DEPARTMENT OF HEALTH AND HUMAN SERVICES

> FOOD AND DRUG ADMINISTRATION
>
> CENTER FOR DEVICES AND RADIOLOGICAL HEALTH
>
> **CIRCULATORY SYSTEMS DEVICES PANEL**
>
> **OPEN SESSION**
>
> Monday, March 4, 2002
>
> 10:10 a.m.
>
> Gaithersburg Marriott Washington Center
>
> 9751 Washington Boulevard
>
> Gaithersburg, Maryland
>
> PARTICIPANTS
>
> Warren K. Laskey, M.D., Acting Chairperson
>
> Lesley Ewing, M.D., Executive Secretary
>
> VOTING MEMBERS
>
> Salim Aziz, M.D.
>
> Janet T. Wittes, Ph.D.
>
> CONSULTANTS
>
> Anthony Comerota, M.D.
>
> James A. DeWeese, M.D.
>
> Michael J. Domanski, M.D.
>
> Francis Klocke, M.D.
>
> Marvin Konstam, M.D.
>
> Steven Nissen, M.D.
>
> Pilar Ossorio, Ph.D., J.D.
>
> Ileana Pina, M.D.
>
> CONSUMER REPRESENTATIVE
>
> Robert A. Dacey
>
> INDUSTRY REPRESENTATIVE
>
> Michael Morton
>
> PATIENT REPRESENTATIVE
>
> Joseph Knapka, Ph.D.
>
> FDA
>
> Bram Zuckerman, M.D.
>
> [C O N T E N T S]{.underline}
>
> [PAGE]{.underline}
>
> [Call to Order: Warren Laskey, M.D. 4]{.underline}
>
> [Conflict of Interest Statement 4]{.underline}
>
> [Open Public Hearing 9]{.underline}
>
> [Sponsor Presentation: Thoratec Corporation]{.underline}
>
> [P910014/S016 HeartMate VE LVAS]{.underline}
>
> [Introduction]{.underline}
>
> [Donald A. Middlebrook 9]{.underline}
>
> [Device Overview]{.underline}
>
> [Victor Poirier 14]{.underline}
>
> [REMATCH Trial Clinical Results]{.underline}
>
> [Eric Rose, M.D. 22]{.underline}
>
> [REMATCH Patient Population]{.underline}
>
> [Lynne W. Stevenson, M.D. 29]{.underline}
>
> [REMATCH Trial Clinical Results]{.underline}
>
> [Eric Rose, M.D. 39]{.underline}
>
> [Summary and Closing Remarks]{.underline}
>
> [Donald A. Middlebrook 55]{.underline}
>
> [FDA Presentation]{.underline}
>
> [Michael Berman, Ph.D., Lead Reviewer 57]{.underline}
>
> [Julie Swain, M.D., Clinical Reviewer 68]{.underline}
>
> [Gerry Gray, Ph.D., Statistical Reviewer 83]{.underline}
>
> [Questions to the Committee 96]{.underline}
>
> [Open Discussion 100]{.underline}
>
> [Panel Recommendations 222]{.underline}
>
> [Open Public Hearing 260]{.underline}
>
> [Sponsor Comments 261]{.underline}
>
> [Panel Voting 262]{.underline}
>
> [\
> ]{.underline}
>
> [P R O C E E D I N G S]{.underline}
>
> **[Call to Order]{.underline}**
>
> [DR. LASKEY: I would like to call this panel meeting session to order.
> This morning\'s topic will be a discussion of the supplement to a
> Premarket Application for Thoratec Corporation\'s HeartMate VE Left
> Ventricular System.]{.underline}
>
> [I would like to now have the Executive Secretary read the Conflict of
> Interest Statement.]{.underline}
>
> **[Conflict of Interest Statement]{.underline}**
>
> [DR. EWING: Good morning. I would like to welcome everyone to the
> meeting this morning and especially I would like to thank the panel
> members for their time in reviewing this application.]{.underline}
>
> [The following announcement addresses conflict of interest issues
> associated with this meeting and is made part of the record to
> preclude even the appearance of an impropriety.]{.underline}
>
> [To determine if any conflict existed, the Agency reviewed the
> submitted agenda for this meeting and all financial interests reported
> by the committee participants. The conflict of interest statutes
> prohibit special government employees from participating in matters
> that could affect their or their employer\'s financial
> interests.]{.underline}
>
> [The Agency has determined, however, that the participation of certain
> members and consultants, the need for whose services outweighs the
> potential conflict of interest involved is in the best interests of
> the Government.]{.underline}
>
> [We would like to note for the record that the Agency took into
> consideration matters regarding Drs. Salim Aziz, Francis Klocke, and
> Marvin Konstam. Each of these panelists reported interests in firms at
> issue, but in matters that are not related to today\'s agenda. Drs.
> James DeWeese and Anthony Comerota reported that their institution has
> an involvement with the firm at issue.]{.underline}
>
> [The Agency has determined that all of these individuals may
> participate fully in the discussions.]{.underline}
>
> [In the event that the discussions involve 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.]{.underline}
>
> [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.]{.underline}
>
> [DR. LASKEY: Thank you, Lesley.]{.underline}
>
> [I would like to now have the panel members introduce themselves
> starting on my right.]{.underline}
>
> [DR. ZUCKERMAN: Bram Zuckerman, Acting Director, Division of
> Cardiovascular and Respiratory Devices, FDA.]{.underline}
>
> [DR. WITTES: Janet Wittes, panel member. I am a statistician at
> Statistics Collaborative in D.C.]{.underline}
>
> [DR. KONSTAM: Marv Konstam from Tufts University, New England Medical
> Center.]{.underline}
>
> [DR. COMEROTA: Anthony Comerota, vascular surgeon from Temple
> University in Philadelphia.]{.underline}
>
> [DR. NISSEN: I am Steve Nissen. I am a cardiologist from The Cleveland
> Clinic.]{.underline}
>
> [DR. AZIZ: Salim Aziz, Associate Professor at the University of
> Colorado Clinic.]{.underline}
>
> [DR. EWING: Lesley Ewing, Executive Secretary.]{.underline}
>
> [DR. LASKEY: Warren Laskey, interventional cardiologist from the
> University of Maryland.]{.underline}
>
> [DR. PINA: Ileana Pina, Cardiology, Case Western Reserve University,
> Cleveland.]{.underline}
>
> [DR. OSSORIO: Pilar Ossorio, University of Wisconsin at Madison,
> bioethicist and lawyer.]{.underline}
>
> [DR. DeWEESE: Jim DeWeese, cardiac and vascular surgeon, University of
> Rochester, New York.]{.underline}
>
> [DR. KLOCKE: Francis Klocke. I am a cardiologist from Northwestern
> University Medical School.]{.underline}
>
> [MR. DACEY: Robert Dacey, Consumer Representative, Boulder,
> Colorado.]{.underline}
>
> [MR. MORTON: Michael Morton. I am employed by Alcon Laboratories, and
> I am the Industry Representative.]{.underline}
>
> [DR. KNAPKA: Joe Knapka, Patient Representative, from Olney,
> Maryland.]{.underline}
>
> [DR. LASKEY: Thank you, members.]{.underline}
>
> [Dr. Ewing, would you now read the voting status statement,
> please.]{.underline}
>
> [DR. EWING: This is the Appointment to Temporary Voting Status.
> 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 March 4, 2002:
> Pilar Ossorio, Michael Domanski, who will be coming soon, James
> DeWeese, Francis Klocke, Anthony Comerota.]{.underline}
>
> [For the record, these people 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 for this
> meeting.]{.underline}
>
> [In addition, I appoint Dr. Warren Laskey to serve as Panel Chair for
> the duration of this meeting.]{.underline}
>
> [I also have another Appointment to Temporary Voting Status to read
> into the record.]{.underline}
>
> [Pursuant to the authority granted under the Medical Devices Advisory
> Committee Charter of the Center for Devices and Radiological Health,
> 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 the meeting on March 4 and 5, 2002: Steven E.
> Nissen, Ileana Pina, and Marvin A. Konstam.]{.underline}
>
> [For the record, Dr. Nissen is a voting member, and Drs. Pina and
> Konstam are consultants to the Cardiovascular and Renal Drugs Advisory
> Committee of the Center for Drug Evaluation and Research. They are
> special government employees who have undergone the customary conflict
> of interest review and have reviewed the material to be considered at
> this meeting.]{.underline}
>
> **[Open Public Hearing]{.underline}**
>
> [DR. LASKEY: I would like to now open this morning\'s session for the
> open public hearing.]{.underline}
>
> [Are there any individuals requesting floor time?]{.underline}
>
> [\[No response.\]]{.underline}
>
> [DR. LASKEY: If not, then, I would like to close the public hearing
> and move on to the sponsor\'s presentation.]{.underline}
>
> [DR. EWING: While the computers are being set up, I would like to
> remind all the speakers, especially the speakers for the sponsor, to
> identify themselves and to state their conflict of
> interest.]{.underline}
>
> [Each time you speak, because we are labeled up here on the panel, but
> the people that are not so labeled, if you could state your name, so
> the transcriptionist can write who is speaking.]{.underline}
>
> **[Sponsor Presentation]{.underline}**
>
> **[Thoratec Corporation]{.underline}**
>
> **[P910014/S016, HeartMate VE LVAS]{.underline}**
>
> **[Introduction]{.underline}**
>
> **[Donald A. Middlebrook]{.underline}**
>
> [MR. MIDDLEBROOK: Thank you, Dr. Laskey, and good morning to
> all.]{.underline}
>
> [My name is Don Middlebrook. I am Vice President of Regulatory Affairs
> and Quality Assurance for Thoratec Corporation. I am also currently a
> shareholder.]{.underline}
>
> [I would like to begin this morning with a word of thanks to the FDA,
> especially to our FDA reviewers, all of the FDA invited panel members,
> and our clinical investigators and experts that are here on our
> behalf.]{.underline}
>
> [All of you, and certainly to all my Thoratec associates, all of you
> have worked hard to prepare for today\'s discussions, and those
> efforts are very much appreciated.]{.underline}
>
> [\[Slide.\]]{.underline}
>
> [This is a brief outline of our presentation that we will be making
> this morning. We will be discussing the very important results from
> the REMATCH trial, a first of its kind clinical trial to compare a
> medical device to a drug therapy for the treatment of end stage
> congestive heart failure in patients ineligible for cardiac
> transplantation.]{.underline}
>
> [\[Slide.\]]{.underline}
>
> [Our speakers this morning are: Victor Poirier, who will provide a
> brief overview of the HeartMate VE LVAS; Dr. Eric Rose from Columbia
> Medical Center, who will discuss the safety and effectiveness results
> documents in the REMATCH trial; and Dr. Lynne Warner Stevenson from
> Brigham & Women\'s Hospital in Boston, who will provide information on
> the patient population study, and also discuss medical management in
> the control treatment group.]{.underline}
>
> [\[Slide.\]]{.underline}
>
> [We have also invited a number of independent REMATCH experts who may
> be called upon to speak on our behalf, who were involved in some way
> in the study, either in the study design, the study management, or in
> the analysis of the results.]{.underline}
>
> [\[Slide.\]]{.underline}
>
> [Just a brief word about our company Thoratec Corporation. The company
> was founded in 1976 in Berkeley, California. We merged with Thermo
> Cardiosystems in February 2001, to be known thereafter as Thoratec
> Corporation.]{.underline}
>
> [Our product focus is circulatory support, vascular grafts, and
> diagnostic blood testing.]{.underline}
>
> [Our corporate offices are located in Pleasanton, California. We have
> 800 employees worldwide, and we are a world leader in cardiac assist
> device technology.]{.underline}
>
> [\[Slide.\]]{.underline}
>
> [We will be presenting a summary of the contents of the PMA that
> contain the results from the REMATCH trial. This is a landmark
> multicenter, prospective, randomized, controlled trial that looked at
> the HeartMate VE LVAS versus optimal medical management.]{.underline}
>
> [This study was initiated under a cooperative agreement between
> Thoratec, the NIH, and Columbia University.]{.underline}
>
> [The PMA we have submitted is seeking approval to expand the current
> HeartMate VE LVAS indications for use to include patients with
> end-stage left ventricular failure who are ineligible for cardiac
> transplantation.]{.underline}
>
> [Before I conclude my opening remarks, I would like to state that the
> REMATCH study has been the subject of a number of important scientific
> publications. I would like to just mention a few of
> those.]{.underline}
>
> [In January 2001, the ACC published a consensus report entitled,
> \"Mechanical Circulatory Support 2000, Current Applications and Future
> Trial Designs.\" This was the proceedings from a conference sponsored
> by leading cardiology and heart failure professional societies and
> included participants from the FDA and the NIH.]{.underline}
>
> [In this report, the REMATCH study was cited several times as a
> benchmark study for evaluating mechanical circulatory support device
> treatment outcomes in patients with end-stage congestive heart
> failure.]{.underline}
>
> [Also, in November 2001, the REMATCH study results were published in
> The New England Journal of Medicine and were presented at the American
> Heart Association annual meeting that same month in Anaheim,
> California.]{.underline}
>
> [In December of 2001, the American Heart Association named the REMATCH
> study the number 2 in the top ten research advances for
> 2001.]{.underline}
>
> [With that said, I would like to ask Victor Poirier to come to the
> podium, who will provide some information on the device
> overview.]{.underline}
>
> **[Device Overview]{.underline}**
>
> **[Victor Poirier]{.underline}**
>
> [MR. POIRIER: Thank you. I am Victor Poirier. I am an employee of
> Thoratec and a shareholder of Thoratec.]{.underline}
>
> [\[Slide.\]]{.underline}
>
> [To begin with, the device that was used in this clinical study is the
> HeartMate Left Ventricular Assist Device. The device is implanted
> either in the peritoneal cavity or in a surgically-created pocket in
> the abdominal wall.]{.underline}
>
> [The inlet of the device is inserted into the left ventricular cavity
> while the outlet is anastomosed to the ascending aorta. With this
> arrangement, blood simply drains from the natural heart into the
> device, and we provide the energy to propel blood through the
> body.]{.underline}
>
> [The device has a volume of 83 ml and can produce in excess of 10
> liters per minute above flow. Power is delivered to the device through
> a percutaneous lead. This is a coaxial lead. The center of the lead is
> an electrical conductor, and surrounding that is a cavity to propel
> air in and out of the system.]{.underline}
>
> [This lead is attached to an external controller that controls the
> function of the device, allows the patient to operate in an automatic
> mode or a fixed rate mode, has all of the alarms that are required,
> and that controller is then attached to the power.]{.underline}
>
> [The power is obtained either from batteries worn by the patient,
> there is one on each side of the patient, or it can be attached to a
> bedside console.]{.underline}
>
> [\[Slide.\]]{.underline}
>
> [When we started the trial, we started with the HeartMate VE system,
> and in that configuration, there are screw rings that are used to
> attach the components. To lock those screw rings in, we utilized
> locking sutures, which were either applied by the physician during
> implant or at the factory.]{.underline}
>
> [In reality, we learned that these were not 100 percent safe. In
> addition to that, from pump migration or patient movement, we also
> uncovered that in some patients, a kink would develop at the outflow.
