            Basically, the present state of affairs is that there is a scientific challenge that we have a number of disease processes, Alzheimer's, AIDS, cardiovascular diseases that need better treatments and we not only need better treatments, but we need better preventative therapies.  At the same time, we're faced with a societal challenge and that is the urgency for timely development of treatments for these diseases.  And not only do we need these treatments to be timely, but we also need these treatments to be affordable.

            In the present state of affairs, there is great optimism based on new biomedical discovery.  We have sequenced the human genome.  We have new genomic and proteomic technologies.  There are advances in medical imaging.  We have nanotechnology advances that potentially can offer the right treatment to the right patient in the right location with far fewer side effects than ever before.  And at the same time, we have been investing to produce these basic biomedical advances.

            There has been an increase in NIH funding of double over the past five years.  And pharmaceutical research and development has also increased at the same rate.  Overall, our society has provided major investments in basic biomedical technology research and this is a graphical representation demonstrating the increase in research spending, both from the pharmaceutical RND side as well as in the NIH budget.

            Now, you would expect that this acceleration in development, this would have translated into increased medical product development.  However, from the drugs and biologic side, in fact, there has been a decline in the number of FDA new products that have been submitted.  Now, this necessarily hasn't been the case for medical devices, but the fact of the matter is we could be doing better.  And this is a graphical representation demonstrating the 10-year trend in pre-market device application showing the number of original PMAs that have been submitted.

            Now, at the same time, we are noticing that, at least on the drug and biologic side, the cost of bringing a new drug to market is estimated to be about $1.7 billion, and the reason for this is largely because there is a high failure rate of new drug candidates late in the clinical development process.  Now, what is the cause of this problem?  Well, some of these new technologies aren't at their full potential.

            And what has been occurring or what we have noticed to occur is that industries have been focusing on easier targets and because of various business arrangements have focused on potentially the cash cows and not necessarily treatments that might affect smaller populations.  They have found that the development process has become uncertain.  Some of the additional challenges that I have mentioned already are that there is a failure late in the clinical development process, at least for drugs and biologics.

            Now, I want to mention that the Critical Path is different for devices.  Device development is different because of the device regulation process.  We have a least burdensome provision of FDAMA, which is different than drugs and biologics.  We are committed to finding a least burdensome path to market.  We have quality systems and design controls that are not prescriptive, but are focused on what the end result is and has the product, indeed, met the expectations that we have requested.

            The innovation process is different for devices.  The small molecule issue is biocompatibility, not necessarily biometabolism.  The process is an iterative process whereby sometimes during the clinical development phase, there might be minor changes in the device.  There is a user learning curve that we face with the use of medical devices and performance and durability are also engineering issues.  Different pharmaceuticals in the device industry is represented by small manufacturers that may not have the resources to put forth all of the time and effort and expenditures that they might need to to bring a product forward.

            Other additional causative factors that have been shown as a hurdle in the medical product development is that some of the basic science investment and progress has surpassed what we are able to actually translate into new medical products.  Essentially, we are using the evaluation tools and infrastructure of the last century to bring forth new medical products of this century.  We are doing randomized controlled clinical trials like we have always done them.

            We are not necessarily using our cumulative knowledge of the society to overcome some of the development hurdles, so that we can bring medical products to market faster without compromising our safety and effectiveness evaluations.  And this has resulted in a bottleneck at the Critical Path for delivering new medical products to patients.

            So the central Critical Path thesis is that there has been a great societal investment in research and development to improve medical product development.  However, there has not been an investment in the tools necessary to translate this basic biomedical research into new medical products.  So what do I mean by this?  Well, tools that might be computer simulation tools or registries or new surrogate markers that have been validated or biomarkers that might be able to identify patient populations that might be most amenable to these treatments that would potentially cut down the size of these various clinical trials.

            There has been a great investment in the basic research, but not investment and attention to the tools to bring this research to translate into medical products.  And some of the problem is that academia is not adequately funded to perform the scientific investigations to develop new tools.  This has generally not been conceptualized up until this point, at least, as being FDA's role.  And any efforts to develop valuative tools in the private sector are proprietary and they are, therefore, not generalizable and available for use for the population at large.

            So the FDA's Critical Path Initiative is an attempt to bring attention and focus to the need for targeted scientific efforts to modernize the techniques and methods used to evaluate the safety, effectiveness and quality of medical products as they move from product selection to design and mass manufacture.  And this diagram demonstrates how Critical Path research differs from what is generally considered translational research.

            You notice that basic scientific research is the type of research that is largely conducted by academic organizations and by our sister agencies like NIH.  NIH is also quite interested in translational research of bringing this new basic research into the clinical arena.  However, Critical Path research is really FDA's arena where this translational research is looked at from the perspective of mass manufacture and mass marketing.