> This would be a complication which we would have to increase the pump
> chamber pressure to overcome this resistance to propel the blood out
> through the outflow.]{.underline}
>
> [In addition to that, rubbing of the adjacent areas of the graft could
> cause abrasion, which could cause a hole to develop. So, we made
> modifications to correct that, and we configured the SNAP
> device.]{.underline}
>
> [What we did is we changed the screw rings to use locking screw rings,
> which essentially replaced the suture with a metal lever to lock the
> rings in place. In addition to that, we added a bend
> relief.]{.underline}
>
> [So, the differences between the VE system and a SNAP system are only
> those two things. There is nothing else that has changed. The internal
> components are identical. So, any information that we gain from the
> endurance testing or the evaluations that we did in the past are still
> valid. The only changes are the rings and the bend relief, and these
> were not evaluated in the in-vitro life test.]{.underline}
>
> [\[Slide.\]]{.underline}
>
> [Four and a half years ago, we started a reliability test. We took 15
> systems and we put them on test. What we learned from that test was
> that there is an 88 percent chance that the LVAD will be free of
> critical failures at one year, and a 76 percent chance that LVAD will
> be free of critical failures at two years, and this is at a 90 percent
> confidence interval. The mean time to failure is 3.1
> years.]{.underline}
>
> [If you look at these results and compare them to what we experience
> clinically, you will see that there is a difference. These results are
> better. So, what happened clinically? There are three factors
> clinically that affect reliability.]{.underline}
>
> [One, it\'s the device itself, is there a design flaw in a device, or,
> the second factor that you need to consider is patient comorbidity, do
> the patients have infection which can affect the long-term durability
> of the tissue valves, or patient management, which is the third factor
> that you have to consider, the patient\'s arterial pressure being
> maintained at low levels, so that the pump does not have to produce
> high pump chamber pressure.]{.underline}
>
> [So, those three factors affect in-vivo reliability. In the in-vitro
> test, we only evaluated the device, and if you only consider the
> device, this is what I think you can expect in terms of
> reliability.]{.underline}
>
> [\[Slide.\]]{.underline}
>
> [We are obviously continuously improving the device. When you develop
> a new technology, improvements are necessary, and if I just give, for
> an example, the pacemakers, the original pacemakers were external and
> the patients had to carry batteries on a cart.]{.underline}
>
> [We all know how that technology has developed through continuous
> improvements, and the same with the implantable defibrillators. Well,
> the same is true here. We started off with a system that incorporated
> a double lead. There was one lead coming out of the system for the
> wire and one lead for the pneumatic operation.]{.underline}
>
> [After we gained some experience, we concluded that one penetration
> would be better than two, so we developed a coaxial exit line, and we
> exited through the lower left quadrant of the patient.]{.underline}
>
> [With more experience we gained knowledge that this was not the most
> optimum site in terms of exit sites, so we changed the exit site and
> we reverted to an exiting at the right upper quadrant of the patient.
> This helped in reducing exit site infections.]{.underline}
>
> [As I spoke before about the SNAP VE, we changed the outflow bend
> relief, we changed the locking screw ring, and we improved the system
> controller battery module. These are the result of experience that was
> gained in the field, and we haven\'t stopped there.]{.underline}
>
> [We have looked at all of the malfunctions that we have experienced in
> the clinical program, the REMATCH with the program in the bridge to
> transplant in the commercial application of these.]{.underline}
>
> [We have addressed all of the malfunctions that we experienced, and we
> made modifications to either eliminate those malfunctions or to
> greatly reduce the possibility of those occurring.]{.underline}
>
> [This is in the XVE configuration, which is now being used in the
> bridge to transplant field. We have extended the leads, we have made
> them smaller, more supple, so that the exit site would heal
> better.]{.underline}
>
> [We modified the way that we hold the diaphragm in place to eliminate
> the stresses that had caused us fractures in the clinical use. We have
> changed the leads on how we attach them to the
> controller.]{.underline}
>
> [We changed the materials at a wire to prevent the wire breakage, we
> use stronger, more durable materials throughout the system, so we are
> continuously improving the technology to try to make it better and to
> have these systems go longer and longer.]{.underline}
>
> [I think if you look at the evolution of this technology and where we
> have come from and where we are going, I think it is quite
> impressive.]{.underline}
>
> [\[Slide.\]]{.underline}
>
> [Our first trial that we were involved with was in 1975, even before
> FDA had any involvement with devices. Our average duration in that
> trial was four days. Our longest patient support was 41
> days.]{.underline}
>
> [The second trial we did, the HeartMate pneumatic device, our average
> duration was 69 days. Our longest duration was 344. The first trial on
> our electric system, 113 days.]{.underline}
>
> [What we tried to do is develop technology that we could improve and
> get longer and longer durations. If you look at what our experience is
> in terms of longevity, we went from four days to 69 days, to 113 days,
> to 276 days, and on the REMATCH program, our average duration, 344
> days, and a maximum duration of support now past 3.1 years, and that
> patient is still ongoing.]{.underline}
>
> [We have made significant progress. This represents 3,100 patients,
> 3,100 implants worldwide, a vast amount of experience and a consistent
> improvement in performance and in reliability.]{.underline}
>
> [\[Slide.\]]{.underline}
>
> [So, in conclusion, clearly, the VE LVAS is clinically proven
> technology for bridge to transplant. Worldwide, the VE LVAS experience
> provides strong platform for expanded indication, and Thoratec is
> dedicated to circulatory support and heart failure patients, and they
> are committed to continuous improvements of this device.]{.underline}
>
> [If you look at the technology today, you might say yes, we have had
> malfunctions, yes, there have been adverse events, yes, there have
> been complications, but even considering all of those things, if you
> look at how has the patient done with the device compared to a control
> group, the patient with the device has done significantly better even
> with all those complications.]{.underline}
>
> [Can we make it better? Of course, we can make it better. We know how
> to design these, we know how to improve them, and we will do that. We
> can make these devices better. We can learn better on how to manage
> patients, we can learn how to pick patients more appropriately for
> this patient category.]{.underline}
>
> [So, for going forward, I think there is a lot of up-side potential
> with this technology.]{.underline}
>
> [With that, I would like to turn the podium over to Dr. Eric
> Rose.]{.underline}
>
> **[REMATCH Trial Clinical Results]{.underline}**
>
> **[Eric Rose, M.D.]{.underline}**
>
> [DR. ROSE: I am Eric Rose. I am the Milstein Professor and Chairman of
> the Department of Surgery at Columbia University, and the principal
> investigator for the REMATCH trial. I have no financial interest in
> Thoratec, and my presence here today is supported financially by the
> company for being here.]{.underline}
>
> [\[Slide.\]]{.underline}
>
> [To get to the punch line first, the REMATCH trial makes the following
> critical clinical findings. There is a clear survival benefit, which
> we strongly believe, as well, is clinically meaningful and quality of
> life in device patients is at least equal to, if not better, than
> medically managed patients in the control group.]{.underline}
>
> [With regard to safety, the incidence of adverse events in context of
> the mortality reduction and the quality of life improvement trends
> provides very reasonable assurance of the safety of the
> device.]{.underline}
>
> [In conclusion, we believe that the VE LVAS is a scientifically
> validated alternative, in fact, now the only scientifically validated
> alternative therapy for end-stage heart failure patients who are not
> candidates for cardiac transplantation.]{.underline}
>
> [\[Slide.\]]{.underline}
>
> [What I would like to walk through in my talk today is the history of
> the trial itself, the trial\'s design and how it was
> administered.]{.underline}
>
> [Lynne Warner Stevenson, a trial investigator and leader of the
> medical management group of the trial will summarize the description
> of the patient population and the nature of medical management, which
> is a critical limb in this trial.]{.underline}
>
> [I will then come back and review the effectiveness results, the
> safety results, and summarize our views.]{.underline}
>
> [\[Slide.\]]{.underline}
>
> [Anyone who works in the field of management to patients with
> end-stage heart disease, and certainly the patients themselves,
> recognize the enormous gap in our treatments available for those with
> end-stage disease.]{.underline}
>
> [Heart transplantation has shown enormous promise, but it is only
> benefitting approximately 2,000 patients per year compared to the many
> more who could potentially benefit.]{.underline}
>
> [We have had enormous experiences Vic just described with more than
> 3,000 patients worldwide using the device that we tested in REMATCH
> for bridging to transplantation.]{.underline}
>
> [Based on that experience, we did a pilot trial we called PREMATCH in
> 1996 to 1998, in which we randomized 10 patients to a control group
> and 11 patients to LVAD, and found that randomization was
> feasible.]{.underline}
>
> [We found that doubling in one-year survival from 20 to 40 percent in
> the device patients, which was not statistically significant, yet,
> these observations generated the necessary clinical equipoise to
> support a full-blown randomized REMATCH trial, and REMATCH trial
> enrollment began in May of 1998.]{.underline}
>
> [\[Slide.\]]{.underline}
>
> [The trial itself is the product of a cooperative agreement between
> Thoratec, Columbia University, and the National Heart Lung, and Blood
> Institute. The trial was coordinated by an independent coordinating
> center, the International Center for Health Outcomes and Innovation
> Research at Columbia led by Annetine Gelijns and Alan
> Moskowitz.]{.underline}
>
> [It was a multicenter, randomized, controlled trial. Patients and
> physicians were not blinded to treatment in this obvious major
> surgical intervention. There was a prospective plan for interim
> analyses to be done by an independent Data Safety Monitoring
> Board.]{.underline}
>
> [The analysis was done by an intent-to-treat, and the primary
> statistical analysis employed the Kaplan-Meier actuarial survival
> method and using a log-rank test to assess differences between the
> entire area under the Kaplan- Meier curve. Paul Meier himself was one
> of our statistical advisers.]{.underline}
>
> [\[Slide.\]]{.underline}
>
> [In order to control bias, first and foremost, this was a randomized
> trial. Again, we used an independent coordinating center independent
> of the sponsor. The sponsor Thoratec was blinded to control
> data.]{.underline}
>
> [Investigators and the InCHOIR staff except for the statisticians were
> blinded to the overall data until the trial ended. We used
> credentialed investigators, both cardiologists and surgeons, at the
> trial sites. An independent gatekeeper reviewed each patient\'s
> eligibility prior to entry into the trial to ensure that patients did
> indeed meet the stringent entry criteria.]{.underline}
>
> [We used an independent Data Safety Monitoring Board appointed by the
> NHLBI, as well as an independent Morbidity and Mortality Committee to
> adjudicate the etiology of adverse events and causes of death, and
> there were Medical and Surgical Management Committees that actively
> met during the course of the trial to ensure that patients got optimal
> care in both limbs.]{.underline}
>
> [\[Slide.\]]{.underline}
>
> [The key study objectives were to evaluate the efficacy of the
> HeartMate on survival of patients with end-stage heart disease who
> were ineligible for cardiac transplantation, and with regard to
> safety, to document and analyze adverse events and the incidence of
> device malfunction and failure, of course, in the context of the
> disease population we studied.]{.underline}
>
> [\[Slide.\]]{.underline}
>
> [The secondary endpoints of the trial included quality of life, the
> patient\'s functional status, the patient days in and out of the
> hospital, cardiovascular mortality, and cost. We will not address cost
> in this discussion today.]{.underline}
>
> [\[Slide.\]]{.underline}
>
> [The key assumptions guiding this trial was that patients and
> clinicians would not adopt use of a device like this unless all-cause
> mortality over a two-year observation period was reduced by a third or
> more.]{.underline}
>
> [Conversely, I think there was generally strong feeling that
> demonstration of this kind of benefit would indeed lead to adoption
> when indicated for this type of technology.]{.underline}
>
> [We also assumed that quality of life with the VAD should equal or
> exceed the OMM group in order to essentially allay the concern that a
> device like this could literally prolong death instead of prolonging
> and enhancing life.]{.underline}
>
> [\[Slide.\]]{.underline}
>
> [The trial was powered to survival and not to secondary endpoints. We
> also hypothesized that survival over time would decay roughly
> exponentially and that the hazard ratio between the two groups of LVAS
> to OMM would be approximately 0.56.]{.underline}
>
> [Using these assumptions, the endpoint is the number of deaths in this
> trial, not the number of patients enrolled, and we calculated that we
> needed to see 92 deaths in order to have an 80 percent power in a
> log-rank test to find the hypothesized benefit.]{.underline}
>
> [We estimated that we would need up to 140 patients in order to prove
> that benefit, but again the 92 deaths was the decided prespecified
> endpoint to this trial. I want to emphasize this trial was not stopped
> early. This trial was stopped when we reached the predefined endpoint
> for the study.]{.underline}
>
> [\[Slide.\]]{.underline}
>
> [The patients were randomized between the two limbs in a 1 to 1 ratio.
> The randomization was stratified by center, and this was put in place
> by blocking on a center-specific basis, and the block sizes were also
> randomly selected so that investigators could not gain the assignment
> to patients.]{.underline}
>
> [\[Slide.\]]{.underline}
>
> [REMATCH study sites included 20 highly experienced centers in cardiac
> transplantation and medical management to patients with end-stage
> heart disease.]{.underline}
>
> [I am going to turn the podium at this point over to Lynne Stevenson,
> who ran our Medical Management Committee in order to describe the
> patient population and medical management.]{.underline}
>
> **[REMATCH Patient Population]{.underline}**
>
> **[Lynne Warner Stevenson, M.D.]{.underline}**
>
> [DR. STEVENSON: Thank you very much. I have no financial interests in
> Thoratec. They are reimbursing me for the cost of travel to this
> meeting.]{.underline}
>
> [\[Slide.\]]{.underline}
>
> [To see where the REMATCH population fits in, let\'s look at the big
> picture of heart failure. It is estimated that there are 4 to 5
> million patients in the United States with heart failure. Of those,
> about two-thirds have heart failure with low ejection fraction or
> systolic dysfunction. The other third have heart failure with a
> preserved ejection fraction which dominates in the
> elderly.]{.underline}
>
> [Some patients over 80 also have heart failure with low ejection
> fraction. In general, they have such comorbidities that they would be
> considered appropriate candidates for cardiac replacement therapy, so
> we will focus on this group here in the turquoise of patients under 80
> with ejection fractions that are reduced.]{.underline}
>
> [It is estimated that approximately one-quarter of those patients have
> Class III to IV heart failure with symptoms that limit their daily
> lives. Multiple models have demonstrated that approximately 50 to
> 100,000 of these patients might be considered as candidates for
> cardiac replacement therapy, but probably a smaller number of these
> are truly appropriate recipients.]{.underline}
>
> [\[Slide.\]]{.underline}
>
> [The REMATCH trial aimed to identify a population of those patients
> for whom primary cardiac replacement could be considered. The initial
> eligibility criteria were New York Heart Association Class IV symptoms
> for 90 days on standard therapy, left ventricular ejection fraction
> less than or equal to 25 percent, peak VO~2~ less than 12 ml or
> inotrope dependent. These criteria were relaxed in late 1999, but, in
> fact, 123 patients enrolled met the original criteria rather than the
> revised one shown in blue.]{.underline}
>
> [The mortality estimates at the time this trial was designed were that
> there would be a two-year mortality of approximately 75 percent. This
> was based primarily on data that we had for potential cardiac
> transplant candidates, but since we additionally required that these
> patients be ineligible for cardiac transplantation, that, in fact, was
> an additional contributor to their mortality.]{.underline}
>
> [\[Slide.\]]{.underline}
>
> [The reasons that patients were not transplant candidates are shown
> here. It was predominantly for age and for diabetes.]{.underline}
>
> [\[Slide.\]]{.underline}
>
> [Let\'s now look at where these patients fall on the spectrum of
> escalating therapies for heart failure. Standard therapies for heart
> failure are angiotensin converting enzyme inhibitors, beta blockers is
> tolerated, digoxin, diuretics for fluid retention, and spironolactone
> when renal function is acceptable.]{.underline}
>
> [We had anticipated that patients enrolled in REMATCH would fall
> somewhere in here, such that multiple additional interventions could
> be made in expert hands. In fact, the patients referred and ultimately
> randomized in REMATCH more often fell approximately here.]{.underline}
>
> [In many of these patients, beta blockers would not even be considered
> due to hemodynamic decompensation. Fluctuating renal function
> frequently made spironolactone not possible, and many of these
> patients had even become intolerant to ACE inhibitor
> therapy.]{.underline}
>
> [Inotropic therapy was frequently employed in these patients with the
> hope that a brief infusion might turn things around. Often that does
> not happen, and one is left with the difficult problem of trying to
> wean therapy to allow hospital discharge, which in some cases was not
> possible.]{.underline}
>
> [\[Slide.\]]{.underline}
>
> [If we look now at the REMATCH therapy at baseline in the OMM arm, off
> of medical management, 75 percent of patients were on IV inotropes at
> the time of randomization, 53 percent were on ACE inhibitors, and
> another 18 percent were on A2 receptor antagonists.]{.underline}
>
> [\[Slide.\]]{.underline}
>
> [If we look at ACE intolerance in advancing heart failure, this again
> defines where we are with this population. This is now looking at a
> number of trials of patients unable to take ACE inhibitor therapy. You
> can see in the two trial here, this is the ESCAPE trial and the OPTIME
> trial in which patients are hospitalized with heart failure at the
> time of treatment, that rates approximately 20 to 25 percent of being
> unable to tolerate ACE inhibitors. In this trial, in fact, it\'s 29
> percent when you consider the patients who were able to tolerate A2
> receptor blockers.]{.underline}
>
> [\[Slide.\]]{.underline}
>
> [Let\'s look now at other REMATCH patient baseline characteristics.
> You can see the age is 67, which is a higher average age than most
> heart failure populations studied. The cardiac index is 2 liters per
> minute per meter squared, and you need to remember that 75 percent of
> patients were on inotropes at the time that this very low cardiac
> index was measured.]{.underline}
>
> [The Minnesota Living with Heart Failure score of quality of life
> shows a higher degree of disability than in any trial previously
> reported.]{.underline}
>
> [\[Slide.\]]{.underline}
>
> [If we look now at renal dysfunction, we are just coming now to
> realize how important a predictor this is for outcome in heart
> failure. Every tenth of a milligram predicts a higher mortality in
> heart failure. REMATCH, with an average baseline creatinine of 1.8 is
> higher than any trial previously reported in heart
> failure.]{.underline}
>
> [\[Slide.\]]{.underline}
>
> [Let\'s now line up the profile of REMATCH patients and compare it to
> other trials of heart failure that is considered to be severe. The
> closest population we can come up with is in the first trial. This is
> a trial in which IV prostaglandin therapy was administered chronically
> through an in-dwelling catheter.]{.underline}
>
> [If we look at other trials, CONSENSUS from 1987 is shown here. This
> is the initial trial of ACE inhibitors in Class IV heart failure. If
> we look at the ejection fraction, it wasn\'t routinely measured at
> that time, but if we move across in trials of what are considered to
> be severe heart failure, you can see that REMATCH has the lowest
> ejection fraction of any of these trials.]{.underline}
>
> [Serum sodium remains a very robust predictor of outcome in heart
> failure, and you can see that the serum sodium is lower in REMATCH
> than in any other patient population studied.]{.underline}
>
> [Perhaps most telling is the systolic blood pressure, which was 103 in
> the REMATCH population, much lower than any other trials. I would
> point out in COPERNICUS, a trial of beta blockers in severe heart
> failure, the average baseline blood pressure was instead 123, which is
> 22 mm higher.]{.underline}
>
> [\[Slide.\]]{.underline}
>
> [In terms of the medical management of the OMM population, this was
> the result of very intensive review and approval by the Cardiology
> Committee of all the investigators with additional input from Dr. Gary
> Francis outside the trial.]{.underline}
>
> [The primary goal was survival without suffering. Specific goals were
> to maintain perfusion for organ function, to relieve congestion, to
> treat exacerbating factors, and then to maintain stability with a
> regimen of neurohormonal antagonists which would be considered
> standard therapy.]{.underline}
>
> [In fact, however, most of these patients were beyond what we
> considered to be standard medical therapy. Inotrope infusion, the net
> use decreased by the first month, but had increased again by the last
> follow up.]{.underline}
>
> [In terms of the ACE inhibitor use, the use increased, but, in fact,
> by the last follow up was lower than at the time of initiation because
> the patients continued to deteriorate.]{.underline}
>
> [\[Slide.\]]{.underline}
>
> [We specifically thought long and hard about what we should say about
> the use of IV inotropic agents. It was recognized that we should make
> every attempt to try to discontinue these agents and use any other
> regimen if possible.]{.underline}
>
> [It was agree this therapy would not be used unless everything else
> had been tried. In fact, there was considerable effort to try to
> modulate the inotrope use. During the initial hospitalization, 20
> percent of patients who started out on inotropic infusions came off of
> the infusions, another 10 percent had the number of drugs infused
> decreased, so they were on fewer inotropic agents, however, 40 percent
> of the patients who were not on inotropic agents at the randomization
> were found to need inotropic agents.]{.underline}
>
> [It was well recognized by all the investigators that inotropic
> therapy is only palliative in this population, that it does not
> improve survival, and, in fact, might even worsen mortality. The
> problem was that current medical therapy had reached and end, and
> there just were not other options.]{.underline}
>
> [\[Slide.\]]{.underline}
>
> [Understanding the profile of the REMATCH population now allows us to
> look at where the mortality of this group fits in. With every factor
> being worse than in the previous trials, it is not at all surprising
> that there was a very high one-year mortality of 76 percent in the
> REMATCH population. They had moved beyond what could be offered by the
> medical therapy.]{.underline}
>
> [\[Slide.\]]{.underline}
>
> [So, in summary, REMATCH patients define a new profile of severe heart
> failure, different than what had been considered severe in previous
> trials. By the time of randomization, REMATCH patients had already
> received optimal management in the most cases and had moved beyond
> current medical therapy.]{.underline}
>
> [\[Slide.\]]{.underline}
>
> [How are we to determine what would be a meaningful benefit in this
> population? In trying to decide, this committee accepts a major
> challenge. We don\'t really have previous precedence that should guide
> us in how to decide this.]{.underline}
>
> [Let\'s review what we do know of therapies that are accepted as
> beneficial in heart failure. If we take ACE inhibitors, the
> cornerstone of our therapy of heart failure at the SOLVD trial is
> considered to be the landmark trial for this, if we look at the
> one-year mortality, it was decreased from 14 to 11
> percent.]{.underline}
>
> [It has become very common in drug trials to look at percent, of a
> percent improvement, which in fact magnifies a benefit that is
> relatively modest. This impacts 3 patients per 100 treated in the
> first year.]{.underline}
>
> [A similar relative benefit was observed in the CONSENSUS trial, an
> ACE inhibitor in Class IV failure, but because the one-year control
> mortality was higher, there is an absolute benefit that is greater in
> terms of the number of patients treated, which here is
> 17.]{.underline}
>
> [Dosing of ACE inhibitors has been felt to be important in optimal
> management of heart failure. That is based primarily on the ATLAS
> trial, shown here, with the one-year mortality, a relative small
> difference between a high and very dose ACE inhibitor, which in fact
> led to a survival benefit of less than 1 patient per 100 in the year
> treated.]{.underline}
>
> [The COPERNICUS trial, demonstrating unequivocally the benefit of beta
> blockers in severe heart failure, had a mortality in the control arm
> that was less than 20 percent, and the RALES trial, showing a similar
> benefit with a slightly higher baseline mortality.]{.underline}
>
> [Accepting these benefits for therapy, how should we now evaluate a
> population in which the one-year mortality on controlled therapy is 76
> percent, do we look at relative benefit, do we look at absolute
> benefit, what will our patients look at? We are stepping into a new
> horizon.]{.underline}
>
> [I would like to turn it back to Eric Rose, who will further discuss
> the results of the trial.]{.underline}
>
> **[REMATCH Trial Clinical Results]{.underline}**
>
> **[Eric Rose, M.D.]{.underline}**
>
> [\[Slide.\]]{.underline}
>
> [DR. ROSE: Almost 1,000 patients were screened for REMATCH, of whom
> 128 were randomized, 67 to the device limb and 61 to medical
> management.]{.underline}
>
> [\[Slide.\]]{.underline}
>
> [The baseline characteristics here in sample for critical ones, age,
> ejection fraction, cardiac index, serum creatinine, IV inotropes,
> Minnesota Living with Heart Failure score, across virtually all
> baseline characteristics. There were no differences between the two
> groups, illustrating the success of the randomization.]{.underline}
>
> [\[Slide.\]]{.underline}
>
> [This is a Kaplan-Meier plot illustrating survival of the VAD group
> compared to the OMM group at the time that the study was stopped in
> June of 2001. The difference, the area under the curve, under the LVAD
> curve, between the two curves, shows a 46 percent reduction in
> mortality hazard over the two-year observation period, again, the
> primary endpoint of the trial, the p-value being 0.003.]{.underline}
>
> [In addition, at this time of analysis, there was a 52 percent,
> one-year survival in the device group compared to 26 in the control
> group, and 23 percent at two years compared to 8 percent in the
> control group. The one-year difference was statistically significant,
> the p-value at two years was 0.09.]{.underline}
>
> [\[Slide.\]]{.underline}
>
> [In terms of causes of death, the overwhelmingly most common cause of
> death in the OMM group was heart failure. In contrast, in the device
> group, the most common cause of death was sepsis related typically to
> the device, following by a range of mortality related to either
> failure or cessation of function of portions of the
> device.]{.underline}
>
> [Two devices failed completely to support the circulation, while three
> had partial failures of the device not meeting the formal definition,
> but did require device replacement ultimately leading to
> death.]{.underline}
>
> [In addition, fortunately, there was only one death due to bleeding.
> The next most common cause of death was cerebrovascular
> disease.]{.underline}
>
> [\[Slide.\]]{.underline}
>
> [To summarize these effectiveness results, the one-year survival
> doubled. There was an absolute reduction of mortality of 27 percent at
> one year meaning that for each 100 patients treated, we would estimate
> that 27 deaths would be averted during that first year.]{.underline}
>
> [The two-year survival was tripled, and the median survival time
> increased to 408 days for LVAS patients compared to 150 days for OMM
> patients.]{.underline}
>
> [\[Slide.\]]{.underline}
>
> [As we said, the all-cause mortality was reduced by 46 percent
> exceeding the primary objective of a 33 percent
> reduction.]{.underline}
>
> [\[Slide.\]]{.underline}
>
> [Now, with regard to safety, looking at serious adverse events, these
> were more common in the device patients, in fact, they were 2.3 times
> more common, a high significant difference.]{.underline}
>
> [Particular types of adverse events, namely neurologic dysfunction and
> bleeding, not surprisingly were also more common in the device
> patients, but interestingly, complications like infection, sepsis, and
> thromboembolic events, these were not statistically significantly
> different between the two groups.]{.underline}
>
> [\[Slide.\]]{.underline}
>
> [Also, of interest is the fact that adverse events are generally
> concentrated early in the postoperative course of these patients, and
> decay off to a lower incidence over time. It does not reach zero, but
> it does decrease over time.]{.underline}
>
> [\[Slide.\]]{.underline}
>
> [Looking in particular at neurologic events, there were 28 neurologic
> events in 67 VAD patients, a total of 40 events in those 28 patients,
> but very importantly, only a quarter of those events were permanent or
> disabling. The overwhelming majority of these events were toxic
> encephalopathy typically early in the intensive care unit after the
> operation, or transient ischemic attacks.]{.underline}
>
> [\[Slide.\]]{.underline}
>
> [Looking at the sum total of serious neurologic events, there were 5
> ischemic strokes, one intracranial hemorrhage, and 2 patients who had
> serious morbidity from air embolism.]{.underline}
>
> [\[Slide.\]]{.underline}
>
> [Also looking at this particular adverse event, we see that the
> majority of events or the highest incidence occurs early in the
> postoperative course and falls off over time.]{.underline}
>
> [\[Slide.\]]{.underline}
>
> [In terms of bleeding, the majority of events were associated with VAD
> implant or reimplantation, which is quite similar to the bridge
> experience.]{.underline}
>
> [Infection was a specific complication of VAD use. There was initially
> in this trial an unappreciated association of infection with
> malnutrition. Patients who were nutritionally depleted generally could
> not heal the drive line sites well, and investigators only began to
> pay specific attention to this late in the course of the
> trial.]{.underline}
>
> [Infection guidelines were developed in the midpoint or in the earlier
> course of the trial with the adoption of specific guidelines that
> investigators adopted on the recommendation of the Surgical Management
> Committee.]{.underline}
>
> [\[Slide.\]]{.underline}
>
> [There were 156 malfunctions of the device reported, 70 were confirmed
> by actual analysis of the device component, 50 of these were external
> components, 20 internal components. The most common malfunction was
> the controller, malfunction with broken lead wires in 27 percent, 14
> percent had the serious complication of inflow valve incompetence seen
> in 14 percent of patients in this trial, and 9 percent of patients had
> a broken Y-connector.]{.underline}
>
> [The top 1 and 3 of these were external device malfunctions, which
> allowed their replacement.]{.underline}
>
> [\[Slide.\]]{.underline}
>
> [Median time spent in and out of the hospital was dramatically
> different between the two groups. As I said before, median survival of
> 408 days compared to 150 at the time of the 92nd death.]{.underline}
>
> [VAD patients enjoyed almost a full year of days out of the hospital
> during a two-year period of observation, where, control patients
> enjoyed approximately 100 days out of hospital.]{.underline}
>
> [VAD patients also spent more time in the hospital with readmissions
> for device complications or other complications, higher than controls,
> and index hospitalization days, as would be expected for the major
> procedure of VAD replacement, the length of hospitalization as 29 days
> for the VAD patients, which was virtually identical to the length of
> stay that we typically see for bride to transplant
> patients.]{.underline}
>
> [\[Slide.\]]{.underline}
>
> [With regard to quality of life, again, our hypothesis was that
> quality of life with the VAD should equal or exceed the OMM group.