            Can these clinical trial results formed in a small population translate into the generalized patient populations that we are approving a device for?  And in evaluating any sort of medical products, you look at three dimensions of Critical Path.  You look at safety.  Can this device adequately perform in a safe manner?  Can this device demonstrate efficacy in the population?  And can this device be mass produced to the point that it is generalizable to not only the premiere centers in the United States, but also to all of the community hospitals?  And can these results that we see in these early clinical trials be ones that can be replicated over and over again in smaller areas?

            And so if we had tools that might be able to help us in our assessment in deciding whether a product is safe or effective or can be industrialized, wouldn't it be great to be able to bring these products to development faster without compromising our safety and effectiveness evaluation?  So basically, the Critical Path science basis is to be able to understand what types of tools we might be able to invest in.

            And FDA potentially could take an organizational role in bringing groups together, consumer groups, patient groups, academia and industry groups to develop some of these scientific tools that might be then available in the public arena for use by all industry groups.  And this is something that NIH and academia have generally not focused on and Critical Path is intended to be something that is supplementing what we already have learned in our translational research basis.

            So the work ahead, basically, this is for scientific improvement.  It is not to be confused with regulatory evolution or streamlining or making the paper pushing faster or easier.  It is, essentially, using the science that we already know to develop tools that help in our evaluations.  The regulatory process is a related effort and can assist with this, but it is not the focus of this initiative.

            So what have we done so far with Critical Path?  Well, basically, there was a Federal Register docket open describing a Critical Path that was open through the summer and we received a number of responses from industry groups, patient groups, professional organizations, individual industries.  This initiative was also presented to the FDA Advisory Board, the Science Board, to receive some of their feedback.  And we have had individual meetings with various scientists, companies, patient groups and many, many others just to get the word out, just to get feedback out.

            This has also been presented at the FDA Science Forum and at many speeches and panel presentations.  And, basically, we have received overwhelming support.  In fact, they have asked FDA to embark on doing things that is well outside of FDA's resources.  And we have heard this really from all of our patient groups and all of our industry groups.

            Submitters actually, again, ask for us to work on a number of things intent actually outside of some of our range.  And some of the things that they suggested is, you know, streamlining clinical trials if we had better biomarkers, if we had a process by which we knew that we could validate a surrogate endpoint and promote effective product development.  What they wanted repeatedly was FDA feedback on particular endpoints and particular surrogate endpoints.  And how we can harmonize internationally so that we could better do this so that a clinical trial in one area of the world would be applicable to the United States, how we could focus on cancer trials, combination products.

            Some industry groups actually have commented on the use of proprietary data.  You know, very tentatively, they mentioned that perhaps FDA might find a way to use some of this information with the consent of all involved parties to further medical product development.  And so, basically, the bottom line is this is an initiative that is intended to use science to integrate into the regulatory process, so that we can make our safety and effectiveness evaluations faster and more cost effectively.

            This is not just an FDA effort.  We can't do this alone.  We need to work with our stakeholders to make this a reality.  And we need to focus on particular scientific areas that first and perhaps expand at a later date.  So the next step on a Critical Path is from the docket we received a number of comments.  We are identifying all of the possible proposals and prioritizing various opportunities for developing valuative tools.  We will be putting forth a national Critical Path opportunities list that reflects all of the comments that we have received.

            We need to find a mechanism by which we can continue to obtain such feedback and update this list so that not only FDA, but other interested parties, might embark on Critical Path research.  Thank you very much for your attention.

            ACTING CHAIR MAISEL:  Thank you very much.  Next, I would like to invite Megan Moynahan, who is the Branch Chief for Pacing, Defibrillator and Leads, to update the Panel on some recent decisions.

            DR. MOYNAHAN:  Good morning.  Thank you very much.  I would like to take a few minutes this morning to update you on the Panel meeting that occurred in July this past year in which the panelists discussed the Guidant Companion application, a labeling review, and the Philips Medical HeartStart Home Over-the-Counter AED.

            Beginning with companion, the FDA raised a number of concerns to the Panel and I'm not going to represent them all here, but the primary one related to whether the Panel felt that the data were sufficient to support an expanded patient population for the Guidant CRT-D Device to include patients who did not have to have a requirement for an ICD.  There was a lot of discussion about the change in definition of hospitalization and the FDA has some concern about how to interpret both the primary and secondary endpoints based on that.

            We asked the Panel to comment on how the indication should be worded and we asked for some broad labeling recommendations on that application.  The Panel recommended that the data supports expanding the indicated patient population, but they had some concerns about how that would be worded in the indication statement.  They specifically asked us to avoid using the term "all-cause hospitalization" in the indication statement.  And they wanted a special separate section of the labeling to call out the benefit with respect to the primary endpoint.