> Toward that end, we carefully chose the instruments that we
> used.]{.underline}
>
> [In particular, we used the SF-36 Health Survey, a general health
> measure, and prespecified two very specific domains - physical
> functioning and role/emotional scores. These were prespecified before
> we even began the trial that these were the particular SF-36 portions
> we were going to look at.]{.underline}
>
> [The Minnesota Living with Heart Failure scale is a disease-specific
> quality of life measure for patients with heart failure.]{.underline}
>
> [The New York Heart Association functional class is probably the most
> broadly used functional status estimator for heart failure in the
> world.]{.underline}
>
> [The Beck Depression Inventory is a widely employed scale for
> measuring clinical depression, and the EuroQOL scale for patient
> preferences.]{.underline}
>
> [We imputed no values for quality of life for dead patients. Had we
> done so, it would have created an even greater benefit documented by
> the device patients, so we specifically did not input these values in
> order not to further bias the data.]{.underline}
>
> [\[Slide.\]]{.underline}
>
> [With regard to role/emotional scores, in this slide and the
> succeeding slide, the VAD patients are in yellow, OMM in purple. A
> higher score here is better, reflects improved quality of life. We
> have very little data after one year, but we see that by 12 months,
> there is a highly statistically significant difference between VAD and
> OMM patients with regard to role/emotional functioning.]{.underline}
>
> [\[Slide.\]]{.underline}
>
> [Similarly, with regard to physical functioning, at 3, 6, and 12
> months, again, a higher number is better quality of life, and what
> this means in terms of the questionnaires is can you walk a block, can
> you walk up a flight of stairs. There were significantly more positive
> answers to those questions in the VAD patients compared to the OMM
> patients, and at 3, 6, and 12 months, this P was less than
> 0.05.]{.underline}
>
> [\[Slide.\]]{.underline}
>
> [With the Minnesota Living with Heart Failure scale, we did see at one
> time point significant improvement, and at 3, 6, and 12 months, a
> trend to improvement for the VAD patients. On this scale, improved
> quality of life is a lower score. The 75 at baseline, to our
> knowledge, is the highest MLHF score in a heart failure population
> subjected to a randomized trial.]{.underline}
>
> [\[Slide.\]]{.underline}
>
> [In terms of New York Heart Association functional class, the
> percentage of patients in Class IV at the time of observation is
> plotted here. There were only three patients alive at 24 months in the
> OMM group, one of whom had improved out of Class IV. Otherwise, at
> virtually all other times, the Class IV representation in the control
> group was almost 100 percent compared to a marked decrement,
> statistically significant decrement in the VAD group.]{.underline}
>
> [\[Slide.\]]{.underline}
>
> [In the Beck Depression Inventory, both groups at the time of
> enrollment met the definition of clinical depression with scores of 17
> or higher. There was a highly significant difference between the VAD
> and OMM groups at 1 and six months, and the p-value was 0.055 at 12
> months between these two groups, suggesting that these patients were
> indeed less depressed.]{.underline}
>
> [\[Slide.\]]{.underline}
>
> [To summarize these Quality of Life findings, VAD scores were never
> worse than the OMM group. I think the argument that these devices
> prolong death is simply not tenable based on this data set. They
> prolong meaningful life.]{.underline}
>
> [The only negative Quality of Life impact was the issue of short-term,
> postoperative pain, which is an obvious result of the operation that
> the patients had.]{.underline}
>
> [The LVAD general Quality of Life was better than OMM at 12 months in
> the key, prespecified SF-36 domains, a physical functioning and in
> role/emotional scores.]{.underline}
>
> [The LVAD disease-specific Quality of Life measurement with the
> Minnesota scale was improved, but not statistically significant at a
> year.]{.underline}
>
> [LVAD functional status measured by the New York Association
> classification was significantly better, and VAD patients had reduced
> depressive symptoms to normal range, below that of clinical
> depression, a phenomenon which was not seen in the OMM
> groups.]{.underline}
>
> [\[Slide.\]]{.underline}
>
> [To put this in context, the LVAD physical function scores, while
> improved, were not normal, but these scores are analogous to patients
> who were receiving long-term hemodialysis, of which there are 300,000
> now in the United States, and moderate heart failure
> patients.]{.underline}
>
> [Similarly, the role/emotional scores are better than those reported
> for clinical depression and similar to those with moderate heart
> failure.]{.underline}
>
> [\[Slide.\]]{.underline}
>
> [The most recent Kaplan-Meier plot is depicted in this slide with very
> little difference essentially in the shapes of these curves. The area
> between them is now significant at the 0.001 level, and the difference
> at two years, the p-value here is now 0.054.]{.underline}
>
> [\[Slide.\]]{.underline}
>
> [In terms of efficacy, REMATCH has shown that the VE LVAS exceeded the
> primary objective of the trial by demonstrating a reduction in
> all-cause mortality of 46 percent in patients who were not candidates
> for cardiac transplantation.]{.underline}
>
> [With regard to safety, the incidence of adverse events associated
> with implantation is higher than OMM patients, but the incidence of
> overall adverse events we believe is clearly acceptable when compared
> to the natural history of this terminal illness.]{.underline}
>
> [In addition, even in this small early experience, multiple
> opportunities for improvement have been identified.]{.underline}
>
> [\[Slide.\]]{.underline}
>
> [To return to Lynne\'s question as what is clinically meaningful
> benefit, we did see an absolute reduction in one year mortality of 27
> percent in this patient population, which in terms of simple magnitude
> is obviously more than comparable, more than favorably comparable with
> those that we have seen for other heart failure therapies that are now
> considered standard.]{.underline}
>
> [\[Slide.\]]{.underline}
>
> [Now, we also would like to address the seven questions which were
> posed to the panel by the FDA to offer our views of these very
> important issues that were raised by the FDA examiners.]{.underline}
>
> [\[Slide.\]]{.underline}
>
> [First, there was the question of whether or not there now are good
> end of pump life indicators. Before I speak to this about the VADs, I
> think it is important to recognize that it is not just the mechanical
> circulatory support that has the issue of end of pump life indicators.
> Heart failure itself, we have difficult issues with regard to end of
> life indicators, whether or not serum sodium or creatinine or inotrope
> dependency themselves are absolute indicators of end of life is
> something that is under intense investigation and deserves further,
> but even in the context of this trial, there are patient indicators
> that can suggest that a person is reaching end of life of the
> device.]{.underline}
>
> [For example, increased alarm frequency and changing pump sounds are
> just simple clinical indicators, and there are device indicators. This
> device\'s motor current waveforms can be measured on an ongoing basis
> and the waveforms analyzed to indicate earlier forms of wear in the
> device, and in addition, particulate matter can be analyzed in the
> filters from the air vent side of the device.]{.underline}
>
> [\[Slide.\]]{.underline}
>
> [In terms of device reliability, are we seeing enough reliability with
> this device, so that is appropriate for destination therapy? In the
> context of the available alternative therapies and the terminal
> illness, the observed failure rates in the REMATCH trial essentially
> define what is acceptable at this time.]{.underline}
>
> [The reliability, even though flawed, is sufficient to produce a very
> measurable survival benefit. Furthermore, we see multiple
> opportunities that address device improvements, patient selection, and
> patient management.]{.underline}
>
> [\[Slide.\]]{.underline}
>
> [The other important question, is the survival benefit that we
> documented clinically meaningful? Now, this was the guiding question
> for the REMATCH trial. Before we embarked on this, we tried to reach a
> consensus among many groups as to what would be a clinically
> meaningful indicator and what could be done practically.]{.underline}
>
> [There was agreement between the REMATCH investigators at 20 sites,
> the NHLBI, the FDA, and Thoratec that the endpoint that we defined for
> mortality was indeed a clinically meaningful benefit if we could
> document it.]{.underline}
>
> [We documented that as a 33 percent reduction in mortality during two
> years with Quality of Life that was greater than or equal to that of
> OMM.]{.underline}
>
> [Indeed, we found that median survival more than doubled in this
> two-year observational trial.]{.underline}
>
> [\[Slide.\]]{.underline}
>
> [The other question raised, is the effectiveness of the system on
> functional status clinically meaningful, in particular because the
> data with regard to a test like six- minute walk and PPO~2~ were
> confusing.]{.underline}
>
> [The trends with regard to all of the Quality of Life indicators that
> were used, that are subjective, admittedly subjective, are consistent
> favorable. With regard to peak VO~2~ and 6-minute walk, there are not
> benchmarks available that have been validated in order to look at
> those and compare them to patient\'s assessment of Quality of Life or
> survival.]{.underline}
>
> [The New York Heart Association class, while flawed, is still the most
> widely used classification of functional status of heart failure
> patients in the world, and the prespecified physical function domains
> and role/emotional scores, again admittedly subjective, we are asking
> the patients how did you do or how do you feel were highly significant
> at 12 months.]{.underline}
>
> [To quote the President\'s Commission for the Study of Ethical
> Problems in Medicine and Biomedical and Behavioral Search, \"Quality
> of life is an ethically essential concept that focuses on the good of
> the individual. What kind of life is possible given the person\'s
> condition and whether that condition will allow the individual to have
> a life that he or she views as worth living, not whether some
> dispassionate third party views the life as worth living,\" and to
> make the judgment that on the basis of a 6-minute walk or a peak
> VO~2~, a life is not worth living, I think is more than a
> stretch.]{.underline}
>
> [\[Slide.\]]{.underline}
>
> [In terms of destination therapy - do the benefits outweigh the
> risks?]{.underline}
>
> [The adverse events in this trial were not calculated independent of
> survival and Quality of Life. Their impact is calculated into the
> survival and Quality of Life analyses, and even in the presence of
> those adverse events, it is clear that the risks outweigh the
> benefits.]{.underline}
>
> [\[Slide.\]]{.underline}
>
> [With regard to the labeling, is it adequate? We feel that reasonable
> labeling has been proposed, but certainly I think anyone reasonable
> will view that recommendations for improvement would be well
> accepted.]{.underline}
>
> [\[Slide.\]]{.underline}
>
> [In terms of postmarket evaluation, I do believe there is a widely
> held view in this field that this is essential going forth and that
> Thoratec shares in that belief.]{.underline}
>
> [I thank you for the opportunity and am proud, on the part of the
> REMATCH investigators, to present this work, and turn it back to Don
> Middlebrook.]{.underline}
>
> **[Summary and Closing Remarks]{.underline}**
>
> **[Donald A. Middlebrook]{.underline}**
>
> [MR. MIDDLEBROOK: Thank you, Lynne, Eric, and Victor for an excellent
> presentation.]{.underline}
>
> [\[Slide.\]]{.underline}
>
> [I would like to summarize and conclude with the following remarks. It
> is our belief that this study has scientifically validated the safety
> and effectiveness of the HeartMate VE LVAS for the proposed
> indication.]{.underline}
>
> [Every aspect of this study has been thoroughly planned and carefully
> executed. The REMATCH study has demonstrated strong scientific
> evidence of clinically meaningful survival benefit.]{.underline}
>
> [If you take a look at the experience we have in the previous clinical
> trials in our commercial use and in this REMATCH study, the VE LVAS is
> a well characterized and a proven technology.]{.underline}
>
> [It is our belief also that the REMATCH trial has demonstrated
> reasonable evidence for safety particularly in the context of terminal
> illness. As Eric said, even in the fact that the REMATCH patients
> faced a higher opportunity for an adverse event, all of the Quality of
> Life instruments showed sustained improvement trends over the optimal
> medical management group.]{.underline}
>
> [The device, as Dr. Lynne Warner Stevenson alluded to, provided
> unprecedented reduction in mortality in end-stage congestive heart
> failure patients when compared to the landmark drug
> studies.]{.underline}
>
> [The VE LVAS is now the only proven alternative therapy for
> non-transplantable end-stage congestive heart failure
> patients.]{.underline}
>
> [\[Slide.\]]{.underline}
>
> [The threshold for PMA approval is reasonable assurance of safety and
> effectiveness. If you consider all of the data we have presented here
> this morning, and contained in the PMA in relation to the patient
> population, the conditions of use, the probable benefit versus the
> probable injury, and the demonstrated reliability, we strongly believe
> that there is clear and compelling scientific evidence that the
> HeartMate VE LVAS should be approved as a new treatment option for
> end-stage heart failure patients ineligible for cardiac
> transplantation.]{.underline}
>
> [Thank you very much for your time and attention. This concludes our
> presentation.]{.underline}
>
> [DR. LASKEY: Thank you all for a most informed and articulate
> presentation.]{.underline}
>
> [I would like to move now to the FDA presentation starting with Dr.
> Berman.]{.underline}
>
> **[FDA Presentation]{.underline}**
>
> **[Michael Berman, Ph.D.]{.underline}**
>
> [DR. BERMAN: Good morning. My name is Michael Berman. I am the FDA
> lead reviewer for this PMA supplement. For the record, this is
> Supplement 16 to PMA P920014. It is being brought by the Thoratec
> Corporation for the their Thoratec HeartMate VE LVAS
> System.]{.underline}
>
> [I will be speaking to the engineering review for this PMA supplement.
> I will be followed by Dr. Swain, who will address the clinical review,
> and then by Dr. Gray, who will address the FDA statistical
> review.]{.underline}
>
> [After that, I will read the questions to the panel into the
> record.]{.underline}
>
> [\[Slide.\]]{.underline}
>
> [These are the folks on the FDA review team for this
> supplement.]{.underline}
>
> [\[Slide.\]]{.underline}
>
> [In this supplement, the sponsor is proposing an expanded indication
> for use for the currently approved VE LVAS system. The current
> approval is as a bridge to transplantation in patients who are
> transplant-eligible. This is the language the sponsor is
> proposing.]{.underline}
>
> [\"The HeartMate VE LVAS is indicated for use as a bridge to
> transplantation in cardiac transplant candidates at risk of imminent
> death from non-reversible left ventricular failure.\" That is the
> approved language.]{.underline}
>
> [This is what the sponsor wishes to add. \"The HeartMate VE LVAS is
> also indicated for use in patients with end-stage left ventricular
> failure who are ineligible for cardiac transplant.\" And for both
> indications, \"The HeartMate VE LVAS is intended for use both inside
> and outside the hospital.\"]{.underline}
>
> [\[Slide.\]]{.underline}
>
> [This is what the FDA has to do during this review. We have to
> determine if the sponsor has provided a reasonable assurance of safety
> and effectiveness. That is the law. And we are obligated to consider
> the following factors: the patient population, in whom will this
> device be used, the conditions of use, how will it be used, what is
> the probable benefit versus the probable injury to the patients using
> the device, and finally, what is the reliability of the device when
> used as indicated.]{.underline}
>
> [\[Slide.\]]{.underline}
>
> [I would like to remind you of the device description. The device
> basically has implanted and external components, the implanted
> components being the blood pump, the valved conduits, and part of the
> percutaneous tube.]{.underline}
>
> [The external components are the controller, the battery packs, and
> what we will call accessories. The accessories are described in your
> panel pack in Tab 3.2, pages 5 and 6. It is just external
> components.]{.underline}
>
> [\[Slide.\]]{.underline}
>
> [This is a figure which the sponsor allowed me to use. This is their
> figure. Just to remind you, this is the blood pump. It sits in the
> chest. It is a rigid titanium shell. It is divided into two halves
> internally. One half contains the electric motor and is connected by
> means of a vent tube to the outside.]{.underline}
>
> [The other half is the blood side. Blood comes from the apex of the
> left ventricle through the valve conduit into the pump. The electric
> motor rotates. There is a cam that converts that rotation to linear
> motion, pushes a pusher plate, pushes the blood out of the blood side
> into the aorta. This also is a valve conduit. So, this is all
> implanted.]{.underline}
>
> [The percutaneous tube carries an air line and an electric line out.
> This is the skin breakthrough site. There is a connector here. There
> is a vent line which allows air to vent in and out of the motor side
> of the pump. There is an electric line, which connects to the
> controller, which has alarms, which conditions power, and so
> on.]{.underline}
>
> [There are two battery packs, only one of which is shown. The system
> can also be powered from a bedside console. The system also comes with
> a battery charger with a system monitor, and so on.]{.underline}
>
> [\[Slide.\]]{.underline}
>
> [This is a very complex system, as you might well imagine. During the
> review of such a complex system, these are the things that the FDA
> will consider. In this case, the sponsor is asking for an expanded
> indication for use for an existing system which is currently approved
> for a bridge to transplant, so all of the things shown here have been
> reviewed in detail, and we have no concerns. Nothing will change for
> these things for the proposed expanded indication for use, the longer
> term use. We have already reviewed this, and we have no
> concerns.]{.underline}
>
> [\[Slide.\]]{.underline}
>
> [These are the things that we do have concerns with: the difference
> between the proposed long-term use, the destination therapy versus
> bridge. The thing that we looked at very hard was device system
> reliability, in particular the reliability of the internal components
> since they would require that the patient have surgery should anything
> go wrong with them. We are less concerned about the externals. It has
> been demonstrated quite readily that they can be changed out rather
> easily and aren\'t a problem.]{.underline}
>
> [In particular, we are concerned with the motor, this is what pumps
> the blood, and the valved conduits as Mr. Poirier spoke to and I will
> speak to again, and we are concerned about a Device End of Life
> Indicator. The sponsor noted that there are several things which could
> indicate end of pump life, but there are no objective indicators or at
> least nothing the sponsor has proposed by which you can tell that this
> particular pump is at end of life and should be replaced and that
> particular pump has six months left.]{.underline}
>
> [\[Slide.\]]{.underline}
>
> [I would like to address the reliability testing, the bench testing
> that was performed by the sponsor, which was described briefly by Mr.
> Poirier.]{.underline}
>
> [Fifteen units were put on test. All of them were VE LVAS, none of
> them were VE SNAP. They were put on test on a mock circulatory loop.
> The implanted components of the system were in water at 37 degrees
> Centigrade to simulate the environment they would see in the patient,
> the temperature. They were pumping water.]{.underline}
>
> [The external components were in air at room temperature as they would
> be in clinical use, and the pumps were run at what is described as
> worst, average, and minimum operating conditions, and they were cycled
> from condition to condition to condition every week, and so cycled
> around and around throughout the course of the test.]{.underline}
>
> [The things that were changed were beat rate, outlet pressure, and
> flow that the pumps were generating. This is the way it is done. This
> is the way this reliability testing is done. The number of units is
> good, the conditions chosen were reasonable or apparently reasonable.
> This testing was conducted in a most appropriate way.]{.underline}
>
> [\[Slide.\]]{.underline}
>
> [This is the results of the testing, which, by the way, is still
> ongoing. As of this past summer\--this testing began in 1997\--as of
> this past summer, 10 pumps had failed, 8 of those failures were main
> bearing failures, 1 was a diaphragm failure, 1 was a commutator
> failure. The commutator is part of the motor. Five units, as of last
> summer remained on test. That is, they still continue to
> function.]{.underline}
>
> [\[Slide.\]]{.underline}
>
> [Looking at the main bearing failures, this is the motor. If the
> bearing fails, if the motor fails, you don\'t have electric pumping.
> The mean run time before the observed failure was about 136 million
> cycles at 75 beats a minute, that comes to about three and a half
> years. That is roughly 40 million cycles a year at 75 beats a minute.
> The standard deviation for that was about half a year.]{.underline}
>
> [The soonest a bearing failed was at about 2.25 years, the longest one
> ran before failing other than the ones still running was about 4
> years. The median is about 3.5 years. What I would like you to look
> at, look at the mean and look at the median. It is out at around 3.5
> years.]{.underline}
>
> [The sponsor has initiated a corrective and preventive action to
> address the problem of the bearing failures. This is an investigation,
> there is no mitigation yet. This is an open investigation, no steps
> have been taken to address the failures, no specific engineering
> changes have been made that we are aware of.]{.underline}
>
> [\[Slide.\]]{.underline}
>
> [Using these numbers and using a mathematical model, a Ybel \[ph\]
> model, one can predict what the reliability of the system should be.
> This is a prediction. 86 percent reliability at 2 years with a 60
> percent confidence, 76 percent reliability at 2 years with a 90
> percent confidence.]{.underline}
>
> [The mean time to failure for the pump with 90 confidence should be 3
> years. Keep those numbers in mind, 3 years.]{.underline}
>
> [\[Slide.\]]{.underline}
>
> [These are observed end of pump life events. They occurred at times
> ranging from 460 to 779 days. These are events observed in patients in
> the clinical trial.]{.underline}
>
> [The cycles are in million of cycles. For instance, looking here, this
> is about 50 million cycles at 75 beats a minute. At 100 beats a
> minute, it is about 67 million, and what was observed, there was dust,
> and when the pump was looked at, it was a bearing
> failure.]{.underline}
>
> [Similarly, for the other ones, the number in parenthesis is either
> the higher estimated rate or, here, for these two, these are numbers
> of cycles estimated by the sponsor based on records of what the beat
> rate was when those patients were seen at follow-up.]{.underline}
>
> [The point here is that these occurred early in the process compared
> to what the bench testing predicted. The sponsor is saying the bench
> testing predicts end of life at between 80 and 120 cycles for the
> pump, and these are occurring early. The clinical observation is they
> occur early.]{.underline}
>
> [\[Slide.\]]{.underline}
>
> [Another malfunction, not failure, a malfunction, is inflow valve
> incompetence that Mr. Poirier spoke of. This has been confirmed, 12
> events in 11 patients. One patient experienced this twice. Six of
> those devices were VE, five were VE SNAP, which calls into concern the
> effectiveness of the 90-degree elbow, which is one of the things that
> differentiates the VE SNAP from the VE.]{.underline}
>
> [The idea was to not allow the outflow valve graft to kink, so that
> the pump would not develop high pump pressure and thereby high back
> pressure across the inflow valve. Roughly half of the events observed
> were in the modified pump.]{.underline}
>
> [We wonder whether this might be related to end of pump life. One of
> the symptoms of inflow valve incompetence is an increase in pump rate
> up to on the order of 100 to 120 beats a minute. That means for a
> given absolute length of time, for a day, the pump will undergo more
> cycles at the higher rate than at 75.]{.underline}
>
> [Consequently, the pump will reach its end of life sooner in time. The
> clinical consequences of inflow valve incompetence can be surgery for
> replacement of the inflow conduit, and so that, by definition, puts
> the patient at some risk.]{.underline}
>
> [\[Slide.\]]{.underline}
>
> [The engineering summary is that the bench testing, in our eyes, did
> not account for all of the observed clinical conditions. In
> particular, it did not account for the elevated pump chamber pressure
> which was seen clinically and/or for the high beat rate which was seen
> clinically, the elevated pump chamber pressure could well be related
> to inflow valve incompetence, which resulted in a higher beat
> rate.]{.underline}
>
> [The observed pump end of life events were at the low end of the bench
> testing reliability prediction. These things may not last as long as
> the bench testing predicted, and there is no objective device end of
> life indicator.]{.underline}
>
> [It was pointed out by Mr. Poirier that, yes, you can look at the dust
> in the vent, and, yes, you can look at the pump current waveforms,
> which by the way, cannot be done by the patient, it does require some
> training to understand and to interpret, and you can listen for the
> pump sounds.]{.underline}
>
> [There is no objective device end of life indicator, and replacement
> of the pump requires major, major surgery.]{.underline}
>
> [At this time, I would like to turn this over to Dr. Swain, who will
> discuss the FDA clinical review.]{.underline}
>
> **[Julie Swain, M.D.]{.underline}**
>
> [DR. SWAIN: My name is Julie Swain. I am on detail to the FDA for the
> last several months. I am a cardiothoracic surgeon and a faculty
> member at Mass. General Hospital.]{.underline}
>
> [\[Slide.\]]{.underline}
>
> [I would like to present our review today. The clinical review was
> performed by Dr. Ewing, cardiology, and Dr. Sapirstein and I in
> cardiothoracic surgery.]{.underline}
>
> [\[Slide.\]]{.underline}
>
> [As Dr. Berman has said, the indication is an expanded use for
> patients with end-stage left ventricular failure who are ineligible
> for cardiac transplantation.]{.underline}
>
> [\[Slide.\]]{.underline}
>
> [The primary effectiveness endpoint was survival benefit, as Dr. Rose
> has said.]{.underline}
>
> [\[Slide.\]]{.underline}
>
> [This was estimated based on mortality at 2 years, and the estimates
> were based on the literature, as Dr. Stevenson has said, based on a
> mortality of 75 percent in the OMM group and 50 percent in the LVAS
> group, calculated for 92 study deaths.]{.underline}
>
> [The worst case power calculation for a power at 80 percent was
> calculated as 60 and 40, so a 30 percent improvement in survival. When
> you look at the results of the study, the observed Kaplan-Meier
> curves, the mortality was 91 and 76 percent at the two-year
> mark.]{.underline}
>
> [\[Slide.\]]{.underline}
>
> [The data that I will be showing you are based on three separate
> submissions from the sponsor. The first was in June, and in each
> slide, I will attempt to have that marked, a June submission. There
> was an update on mortality curves in November, and another update in
> February.]{.underline}
>
> [So, the survival will be based on the February update from the
> sponsor. We received the serious adverse event update about three
> working days ago. It was too late to include in the presentation, but
> on first pass, it appears to be not substantially
> different.]{.underline}
>
> [\[Slide.\]]{.underline}
>
> [The inclusion criteria used originally for when the study was
> designed, which was used for 124 of the 129 patients, is as shown,
> that the patients were ineligible for transplantation, NYHA Class IV
> for greater than 90 days, 70 percent of these patients turned out to
> be on inotropes, intensive medical therapy, LVEF lower than 25
> percent, VO~2~ max less than 12. VO~2~ max was performed at baseline
> on about 50 percent of the patients in the study.]{.underline}
>
> [\[Slide.\]]{.underline}
>
> [Later, in order to increase enrollment in the study, the criteria
> were changed slightly, and this was for five of the patients in the
> study. It was NYHA Class IV for greater than 60 days as opposed to 90,
> and added NYHA Class III or IV for greater than 28 days, and inotropic
> therapy or balloon pump. Also, increased VO~2~ criteria to less than
> 14 rather than 12.]{.underline}
>
> [\[Slide.\]]{.underline}
>
> [The exclusion criteria are as shown, in particular, patients smaller
> than 1.5m^2^, history of stroke, neurological complications, things of
> that sort.]{.underline}
>
> [\[Slide.\]]{.underline}
>
> [Baseline characteristics were equal between the two groups or nearly
> equal in the number of patients able to do the 6-minute walk, the
> distance of the walk, NYHA IV, 65 and 2 in Class III versus 60 and 1,
> so, in general, this was a study of NYHA Class IV
> patients.]{.underline}
>
> [\[Slide.\]]{.underline}
>
> [This is based on the February 02 data, and the study design, as Dr.
> Rose has said, 968 patients were screened as possible enrollees in
> this trial, and patients enrolled, 129. That gives you a ratio of 7.5
> to 1. You will see slight differences in our slides, 128 versus 129
> patients, 67 versus 68. This reflects one patient who was consented
> for the trial before the end of the trial, but received his device
> after the end of the trial, and these are included in the survival
> data, this one particular patient.]{.underline}
>
> [What we see is that 7 patients reached the two-year end of study mark
> in the left ventricular assist group, 45 patients died at less than
> two years, and there are, as of February 02 data, 16 patients alive
> less than two years.]{.underline}
>
> [For the medical management group, 3 patients survived to the two-year
> mark, 5 are alive less than two years, and 53 patients have
> died.]{.underline}
>
> [\[Slide.\]]{.underline}
>
> [All of my slides that have percents are zero to 100 scale, those with
> number of patients are zero to 70 scales just to keep things
> consistent.]{.underline}
>
> [Looking at the Kaplan-Meier curves for the data that you just saw,
> one-year survival, n equals 16 for medical management, and medical
> management in my slides are in gold as the gold standard, and blue for
> the device, and 33 patients were the basis of the KM curve, survival
> curve at one year at 57 percent.]{.underline}
>
> [At two years, the curves are based on 3 patients and 7 patients
> respectively in the two groups. By 12 weeks later, at the end of the
> trial, this is the February 02 data again, 4 of the 7 device patients
> had died, and all 3 of the medical management patients had died by 12
> weeks past the end of the two-year trial.]{.underline}
>
> [\[Slide.\]]{.underline}
>
> [Serious adverse events occurred in 64 of 68 of the device patients,
> 36 of 61 of the medical patients, P less than 0.001.]{.underline}
>
> [\[Slide.\]]{.underline}
>
> [Then, comparing for safety, the use of this device in destination
> patients versus bridge to therapy patients, there are several problems
> as the sponsor has pointed out in making the comparisons. They are
> certainly different patient populations, different definition for many
> of the SAE\'s, the studies were done in different times periods with a
> different patient care team, which makes comparison of SAE\'s between
> the bridge data set and the current data set to somewhat
> problematic.]{.underline}
>
> [\[Slide.\]]{.underline}
>
> [I am going to discuss just a few of the SAE\'s, and the slides all
> contain two graphs. One is the percent of patients experiencing the
> event, the other is per 100 patient days, as Dr. Rose has shown. I
> think it is important to do it both ways.]{.underline}
>
> [There are certain complications like the need for transfusion that
> would probably be more appropriate looking at patient days, events per
> 100 patient days. However, other complications, such as a stroke, it
> might be more important or clinically more important I think to look
> at the percentage of patients experiencing the event it would tend to
> overshadow other events occurring, and not be able to detect lesser
> strokes and lesser neurologic dysfunctions in this case.]{.underline}
>
> [Also, for situations like sepsis, a patient who has sepsis and then
> has sepsis for the remainder of the time in the study would not be
> reflected in events per 100 days, but probably would be reflected more
> clinically relevant in percent of patients.]{.underline}
>
> [So, when we look at neurologic dysfunction, we find a statistically
> significant difference between device versus medical therapy, 27
> percent of the patients having a serious adverse event in neurologic
> dysfunction.]{.underline}
>
> [It is important to note that this study was designed in the
> early-to-mid-nineties when we had less of a knowledge of neurologic
> events than we do now in cardiac surgery, so the definitions of
> neurologic events are really based on the NIH stroke score and a
> clinical examination, there are virtually no cognitive function being
> done other than what is present in the NIH stroke score, which is
> truly a stroke score, and that is really two questions relating to
> alertness and ability to function.]{.underline}
>
> [These are the results of neurologic dysfunction.]{.underline}
>
> [\[Slide.\]]{.underline}
>
> [When you look at local infections, we also look at a P equals 0.07
> difference, less of a difference between the two groups, and less than
> 0.1 when look at it per 100 patient days.]{.underline}
>
> [\[Slide.\]]{.underline}
>
> [When you look at sepsis, and you look at the individual patient
> summaries, you will see very often that local infections may lead to
> implant infection, sepsis, and that sort, so a lot of these SAE\'s are
> not independent at all. They are very much interrelated.]{.underline}
>
> [When you look at sepsis, the difference is 31 percent versus 13 in
> the two groups, and percent of patients, which is a 0.02 difference
> significantly. Likewise, when you look at per 100 days, a P less than
> 0.2 difference in that particular SAE.]{.underline}
>
> [\[Slide.\]]{.underline}
>
> [Now, for complications that only the device patients could have,
> looking at percutaneous or pocket infections, 24 percent of the
> patients and a 0.11 event per 100 day level, and this is again based
> on the June data.]{.underline}
>
> [\[Slide.\]]{.underline}
>
> [Looking at pump housing inflow or outflow tract infections, which
> could be extremely serious, 13 percent of the patients had that
> complication.]{.underline}
>
> [\[Slide.\]]{.underline}
>
> [Look at bleeding. This is not perioperative bleeding, this is
> bleeding after the perioperative period, a statistically significant
> difference between the two groups here with the device patients having
> 25 percent versus 3 percent incidence of bleeding, and again, a
> statistical difference when you look at event rate.]{.underline}
>
> [\[Slide.\]]{.underline}
>
> [Perioperative bleeding, which obviously can only be present in the
> device patients, 34 percent of the patients and this event
> rate.]{.underline}
>
> [\[Slide.\]]{.underline}
>
> [When we look at SAE\'s of all types, and look at operations, and this
> excludes the original implant operation obviously, it includes all
> operations in the medical group and every operation after the original
> implant in the left ventricular assist group, we can see the number of
> reoperations, the number of patients having 1, 2, and up to 10
> reoperations. This includes all reoperations, everything from a
> Hickman catheter to replacement of the device itself.]{.underline}
>
> [\[Slide.\]]{.underline}
>
> [What about the device malfunction analysis that Dr. Berman has
> mentioned? When you look at the various types, implant, as he has
> explained, which is the most serious, external element replacement,
> and then device malfunctions, and the definition of malfunction, 20
> elements in 19 patients had implant element replacement. Of the 12
> pumps removed, 8 pumps were replaced, 7 of those 8 patients died, 6 of
> those 7 in the postoperative period.]{.underline}
>
> [Of 4 devices removed, but not replaced, all of those patients died, 3
> of them were removed for unrelenting sepsis, and 1 patient chose not
> to have the device replaced.]{.underline}
>
> [\[Slide.\]]{.underline}
>
> [When we look at withdrawal from treatment in the two groups, 4 of the
> medical management patients chose to have the treatment withdrawn
> within one month of randomization, of choosing to be in the study and
> being randomized to medical therapy, they chose to have treatment
> withdrawn. Eight others chose to have treatment withdrawn at some time
> later in the study. So, a total of 12 of the 61 patients in optimum
> medical management chose to have their treatment
> withdrawn.]{.underline}
>
> [In the left ventricular assist group, 7 patients or their family
> chose to have the device turned off or did not agree to replacement
> when replacement was recommended, and 6 more chose to have treatment
> withdrawn, so a total of 13 of the 68 patients chose to have their
> treatment on the device withdrawn.]{.underline}
>
> [\[Slide.\]]{.underline}
>
> [Now we look at secondary endpoints, which were originally part of the
> study design, and that includes NYHA class, QoL\'s, functional status
> by way of 6-minute walk, VO~2~ max, number of hospitalizations, and
> what we have just spoken about, adverse events and device
> malfunction.]{.underline}
>
> [\[Slide.\]]{.underline}
>
> [When you look at NYHA class, as Dr. Rose has shown, there is an
> excellent result in comparing the device, that is statistically
> significant at 6 and 12 months, and there was very little data after
> 12 months. It is important, as Dr. Rose said, that no values were
> imputed. We standardly looked for values that are imputed, and that
> can either be done by taking the last result in the chart that was
> done and imputing results, which would give you different results from
> here, very good, or to look at data that was not collected because the
> patient died or could not do the test and impute the worst possible
> result, which would also give you very different results from shown
> here.]{.underline}
>