            The approved indications appears as follows, and as you see, it only indicates the intended patient population, so it is indicated for patients with moderate to severe heart failure who remain symptomatic despite stable optimal heart failure drug therapy and have an LVEF of less than 35 percent and a QRS no greater than 120.  And now, there is a new clinical outcome section that appears in the labeling just after the indication statement in which we go into more detail as to the clinical benefit to patients.

            Here is where we identify the reduction in risk of all-cause mortality or first hospitalization, is how it is presented, and then we go onto define how hospitalization was used in that trial, including noting that the hospitalizations did not include the device implant attempt or any reattempts.  We also identified the reduction and risk of all-cause mortality and we mentioned the reduction of heart failure symptoms.

            The Panel also made a number of other recommendations with respect to the labeling and, in particular, they were interested to see how we were going to be presenting hospitalizations.  While they agreed that the representation of the primary endpoint should not include the index or implant hospitalization, they felt that it would be important to present in clinically meaningful information to physicians and patients that describe hospitalizations in general.

            And so this is an example of the approved labeling that we've worked with the company to develop.  This is the original Kaplan-Meier curve for the primary endpoint of all-cause mortality or first heart failure hospitalization and this is the same as what you would see in the published literature.  But the labeling also represents a number of hospitalizations per patient year and that was done to account for the difference in follow-up for the two different groups.

            It presents this information comparing the OPT or the control group to the CRT-D group and it also gives you an idea of the relative contribution of the implant hospitalization in both cases.  There is also a graph in the labeling that depicts the number of hospitalization days per patient year, again distinguishing between the OPT group and the CRT-D group and also indicating a relative contribution of the implant hospitalizations that occurred in both groups.

            And finally, there is a representation of the number of heart failure hospitalization days per patient year comparing the OPT group to the CRT-D group.  Based on their Panel recommendations, the FDA approved the companion submission on September 14, 2004.

            Now, moving on to the Philips Medical Over-the-Counter AED, the FDA raised a number of concerns to the Panel that day including asking whether the data was sufficient to support over-the-counter availability of the device and, in particular, we wanted them to comment on the adequacy of the user testing and whether the sponsor had appropriately integrated CPR prompts and notifications to dial 911 or to notify the Emergency Medical Services.

            We asked the Panel to comment on whether the data were sufficient to support over-the-counter availability of the pediatric pads.  We asked broadly for labeling recommendations and to comment on the sponsor's methods for tracking devices in the event of a recall or adverse event reporting and whether they believe that a post-market study would be required.  Because this was a 510(k) application, there was no vote.  However, the Panel was felt to be generally in favor of over-the-counter availability of the device.  They felt that the usability testing was adequate and that the voice prompts for CPR and the visual prompts for calling 911 were felt to be adequate.

            There was no consensus, however, on whether the pediatric pads should be available over-the-counter.  There were quite a number of specific labeling recommendations that were given to us and the Panel recommended a post-market study, but asked FDA to review the tracking and adverse event reporting methods.  FDA ultimately concurred with the Panel that there was sufficient usability testing and we did not require additional testing on the part of the sponsor.  We felt that the prompts for CPR were appropriate and with minor modifications to the 911 reminders we felt that they were appropriate as well.

            Importantly, the pediatric pads were not included in our over-the-counter decision and they still remain available as a prescription accessory.  And that was done for a number of reasons.  We felt that ultimately this would simplify a very complex purchasing decision by not offering too many options or accessory products to the user.  We felt that it sent an important message that underscores that sudden cardiac arrest is an adult public health concern, one that's not shared equally by the pediatric population.

            We feel that this decision ensures safe and effective use on both adults and children.  And we felt that this was not going to impact availability too detrimentally of families who have higher risk children, because those families should be well-integrated into the medical system and would easily be able to get a prescription for the products.

            We made substantial labeling modifications based on Panel recommendations.  I'm not going to go through all of them, but I'll give you one example.  The Panel felt that the outer box should be designed to help customers make an informed purchase decision and these are some of the things that appear now on the outside of the box and also appear on websites that are offering this product for over-the-counter sale.

            For example, it mentions that you should speak to your doctor and that a defibrillator does not take the place of seeking medical help, that you can't use the device on yourself, that users may need to perform CPR, that responding to cardiac arrest may require you to kneel, that voice instructions and materials are in English and that the HeartStart provides audible and visible indicators for maintenance.

            FDA's clearance decision included acceptance of the sponsor's methods for post-market tracking and adverse event reporting and we're continuing to work with the sponsor on developing the Post-Market Study Plan.  Ultimately, FDA cleared this product for over-the-counter use on September 16, 2004.  Thank you very much.