> [So, no data was imputed, these are all the real data that were
> collected.]{.underline}
>
> [\[Slide.\]]{.underline}
>
> [When you looked at Quality of Life results, the problem in an
> unblinded study, and necessarily this was unblinded to both physicians
> and to patients, and what is the effect on both the physicians and the
> patients of not being selected for the test device or the test
> therapy.]{.underline}
>
> [We are often concerned about the placebo effect in any unblinded
> study, and this may be very important, up to a 30 percent difference
> in results.]{.underline}
>
> [There may be sample bias for missing data. A patient who has had a
> large CVA would not necessarily be expected to be able to complete any
> of the QoL questionnaires or the walk or VO~2~ data.]{.underline}
>
> [We also expect consistency, statistical consistency between the
> Quality of Life and functional measures, and clinical concordance, you
> expect things to move in the same direction with the same relative
> magnitude.]{.underline}
>
> [\[Slide.\]]{.underline}
>
> [What about the data, what amount of data do we have for Quality of
> Life? When you look at the questionnaires, we can see these number of
> patients had completed QoL questionnaires. At one year, the LVAS
> patients, 22 of them, and 4 at two years, 6 and 3 in the OMM patients
> completing the questionnaires, of which we are looking at the QoL
> data.]{.underline}
>
> [\[Slide.\]]{.underline}
>
> [When we look at 6-minute hall walk, the number of tests performed, 37
> of the 68 patients in LVAS either never or only once had a 6-minute
> hall walk, and 29 had multiple performances, two or more performances
> of this test.]{.underline}
>
> [OMM patients, 44, and 17 had multiple performances of the test. So,
> there really are inadequate data for a comparison of these
> groups.]{.underline}
>
> [\[Slide.\]]{.underline}
>
> [When you look at the data, this is clear. Of the patients who did
> have the test performed, these are the median distances in meters
> performed.]{.underline}
>
> [\[Slide.\]]{.underline}
>
> [Look at peak VO~2~ data, which is one of the inclusion criteria for
> the study. About half of the patients in both groups had baseline
> performance of data. When we look out to one year and two years, 15 of
> the LVAS groups and 3 of the OMM group had data, 2 and 1 at two years,
> and you look at the data obtained, and again no statistical difference
> in this small sample size.]{.underline}
>
> [\[Slide.\]]{.underline}
>
> [Another way of look at hospitalization is the percent of the
> remainder of life out of the hospital. According to the June 01 data,
> when we look at the average and median for the device group, 50
> percent of the remainder of their life after randomization was found
> out of the hospital, median of 64 percent.]{.underline}
>
> [On the OMM group, 71 percent of the remainder of their life was spent
> out of the hospital versus 83 in the median numbers.]{.underline}
>
> [\[Slide.\]]{.underline}
>
> [Death during hospitalization, 20 of the LVAS patients and 6 of the
> OMM patients died during their initial hospitalization. Of the OMM
> patients who died, of the 6 who died, several had treatment withdrawn,
> 1 patient had ventricular fibrillation on the day of randomization and
> died on that day. Another patient within a week of randomization was
> found to have critical aortic stenosis, underwent urgent cardiac valve
> replacement, and died in the postoperative period.]{.underline}
>
> [\[Slide.\]]{.underline}
>
> [Our clinical summary is that in a very advanced heart failure
> population, the device used produced a survival benefit. The mortality
> and morbidity associated with use of the LVAS was
> considerable.]{.underline}
>
> [Interpretation of functional testing data is limited by the amount of
> data available.]{.underline}
>
> [Thank you.]{.underline}
>
> **[Gerry Gray, Ph.D.]{.underline}**
>
> [DR. GRAY: Good morning. My name is Gerry Gray. I was the statistical
> reviewer for this device.]{.underline}
>
> [\[Slide.\]]{.underline}
>
> [Just give a synopsis of a couple of things you have already seen in
> this study so far, patients were randomized in this study 1 to 1 to
> Optimal Medical Management versus Left Ventricular Assist
> System.]{.underline}
>
> [The primary endpoint of the trial was two-year mortality. By that, I
> mean the trial was designed to detect a difference in survival over
> the course of the two-year period between the two arms of the
> trial.]{.underline}
>
> [There were three interim analyses designed into the trial at 23
> deaths, the trial was designed to stop after 92 deaths.]{.underline}
>
> [For the survival analyses we have complete follow-up. There is no
> missing data for survival.]{.underline}
>
> [As of the end of last June, there were 128 patients enrolled, 61 OMM,
> 67 LVAS. At that time, we had 40 deaths in the LVAS arm, and the
> remaining 52 in the OMM arm.]{.underline}
>
> [Some of my slides will use the updated survival data, that was
> updated as of the beginning of February of this year.]{.underline}
>
> [\[Slide.\]]{.underline}
>
> [The primary endpoint for the trial was all cause mortality. This is a
> graph of the survival curves showing the all cause mortality for the
> two arms of the trial. The X axis shows months since randomization,
> the Y axis, the estimated survival probability.]{.underline}
>
> [The thick red line is the LVAS arm, the thick black line is the OMM
> arm. The thin line show 95 percent confidence intervals at each point
> over the course of the trial. The blue circles indicate the estimated
> median survival for the two groups. That was 150 days for the OMM arm
> versus 408 days for the LVAS arm.]{.underline}
>
> [Below the graph are the numbers of patients who survived up to 0, 6,
> 12, 18, and 24 months. So, all the results past that are primarily on
> those patients.]{.underline}
>
> [Some features to note in this graph, you might note the survival up
> until the 30-day point was pretty much identical for the two groups at
> which point they diverged. The LVAS arm stayed above OMM up until
> maybe around 22 months, where there was somewhat of a decline in LVAS
> survival, but again, that is only based on a very few patients. I
> think there were only 11 patients who survived up to 22
> months.]{.underline}
>
> [As has already been stated, the log-rank test for the overall
> difference is significant with a p-value of 0.003. The two median
> survival times of 150 and 408 days are significantly different. At the
> one-year point in the June 2001 data, there is a significant
> difference in survival.]{.underline}
>
> [\[Slide.\]]{.underline}
>
> [The updated survival curves shown on this graph are pretty much the
> same. I am going to go back and go forward, and you see that the only
> real difference is that the confidence bounds got slightly smaller
> because we had more follow-up.]{.underline}
>
> [This data of February 2002 had seven months more follow-up than the
> previous. The basic features are still unchanged. We still have a
> significant difference between the two curves using the log-rank test.
> We still have potential drop-off in LVAS survival around the 22-month
> point.]{.underline}
>
> [Using these data at 24 months, pointwise, there is a marginal
> difference in survival. The p-value is around 0.05.]{.underline}
>
> [\[Slide.\]]{.underline}
>
> [One of the secondary endpoints of the trial was cardiac mortality.
> This graph shows the deaths due to cardiac mortality in the two arms
> of the trial. Again, red line is LVAS, black is OMM.]{.underline}
>
> [In this analysis, deaths that are not due to cardiac causes are
> considered to be censoring. Those patients are censored. When you look
> at the data in this way, the LVAS arm is very much superior to OMM.
> There still might be a drop-off in LVAS survival at 22, but again,
> this is very, very few patients.]{.underline}
>
> [There is a problem in looking at this kind of analysis. In this case,
> the cardiac and non-cardiac mortality are not independent. In
> statistical terms, you would say that the censoring is independent of
> the mortality.]{.underline}
>
> [\[Slide.\]]{.underline}
>
> [This graph shows the converse of the previous mortality due to
> non-cardiac causes. When you look at it this way, the OMM arm looks to
> be superior to the LVAS arm. You will recall that only 1 out of 52
> deaths at the stopping point were due to non-cardiac causes in the OMM
> arm, whereas, 29 of the 40, about three-quarters of the LVAS deaths,
> were non-cardiac causes.]{.underline}
>
> [So, you have to look at these two graphs sort of together to
> interpret meaningfully. So, again, it would appear that the causes or
> mortality, at least cardiac versus non-cardiac, are not independent,
> and it would appear that the LVAS device reduces the cardiac mortality
> and, at the same time, increases the non-cardiac mortality to some
> degree.]{.underline}
>
> [\[Slide.\]]{.underline}
>
> [So, to summarize the mortality results, there is a significant
> increase in the median survival time, 150 days versus 408 days. There
> is a significant difference between the two survival curves using the
> log-rank test with a p-value of 0.003.]{.underline}
>
> [There is a significant difference in the mortality at one year, 50.8.
> That says \"mortality,\" it should say \"survival.\" The survival at
> one year was 50.8 percent versus 24.4.]{.underline}
>
> [Using the updated data, updated as of early February, there is
> marginal statistically significant difference in mortality at the
> two-year point.]{.underline}
>
> [The cardiac and non-cardiac mortality don\'t look to be independent,
> and there might be a drop-off in LVAS survival starting at around 22
> months, but again, that is based on only 11 patients who survived
> after that point.]{.underline}
>
> [\[Slide.\]]{.underline}
>
> [Also, as has been previously noted, survival benefits didn\'t come
> without a cost. There were significant increases in the number of
> adverse events and serious adverse events per person and in the rates
> per 100 days in the LVAS arm.]{.underline}
>
> [\[Slide.\]]{.underline}
>
> [This graphic shows the death and serious adverse event rates per 100
> days in the two arms of the trial, the red bars on the left LVAS, the
> gray bars the OMM arm.]{.underline}
>
> [The top five bars in here are device-related events that could only
> have happened in the LVAS patients. Overall, as has also been stated,
> the LVAS rates were significantly higher than the OMM, especially the
> bleeding and neurologic dysfunction down at the bottom were very
> different.]{.underline}
>
> [\[Slide.\]]{.underline}
>
> [Cutting the time at 30 days or less versus events that happened at
> more than 30 days is shown in this graph here, the lefthand side being
> what you might call peri-operative events that happened at 30 days or
> less, the righthand side being events after 30 days.]{.underline}
>
> [Again, these show rates per 100 patient days, so they are adjusted
> for the different survival times for the two arms of the
> trial.]{.underline}
>
> [You will note that the X axes are not the same in these two, and that
> is because the rate per 100 days did drop off significantly for both
> groups after 30 days. Bleeding and neurologic dysfunction stayed high
> in the LVAS arm, and for both of these time periods, the event rates
> were significantly higher for the LVAS patients.]{.underline}
>
> [The mortality at the bottom, the death rate for the two arms was
> nearly identical for the first 30 days. After that, the LVAS rates
> were much better.]{.underline}
>
> [\[Slide.\]]{.underline}
>
> [Associated with this increase in serious adverse event rates, the
> hospitalization time was significantly higher for the LVAS arm, a
> median of 61 days in the hospital versus 16, 24 percent of the total
> days in the LVAS arm were spent in the hospital versus 15 percent in
> the OMM arm.]{.underline}
>
> [I am not sure about this 141. I got it out of the panel pack, and the
> sponsor seemed to indicate that was more like 300 days, so I am not
> totally clear why that says 141.]{.underline}
>
> [\[Slide.\]]{.underline}
>
> [One of the panel questions asks the panel how to combine or how to
> make the tradeoff between mortality benefit and adverse
> events.]{.underline}
>
> [I am going to take a little sidetrack here and talk about two
> possible ways that you might formally try to combine those into one
> analysis, the first one being an analysis based on a hierarchical
> ranking of patients, the second one being survival to not just death,
> but death or some other bad thing. These are by no means the only two
> possibilities.]{.underline}
>
> [\[Slide.\]]{.underline}
>
> [First, using a hierarchical ranking, what you might think of doing is
> trying to rank patients by whatever the most important outcome is, and
> then if there are any ties, to break those ties using secondary
> outcomes.]{.underline}
>
> [In this trial, the obvious example is to first rank patients by how
> long they survived, and if they survived to the end of the trial, to
> try to rank them by some other secondary objective like how many days
> they spent in the hospital or perhaps how many serious adverse events
> they had.]{.underline}
>
> [The bottom line here is if you believe in this kind of analysis and
> you can meaningfully rank patients using this hierarchical method, if
> you use the death time as the first ranking factor, then, regardless
> of how ever else you rank patients after that, there is always a
> significant improvement in favor of the device.]{.underline}
>
> [So, if you like this kind of analysis, the device would always look
> better.]{.underline}
>
> [\[Slide.\]]{.underline}
>
> [The other method you might do is to try to combine death and other
> serious adverse events into one analysis. This is again Kaplan-Meier
> survival curve that shows the survival up until the time of the first
> serious adverse event or death. In this analysis, death and serious
> adverse events all count the time, there is no
> differential.]{.underline}
>
> [The median LVAS survival time in this analysis is much less, 13 days,
> versus 87 days in the OMM arm. After about five or six months, the
> rates level out to be about the time. The medians again are shown by
> the blue dots.]{.underline}
>
> [\[Slide.\]]{.underline}
>
> [If you are wondering how we reconcile this with the mortality
> results, remember that although the time to the first bad event, the
> first serious adverse event in the LVAS arm is much less, the
> classification of that bad event is much different.]{.underline}
>
> [So, out of the 58 people who had death or some serious adverse event,
> the first thing that happened to them in the LVAS arm for two of those
> people was death, whereas, in the OMM arm, the first thing that
> happened to more than half of the patients was they died, so although
> the rate was higher in the LVAS arm, the seriousness of the event I
> guess you would say was different.]{.underline}
>
> [\[Slide.\]]{.underline}
>
> [Now, there was a clinical impression from the clinical reviewers that
> when they read the case reports, that the first bad event initiates
> this cascade of things that leads ultimately to the death of the
> patient, and the question to me was, is that impression borne out in
> some formal analysis, and if it is, is there is some difference
> between the two groups in the timing of those subsequent
> events.]{.underline}
>
> [\[Slide.\]]{.underline}
>
> [This graph shows the results of such an analysis. Again, it is
> Kaplan-Meier survival curves of conditional survival to death or
> serious adverse event. The two upper lines here are the time up until
> the person had their first serious adverse event, and those are the
> two lines that we have already seen in a previous graph.]{.underline}
>
> [The two lower lines show if you survive that first adverse event, how
> long was it until you had some other bad thing happen to you. The
> point here to note is that after the patient has their first bad
> event, the second and third and fourth events come very rapidly, and
> actually, they come at about the same rate for the two
> arms.]{.underline}
>
> [So, the main difference between the two groups is the time up until
> the first event. After that, events occur rapidly at median times of
> about three to five days, at about the same for the two
> groups.]{.underline}
>
> [\[Slide.\]]{.underline}
>
> [This table summarizes the functional status and Quality of Life
> results that we saw in the trial. The entries in the table are the p
> values for tests between OMM and LVAS improvement over
> baseline.]{.underline}
>
> [These results generally favor the LVAS arm especially for NYHA, where
> LVAS consistently improved significantly more than the OMM arm. The
> hall walk and the peak VO~2~ are pretty much inconclusive partly
> because there were very few patients who could complete
> those.]{.underline}
>
> [The Quality of Life results somewhat favor the LVAS especially for
> the EuroQOL, less so for the Beck and less for the Minnesota Living
> With Heart Failure and the SF-36.]{.underline}
>
> [I would note that the samples sizes are very small at the 6- and
> 12-month point. At 6 months, there were 30 LVAS and 21 OMM patients,
> and at 12 months, there were 22 LVAS and 6 OMM patients who are
> represented here.]{.underline}
>
> [\[Slide.\]]{.underline}
>
> [To summarize the statistical results, there was a significant
> decrease in mortality for the LVAS arm whether you measure by median
> survival time or you use a log-rank test, or compare pointwise at one
> and two years.]{.underline}
>
> [The significant adverse event rates were much higher in the LVAS arm.
> The LVAS treatment resulted in decreased cardiac mortality rates and
> increased non-cardiac mortality rates.]{.underline}
>
> [Survival much past two years was poor in both groups.]{.underline}
>
> [There may be some indication of a relative LVAS drop-off in survival
> at about 22 months, but there were very few patients, only 11, that
> survived that far.]{.underline}
>
> [The difference between the two groups is almost entirely in the time
> up until their first event, not to the time between subsequent events
> after that, and any stage, the odds of death versus some other serious
> adverse event is always higher for the OMM arm.]{.underline}
>
> [The functional status results favor the LVAS arm, but not
> consistently.]{.underline}
>
> [Thank you.]{.underline}
>
> [DR. LASKEY: Mike, did you want to read the questions for the
> panel?]{.underline}
>
> **[Questions to the Committee]{.underline}**
>
> [DR. BERMAN: For the record, I am Michael Berman. I am going to read
> into the record the questions.]{.underline}
>
> [Panel, as you deliberate this afternoon, we ask that you please keep
> these questions in mind.]{.underline}
>
> [1. The bench testing performed to assess device reliability did not
> account for all observed clinical conditions, in particular, higher
> than expected pressure in the pump chamber and higher than expected
> beat rates. Accordingly, the observed times to device failure and/or
> device malfunction seen in the clinical study are less than those
> predicted by the reliability model. As well, there is no reliable
> end-of-pump-life indicator. Please discuss the clinical implications
> of the observed reliability for the indication proposed, which is long
> term.]{.underline}
>
> [2. Are the device failure and malfunction rates and their times to
> occurrence appropriate for a device intended for use for destination
> therapy?]{.underline}
>
> [3. Given the Kaplan-Meier survival curves and the fact that 7 device
> patients and 3 control patients, as of February 02, had survived to 24
> months, have enough patient data been reported to demonstrate a
> clinically meaningful survival benefit?]{.underline}
>
> [4. The New York Heart Association, the Quality of Life, and the
> functional testing results are not consistent. From these data, can we
> determine that there is a clinically meaningful improvement in
> functional status?]{.underline}
>
> [5. This device demonstrated an increase in median survival time and
> showed an overall difference in survival. However, this benefit
> diminished at two years and was associated with serious adverse events
> and hospitalizations throughout the course of the study. Do the
> benefits of this device outweigh its risks?]{.underline}
>
> [6. One aspect of the premarket evaluation of a new product is the
> review of its labeling. The labeling must indicate which patients are
> appropriate for treatment, identify potential adverse events with the
> use of the device, and explain how the product should be used to
> maximize benefits and minimize adverse events.]{.underline}
>
> [6(a). Please discuss the appropriateness of the proposed indications
> for use for this device, which reads:]{.underline}
>
> [\"The HeartMate VE LVAS is indicated for use as a bridge to
> transplantation in cardiac transplant candidates at risk of imminent
> death from nonreversible left ventricular failure. The HeartMate VE
> LVAS is also indicated for use in patients with end-stage left
> ventricular failure who are ineligible for cardiac transplantation.
> The HeartMate VE LVAS is intended for use both inside and outside the
> hospital.]{.underline}
>
> [6(b). Does the labeling accurately inform patients of the risks of
> the device?]{.underline}
>
> [6(c). Does the labeling adequately inform patients of the expected
> duration of use for this device?]{.underline}
>
> [6(d). Are there any other issues of safety or effectiveness not
> adequately covered in the labeling?]{.underline}
>
> [7. Based on the clinical data provided in the panel pack, do you
> believe that additional clinical follow-up or postmarket studies are
> necessary to evaluate the long-term effects of this device? If so, how
> long should patients be followed, and what endpoints and adverse
> events should be measured?]{.underline}
>
> [Thank you.]{.underline}
>
> [DR. LASKEY: Again, thank you all to the presenters and the FDA
> reviewers. A well-deserved lunch break, and we would like to reconvene
> promptly at 1 o\'clock. Thank you.]{.underline}
>
> [\[Whereupon, at 12:00 noon, the proceedings were recessed, to be
> resumed at 1:00 p.m.\]]{.underline}
>
> [AFTERNOON PROCEEDINGS]{.underline}
>
> [\[1:10 p.m.\]]{.underline}
>
> **[Open Discussion]{.underline}**
>
> [DR. LASKEY: I would like to start off the afternoon by having Drs.
> Aziz and Konstam deliver their reviews and ask questions of the
> sponsor.]{.underline}
>
> [Dr. Konstam, do you want to begin?]{.underline}
>
> [DR. KONSTAM: Sure. First, I just want to say a couple of things. One,
> I want to congratulate Dr. Rose and his colleagues and the sponsor for
> conducting this study. I think it is going to stand as a landmark
> study and showing that a study like this can be done, and I just want
> to compliment them for embarking on it and carrying it out as
> successfully as they did.]{.underline}
>
> [I also think that the FDA reviewers were fabulous. I think that they
> have hit all the critical issues, at least that I am aware of, and
> maybe some that I am not aware of, but I think they did a fabulous job
> of summarizing everything.]{.underline}
>
> [I find sort of six categories of discussion, and just to go through
> what I think they are. The first is the primary endpoint met. I think
> there is a little bit of discussion that is required here, maybe I can
> ask Eric.]{.underline}
>
> [As I read the protocol, it seemed as though it was your intent to
> show a significant improvement at two years.]{.underline}
>
> [Do you want to comment on that because that isn\'t quite met and
> maybe you could comment on that.]{.underline}
>
> [DR. ROSE: In earlier incarnations of the protocol, that was indeed
> the intent. When we formed a DSMB, and actually once we had NHLBI
> involvement, as well, and a DSMB had been constituted, there was a lot
> of consideration of what the primary endpoint ought to be and concern
> that a discrete, single endpoint would pose potential difficulties in
> monitoring data or the safety of the trial in terms of outcomes, and
> instead, the area under the curve would be something that would be
> more easily monitored and monitorable, and for which you could set
> stopping rules as time went on.]{.underline}
>
> [So, the statistical plan and the primary analysis then focused on a
> two-year duration observation, and that indeed became the primary
> analysis, and the final statistical plan was agreed to by the NHLBI,
> the Date Safety Monitoring Board, and the FDA.]{.underline}
>
> [So, I think it is fair to say that that evolved over
> time.]{.underline}
>
> [DR. KONSTAM: Personally, I can accept that. That might be some cause
> of discussion on the part of the panel. I think we are going to circle
> back on that when we deal with the clinical relevance of the finding
> more than the statistical significance, but I guess it is worth just
> mentioning the fact that the timing of the primary endpoint has
> changed a little bit.]{.underline}
>
> [I guess the statistics of the log-rank test seem pretty strong. One
> must ask whether the two groups are similar. They seem similar in most
> regards. There are a couple of things a little bit different between
> the two groups. One I noticed is difference in warfarin use between
> the two groups, and you might want to comment on that.]{.underline}
>
> [The other thing which is a little bit more troublesome is that there
> is a discrepancy between the two groups in the number of\--as I read
> it, unless I am misreading it\--in the number of patients enrolled
> within the last year at least by my count.]{.underline}
>
> [Looking at the FDA document, 34 percent of the LVAD patients were
> enrolled with less than one year of follow-up, was only 23 percent in
> the medical management arm, which leads to a couple of issues, but one
> is, does this suggest some difference between the two groups, and why
> is that, what would there have been that difference?]{.underline}
>
> [DR. ROSE: On the warfarin issue, I have no idea. You look at 20
> variables on a randomization, and you use a p-value of 0.05, one of
> them is going to turn out to be that way. How that one ended up being
> the case, it is not the issue that clinicians have not viewed them as
> candidates for some kind of anticoagulation because the converse
> aspirin use was higher in the device patients. If anything, that might
> have disadvantaged the device patients because going into the surgery,
> which had to happen within a brief time after randomization on aspirin
> is something that I think we would find less than desirable, knowing
> the frequency and severity of the bleeding issues.]{.underline}
>
> [With regard to that difference over the later part of the trial, as I
> said, we did block these by center, and the blocks were random. I
> don\'t think that this reflects any degree of bias, and just is the
> way the cards fell out.]{.underline}
>
> [DR. KONSTAM: Well, I suspect you are right.]{.underline}
>
> [DR. ROSE: We also still had, in terms of the blocks, you know, the
> enrollment after the trial was stopped before the 140 that we expected
> to enroll.]{.underline}
>
> [DR. KONSTAM: Well, those are the caveats I find regarding the
> decision that the primary endpoint is met. I think that the statistics
> are strong that there is an effect on survival. Those are the only
> holes I can find to pick at, but I am not concerned about those
> greatly.]{.underline}
>
> [I think the second issue to discuss, and to me, in fact, I think the
> whole decision about approvability centers around this, which is the
> clinical relevance, and then where the clinical relevance comes up for
> discussion is what is going on at two years. To some extent, this is
> going to be a very subjective decision about, you know, what does it
> mean that there is a statistically significant effect at one year, and
> you lose it at two years, but more than lose it at two years, most of
> the patients essentially are dead at two years. They are either dead
> at two years or they are dead within a month or two of two
> years.]{.underline}
>
> [Now, there are a number of aspects of this. One is the reliability of
> the device and to what extent is a less than anticipated reliability
> of the device contributing to the mortality of two years.]{.underline}
>
> [The second problem is we don\'t have that many patients reaching two
> years, in part because again 34 percent of the patients in the LVAD
> group were enrolled within less than one year from the time the study
> ended.]{.underline}
>
> [Maybe I just can ask you again, Eric, about this two-year thing. When
> you set up the protocol originally, the primary endpoint was I think
> you said envisioned at the two-year endpoint, but there is a couple of
> aspects of that.]{.underline}
>
> [One is that when you looked at your pair analysis, the pair analysis
> was constructed saying that you wanted to see, you anticipated 75
> percent more mortality at two years in the control group. You hoped to
> achieve a third reduction. That gives you 50 percent survival at two
> years.]{.underline}
>
> [Now, I guess the question I have for you, is that just a numbers
> game, but you had to put some numbers in to have a pair analysis, or
> are you implicitly making some kind of value judgment about the
> survival of 50 percent at two years, are you sort of saying\--I guess
> what I am leading to is does this help us in terms of the overall
> judgment about the clinical relevance?]{.underline}
>
> [Were you saying at the beginning that we wanted to have a device that
> is clinically relevant by virtue of the fact that half of these
> patients are going to be alive at two years? I don\'t know whether you
> can comment on that.]{.underline}
>
> [DR. ROSE: I think the issue of clinical relevance has been part of
> the discussion throughout the generation of this trial. We initially
> did a preliminary randomization where our initial modeling of
> mortality, we anticipated that it would be worse in the VAD patients
> and that the two curves would cross late, that that would be the way
> this would shake out.]{.underline}
>
> [After pre-match, we actually revised our thinking in that regard, and
> that is what allowed the more appropriateness of the log-rank as
> opposed to other types of analysis.]{.underline}
>
> [With regard to whether or not we wanted to see 50 percent of the
> patients alive at two years, of course, we would have preferred that,
> but our thinking also early was that the control group mortality was
> not going to be as high as indeed we saw.]{.underline}
>
> [That was a surprise to us even knowing how sick these patients were.
> We thought that that longer term survival of the control group at a
> rate higher than 8 percent was likely to result. Now, that clearly was
> not the case, and I think, you know, would we have preferred to see 50
> percent survival at two years?]{.underline}
>
> [Certainly, but to come up with tripling of survival at two years with
> a quarter of the patients still alive, and a large number still
> ongoing, and this field being in its infancy, I would have to say that
> for patients now, I think this is clinically relevant and important
> survival benefit that we have documented, and it is time to let this
> field begin what I believe will be a ascent to better
> outcomes.]{.underline}
>
> [With regard to the issue is device reliability accountable for the
> lower survival rate than I think a lot would have like to have seen at
> two years, that is only part of it. Don\'t forget that half of these
> patients, as well as they did do in the first, half died in that first
> year, as well, and the overwhelming numbers of death occurred during
> the initial index hospitalization. About a third of patients with this
> type of therapy die in hospital with the index
> hospitalization.]{.underline}
>
> [I believe that we can cut that down substantially as we learn more
> over time, but that way you end up with more patient
> eligible\--]{.underline}
>
> [DR. KONSTAM: Let me ask this then. I mean it seems what happened is
> the device was exceedingly good at preventing cardiovascular deaths,
> and the fact that the mortality was so high in the medical management
> group means that this is an incredibly sick population, and so they
> were appropriate for consideration of this type of treatment, so that
> it good.]{.underline}
>
> [But since the device was so good at preventing cardiovascular deaths,
> the fact that you have so few people alive at two years, I guess
> implies there are more other kinds of things happening than you would
> have anticipated.]{.underline}
>
> [DR. ROSE: Another way to view it would be, though, to say that half
> the people that are alive at one year, are alive at two years, and in
> that regard, the device has a degree of reliability that is still
> potent. That is not to say that reliability is not a problem, but
> there are other issues that limit survival in this patient population
> if we are going to holistically improve it.]{.underline}
>
> [DR. KONSTAM: Well, part of the problem is we have so few patients at
> two years. I mean we don\'t really know what the right number is at
> two years because there aren\'t that many patients there. So, I just
> would comment on that.]{.underline}
>
> [Just to ask rhetorically, I mean if you are putting in a device that
> is clearly life-sustaining, what would you like out of that device in
> terms of its mechanical reliability, and what would you like out of
> that device in terms of warning signs that it is going to
> fail?]{.underline}
>
> [These are I think again questions that are going to come
> back.]{.underline}
>
> [The next category I think is the whole issue of Quality of Life
> assessment. I see some very reassuring things in the data set. I see
> some confusing things in the data set.]{.underline}
>
> [The confusion I think stems from the fact that there is such a high
> dropout rate in large part due to mortality and to some extent due to
> perhaps patient incapacity that it is extremely difficult to know
> exactly what the numbers for each of these tests are saying to
> us.]{.underline}
>
> [I can, however, accept the fact that things look better in the device
> group than in the medical therapy group, certainly in terms in your
> Heart Association class and in some of the Quality of Life
> parameters.]{.underline}
>
> [I guess one question that I want to ask you about, though, and the
> problem then, of course, in any of these, so part of the problem is
> the dropout rates that we are seeing and what do you do with that, but
> the other problem is that we don\'t have a blinded study, and we are
> going to be stuck with that.]{.underline}
>
> [The specific thing I wanted to ask about that is if you look at the
> numbers, let me say a positive thing. I am really reassured by the
> fact that a lot of the Quality of Life scores, forgetting about the
> comparisons, but if you just look at the LVAD group, a lot of the
> Quality of Life scores and a lot of the New York Heart Association
> class scores are pretty good.]{.underline}
>
> [What we can glean out of those numbers, it really seems to be,
> despite all the complications that we do see, there still are a number
> of patients, a fair number of patients at three months, six months,
> and 12 months, who seem to be doing pretty well. I get a lot of
> reassurance from that.]{.underline}
>
> [The one specific question I was to ask, though, is if you look at the
> number of patients who are said to be New York Heart Association Class
> I and II in the LVAD group, it seems that that number is disparate
> from the number of patients participating, for example, in the
> 6-minute walk.]{.underline}
>
> [The number of patients having repeated measures\--I don\'t have it in
> front of me exactly\--but the number of patients having repeated
> measures in the 6-minute walk is very small, I think, and smaller than
> the number of patients reported to be in New York Heart Association
> Class I and II, whom I would have expected could participate in the
> 6-minute walk as an objective question.]{.underline}
>
> [Can you comment on that, and why shouldn\'t we be concerned from
> that, that there is just some kind of a bias being injected in the New
> York Heart Association class grade?]{.underline}
>
> [DR. ROSE: Specifically, with regard to the 6-minute walk and the peak
> VO~2~ measurements, I think it is not unfair to say that a lot of
> investigators viewed the tests themselves as tests that could impair
> patients\' Quality of Life. They didn\'t like doing these
> things.]{.underline}
>
> [Secondly, I think that we did come to the conclusion that the more
> subjective measures of Quality of Life were a lot more reasonable and
> reflected more what is relevant to the patients than anything we would
> have measured in a 6-minute walk or a peak VO~2~
> measurement.]{.underline}
>
> [So, in all those regards, we did not push investigators in the way I
> wish we had, and the way that the data has turned out to generate
> those data. That, notwithstanding, also, the correlation between
> 6-minute walks and peak VO~2~\'s and Quality of Life for any degree of
> heart failure are not well established, and we certainly did not have
> a large enough N to do that in this trial, and their correlation with
> survival is not well established, if at all, as well.]{.underline}
>
> [So, for all those reasons, I would say we would have to be criticized
> as remiss in terms of not pushing to get them, but I don\'t think it
> reflects any bias on our part towards one group or another in
> assessing them.]{.underline}
>
> [Actually, if you look at the data, you don\'t see much of a
> difference between the two groups.]{.underline}
>
> [DR. KONSTAM: Bias is not necessarily a bad thing. It is just a
> reality. That is why we blind drug trials. You can\'t escape it. If
> you know what group of patients it is in, it is a potential bias in
> how you grade it. That just has to be said.]{.underline}
>
> [I think, however, I just give you my conclusion again, which is that
> it certainly does not appear as though everybody alive with the LVAD
> is alive, you know, miserable in bed, it does not appear that, and I
> do get that out of the Quality of Life data and the New York Heart
> Association classes.]{.underline}
>
> [The next broad category is the adverse events. I think that is really
> there juxtaposed against the survival benefit, and it was nicely sort
> of delineated by the statistical reviewer about different ways of
> looking at this.]{.underline}
>
> [If you look at all serious adverse events including death as equal,
> you have got a problem on your hands from the perspective of this
> trial. I certainly don\'t look at it that way. I would create a
> hierarchy where survival is better, and so we are really going to have
> to face that.]{.underline}
>
> [I have some specific questions about the adverse events. There seem
> to be a high number of neurologic adverse events, and there seem to be
> also a higher number\--there are some septic events\--but there are a
> higher number of bleeds than I would have anticipated even remote from
> the time of the operation.]{.underline}
>
> [I just wanted to go through your thoughts about a few of those
> things.]{.underline}
>
> [DR. ROSE: You mean non-neurologic? There was only one
> intracranial.]{.underline}
>
> [DR. KONSTAM: Non-neurologic bleeds, yes, two different things. So,
> there is strokes, which I guess are predominantly embolic. There are
> other neurologic events, and then there are some bleeds,
> non-neurologic bleeds. I guess those are the things that caught my
> eye.]{.underline}
>
> [Just to take them in order. Do you want to comment on the strokes? I
> guess I would have anticipated with the non-thrombogenic surface that
> we are dealing with, that we wouldn\'t have seen this many
> cerebrovascular accidents.]{.underline}
>
> [DR. ROSE: I think that the disparity in that regard is that many of
> the strokes occurred in a setting of device infection, so they are
> septic emboli.]{.underline}
>
> [DR. KONSTAM: Really?]{.underline}
>
> [DR. ROSE: Yes.]{.underline}
>
> [DR. KONSTAM: Is that just your impression or do we have some evidence
> of that?]{.underline}
>
> [DR. ROSE: The particular question is with the textured surface and
> everything else, should we have seen an overall smaller incidence of
> stroke.]{.underline}
>
> [DR. KONSTAM: You are saying it in a different light than I was
> thinking. I thought that these were for embolic events.]{.underline}
>
> [DR. ROSE: We have a summary slide on neurologic adverse
> events.]{.underline}
>
> [\[Slide.\]]{.underline}
>
> [The frequency actually of disabling stroke was, at least for the
> device literature, in this trial remarkably low especially considering
> the length of time that the patients were on devices. All neurologic
> events here were not strokes.]{.underline}
>
> [DR. KONSTAM: I understand that, and I was going to come to that, too,
> but there are strokes.]{.underline}
>
> [DR. ROSE: Yes.]{.underline}
>
> [DR. KONSTAM: And there are more strokes, if you sort through it, you
> are still left with a certain number of strokes that I am inferring at
> thromboembolic strokes.]{.underline}
>
> [DR. ROSE: Yes.]{.underline}
>
> [DR. KONSTAM: And I guess it would be important to note this, and I
> would presume, unless we have information otherwise, that the device
> is somehow contributing to this, because I think if that is the case,
> then, going forward, we ought to think about ways or preventing that
> including one question I would have is should anticoagulation be
> reconsidered with the device.]{.underline}
>
> [DR. LONG: I am Jim Long. I am the co-director of the surgical arm of
> this REMATCH trial. I guess for the sake of completeness I ought to
> also declare that I do not have a conflict of interest financially
> with Thoratec although they are paying my expenses at this
> meeting.]{.underline}
>
> [There are a number of factors that went into the stroke, a couple of
> which were not specifically device related, but management related.