            ACTING CHAIR MAISEL:  Thank you, Megan, for those updates.  At this point, we will begin the open public session of this morning's meeting, both the Food and Drug Administration and the public believe in a transparent process for information gathering and decision making to ensure such transparency at the open public hearing session of the Advisory Committee meeting, FDA believes that it is important to understand the context of an individual's presentation.

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

            Likewise, FDA encourages you at the beginning of your statement to advise the Committee if you do not have any such financial relationships.  If you choose not to address this issue of financial relationships at the beginning of your statement, it will not preclude you from speaking.  At this point, I would like to invite Dr. Rodney White to approach and address the Panel.

            DR. WHITE:  Thank you very much.  It's a pleasure to be here today.  I'm representing the Society for Vascular Surgery and a project that you have heard about before, I think, that we would like to update you on.  The Lifeline Registry, which now is the SVS/American Vascular Association Outcomes Registry has been an effort that we have updated Panels on serially related endoluminal grafts.

            At the beginning of this, I would like to tell you that my Conflicts of Interest are that I have no commercial interest in Gore.  I'm not a Gore investigator.  I am here representing the Society for Vascular Surgery as the Secretary and Chairman of the SVS/AVA Lifeline Registry Committee.  I'm an academic surgeon.  I make my living treating these kinds of patients and get promoted based on publishing papers, so I think my major conflict is I make a living doing this sort of stuff.

            The Lifeline Registry was established in 1997 to look prospectively at post-approval of abdominal aortic aneurysms.  The SVS has now recently, in association with the American Vascular Association, an expansion of our nonprofit foundation efforts, extended the SVS capability to look at outcomes analysis, not only to the endoluminal grafts, but to the technologies we're talking about today, thoracic grafts or in a concurrent effort to carotid stents and endarterectomy.

            A unique aspect we offer is that we can look at both of these technologies concurrently and in that regard, we would like to emphasize from the beginning that the SVS is going to make a specific effort to make available operative data related to these technologies, so as we move into these other areas, it will be relevant.

            Registry is unique in that the initial attempt was to do something that hadn't been done successfully previously and that was to look prospectively to establish a registry that would take scientific data, put it together over time and actually look at a number of stakeholders involved in this, including the societies and clinicians, the foundation that I mentioned, federal agencies, and we have been very fortunate to have both FDA and CMS active in these efforts with their input.

            An industrial advisory committee made of, in this case, the following companies which have supported that effort, I will emphasize that of the group today W.L. Gore was a founding member of the registry, has been very proactive in supporting this effort and that this has been an important part in how we progress.  The registry goals were to evaluate long-term and prospectively endoluminal graft function.

            Because of the requirement for post-market surveillance, I think this is a topic that will come up later, we were able to establish with a central registry committee working beneath the foundation and again with the ex officio input of the FDA, NIH, CMS and this industrial advisory committee and our data center, New England Research Institute, a way to be able to collect this data, put it together and report it.

            The funding mechanisms are by the foundation itself and industrial partners feeding this data and collecting it.  The registry then initially was to look at the post-market IDE data, collect that and look at it over the five-year surveillance interval that was available.  Now, if you think about that, that makes it a very high compliance audited data set.  There are then two parts to this registry I'll tell you about briefly, because we've got now six-year results to look at, was to take this five- year PMA model, look at these patients over time and because of the post-approval market, we're able to look at the requirement of the Agency to have the manufacturers submit this data and work out a collaborative effort to collect this.

            The long-term results of the FDA devices have then been evaluated and in a collective fashion you will see.  Now, these are just some numbers to give you an idea of how these can be powered over time, but with four approved devices and some commercial site entries, you will see we're now nearly at 3,000 patients.  A very important part of this is we also have a concurrent surgical control group of patients that can be compared for outcomes analysis.  And in the kinds of considerations we're doing today, these are particularly important.

            Primary and secondary endpoints that I won't list in detail were looked at and were able to, in almost all cases now, start to look at very important outcome issues and patient selection parameters and have reached statistical significance in many of these related to the outcome comparing endoluminal grafts to the conventional stent graft technologies.  The same for hospital parameters, ICU stays, things that are routinely looked at and again we can compare these two groups.

            What we have come up with then, now, these are six-year curves, are comparisons of morbidity, mortality, aneurysm-related mortality, freedom from rupture, gender analysis, this has been highlighted in other examples, freedom from surgical conversion.  And again, just to highlight this very briefly, there is a data set that was presented at the SVS this year in a publication submitted to the Journal of Vascular Surgery that will summarize these six-year data outcomes and forward.  But in general, it gives us a very good standard to be able to apply this to and have a surgical cohort group.