> For example, two of those were air emboli that occurred at the time of
> operation, so included in this are not only device-specific issues,
> but management issues.]{.underline}
>
> [Also included in this, and I am sorry I don\'t have those numbers at
> my fingertips right now, but also included in this are patient
> factors, and as Eric alluded to, a fair number of these strokes
> occurred in the setting of sepsis. That is a fairly well documented
> occurrence in this field with this technology.]{.underline}
>
> [DR. ROSE: With regard to the question of anticoagulation, obviously,
> one of the unique aspects of this device is that we did not routinely
> use systemic anticoagulation here, and whether or not it would have
> made a difference in stroke rate, we don\'t know the answer to
> that.]{.underline}
>
> [Certainly, the N that we studied here with 68 device patients, even
> had we randomized them, it was not even close to something that would
> have allowed us to power this to judge whether or not anticoagulation
> ought to be part of the management of these patients.]{.underline}
>
> [DR. KONSTAM: I understand.]{.underline}
>
> [DR. LONG: Here is a summary of the neurologic events just for frame
> of reference.]{.underline}
>
> [\[Slide.\]]{.underline}
>
> [Eleven strokes, 10 in the LVAD area. Two of those were, as I
> indicated, air emboli, two to intracranial hemorrhage, and two
> presumably due to thromboembolic events, six of those in the LVAD arm,
> and that is by way of frame of reference, relative comparison to the
> VE bridge to transplant experience, which you see in the bottom, 0.45
> events per year in the REMATCH group versus 0.51 events per year in
> the VE bridge, so actually a lower incidence.]{.underline}
>
> [DR. KONSTAM: I accept that. I am just making note of the fact that
> there are strokes, that there are events that seem to be
> thromboembolic strokes, that is far from a zero rate. It\'s a
> significant difference between the two treatment groups in this
> regard.]{.underline}
>
> [There are other events that are TIAs that I think many of which are
> likely to have been thromboembolic. So, I think it is worth noting
> this because I think if that is the case, and if some of the patients
> are really\--if this is a cause of morbidity and perhaps mortality
> that is contributing to the overall problem, well, then you have to
> think about that, and perhaps even rethink the whole anticoagulation
> question in some regard, you know, whether it be antiplatelet or
> whether it be warfarin anticoagulation. It is worth rethinking in
> future trials or future experiences.]{.underline}
>
> [I guess that sort of brings me to the other part, is that there seem
> to be some bleeds that occurred, that were not limited to the
> perioperative period, non-intracranial bleeds.]{.underline}
>
> [Do you want to comment on those? What were they and why were patient
> bleeding?]{.underline}
>
> [DR. LONG: The vast amount of the non-neurologic bleeds were
> associated with operations or reoperations for the device
> specifically, but there were bleeding episodes in addition to that,
> that were counted in that, for example, femoral puncture leading to a
> retroperitoneal hemorrhage got included in that as a bleeding
> episode.]{.underline}
>
> [There are a fair number of those, but the vast majority of them are
> perioperative bleeding episodes either at the time of device
> implantation or at the time of device replacement.]{.underline}
>
> [DR. KONSTAM: I couldn\'t tell that from the data because many of them
> were temporally removed from the time of the initial
> implant.]{.underline}
>
> [DR. ROSE: But some of those were device related, though, too, if we
> can get the device slide comparing the VE SNAP to the old
> VE.]{.underline}
>
> [DR. KONSTAM: The overall bleeding rate looks like about 0.15 per 100
> patient days compared to something like 0.01 in the other group. If
> you look at rate after the first 30 days, it is still about 0.12 or
> something per 100 patient days.]{.underline}
>
> [DR. ROSE: One of the mechanisms you see is illustrated in this
> slide.]{.underline}
>
> [\[Slide.\]]{.underline}
>
> [Without strain relief, you essentially have a kink in the graft, and
> you then have friction rubbing against it, so that what can and did
> happen with both this patient population and the bridge patient
> population is we would see delayed bleeding from erosion of the
> outflow graft due to this kind of kinking.]{.underline}
>
> [DR. KONSTAM: I see.]{.underline}
>
> [DR. ROSE: That is what generates this kind of strain.]{.underline}
>
> [DR. KONSTAM: If that is the case, you might be able to see a
> difference in the VE SNAP patients when you analyze them separately. I
> mean that is something that seems like it would be worth looking
> at.]{.underline}
>
> [As I read it, both of those things concern me, the strokes and the
> bleeds, and I think it is worth some detailed analysis, and I also
> think that, again, it is worth rethinking the anticoagulation question
> in my mind in light of those things.]{.underline}
>
> [If you believe that the bleeding problem is solved technically from
> this, and if you know that most of the other bleeds are occurring at
> the time of an operation, then, maybe the patients could benefit from
> some form of anticoagulation to prevent some of the thromboembolic
> events that do seem to be occurring.]{.underline}
>
> [DR. ROSE: That is absolutely fair.]{.underline}
>
> [DR. LASKEY: Marv, excuse me. Just in fairness to process, we are
> going to try and finish.]{.underline}
>
> [DR. KONSTAM: That\'s fine. I am sorry for going on. I will just skip
> some of the other things. The only thing else I would say is that if
> we go forward, if this device is approved for this indication, I guess
> I would like to see a lot more clearly defined for whom is it
> indicated.]{.underline}
>
> [Certainly, the proposed wording by the sponsor\--and we can talk
> about this at more length\--doesn\'t come close to satisfying what I
> would like to see, and certainly doesn\'t recapitulate in any way the
> entry criteria of the study.]{.underline}
>
> [So, particularly in light of the large number of adverse events and
> the fact that at this point in time, very few patients are alive at
> two years, there is going to need to be an awful lot of consideration
> given to exactly who is a candidate for this and make sure that the
> genie doesn\'t get out of the bottle in terms of overusing this
> device.]{.underline}
>
> [Sorry for going on.]{.underline}
>
> [DR. LASKEY: No, no, please don\'t apologize. This is a terribly
> important discussion particularly for the lead reviewers, but I will
> ask subsequent reviewers to just try and limit their time to about 15
> minutes if possible to get through the table. We will have a second
> round.]{.underline}
>
> [Did you have more questions, Mr. Konstam?]{.underline}
>
> [DR. KONSTAM: Nothing worth going on about.]{.underline}
>
> [DR. LASKEY: Well, you never know.]{.underline}
>
> [Dr. Aziz.]{.underline}
>
> [DR. AZIZ: Let me also echo the early statements. I think the
> presentation was extremely well done by Dr. Rose, the company, and I
> think it is a good model to have industry, academia, and the NIH
> involved in helping to answer some important questions.]{.underline}
>
> [I have a lot of questions, but I will try to limit them in the
> interests of time.]{.underline}
>
> [Going through the sites, first of all, the Cleveland Clinic was
> involved and then it withdraw. I wonder if I can ask what the reason
> behind that was.]{.underline}
>
> [DR. ROSE: At the time we began the trial, they began their interest
> in the Batista operation, and accumulated an experience over a couple
> of years of in excess of 50 patients for the Batista.]{.underline}
>
> [I think they viewed us potentially competitive with this protocol and
> withdrew for that reason.]{.underline}
>
> [DR. AZIZ: In Table 4, it says, \"Reasons Patients were not Enrolled,
> 187 patients refused the device.\" This is in your selection criteria.
> Was there any particular sort of events, or were they afraid of an
> operation? It seems a high number of patients refusing such a
> therapy.]{.underline}
>
> [DR. ROSE: You mean from the screening criteria?]{.underline}
>
> [DR. AZIZ: From the screening criteria, yes.]{.underline}
>
> [DR. ROSE: I think based on everything we have shown, it is not
> surprising that there is a considerable degree or range of patient
> responses to the prospect of this kind of therapy. At the other end,
> we saw patients who absolutely wanted the device and others who
> absolutely didn\'t. Certainly, at least willingness to have a device
> insertion was essential for the informed consent process in a patient
> who categorically wouldn\'t want a device, we excluded from the
> trial.]{.underline}
>
> [DR. AZIZ: Going to certain other issues, in the neurological sort of
> events, in one of the tables they mentioned there were two patients
> that had seizures. When I was going through the patients who had
> expired, actually, there were at least sort of four patients who had
> grand mal seizures.]{.underline}
>
> [Were there any indications as to the etiology of that?]{.underline}
>
> [DR. ROSE: They were toxic metabolic-related seizures.]{.underline}
>
> [DR. AZIZ: Because I mean those were four patients that had actually
> died.]{.underline}
>
> [Again, going to the patients who had actually died, I came across at
> least seven patients who, at autopsy, had evidence of thrombosis
> either in the graft or on the valves. Now, that again seems like a
> fairly high incidence. I mean I could understand the value obviously
> of no anticoagulation and having a textured surface, but do you think
> that this is, on the other side of the equation, where not being
> anticoagulated does result in sort of some of these other dramatic
> events?]{.underline}
>
> [DR. ROSE: I don\'t think we can dispute that we don\'t know the
> potential value of anticoagulation in these patients, but
> counterpoised against it also is there is a lot of bleeding morbidity
> in these patients, as well, so what we would rather see is a better
> anticoagulant. I think if we had that, that we wouldn\'t hesitate to
> use it.]{.underline}
>
> [DR. AZIZ: Also going to the sort of patient profile, there were two
> patients that had aortic dissections in the surgical
> group.]{.underline}
>
> [DR. ROSE: Yes.]{.underline}
>
> [DR. AZIZ: I think one of them ended up dying. I think both of them
> actually died.]{.underline}
>
> [DR. ROSE: Yes. That is another late bleeding complication from these
> devices, and there is tension, gravitational force that is delivered
> to the ascending aorta by the outflow graft that I think was an
> under-appreciated potential complication, and the way that outflow
> grafts are sewn to the ascending aorta I think evolved considerably
> during the course of the trial to a much more meticulous technique
> with attempts at strain relief at the aortic anastomosis.]{.underline}
>
> [DR. LONG: Another factor that contributed to that is small patient
> size seemed to be a predisposing factor, small aorta with a fairly
> good-sized graft.]{.underline}
>
> [DR. AZIZ: What was the incidence of hypertension, bad hypertension
> postoperatively in the majority of these patients?]{.underline}
>
> [DR. ROSE: Uncontrollable hypertension was not common, but the need
> for antihypertensive medications in these patients was very
> common.]{.underline}
>
> [DR. AZIZ: Was uniform.]{.underline}
>
> [DR. ROSE: I can\'t say that it is uniform, but I would say it is
> fairly typical of a patient on a VAD that they need a lot of the
> agents, for example, ACE inhibitors and beta blockers they were on
> preoperatively, they go back on them for other reasons.]{.underline}
>
> [DR. AZIZ: Let me move on to certain issues related to device
> dysfunction, either the motor or the valves. The valves are stented
> valves, I presume, or unstented valves, so they are exposed to a very
> high pressure particularly because of the pressure generated in the
> LVAD itself.]{.underline}
>
> [Now, compared to what the bench testing showed, the longevity was I
> think about three and a half, four years, but what we actually see in
> reality clinically, and I am sure there are a number of factors, is
> that it really isn\'t that long.]{.underline}
>
> [What troubles me a little bit is I think this device is clearly good
> as a bridge to transplantation. I think what we are asking of this
> device now is to really function for a much longer period of time with
> the repeated stresses on the valve and other components, and I am not
> completely convinced that something like this could be, let\'s say,
> advocated for a four-year period or a five-year period, the reason
> being I think again the bench testing values defer from what we find
> clinically, and particularly there were some patients where the inflow
> valves I think become dysfunctional fairly quickly.]{.underline}
>
> [How would you address that, because I mean what we are trying to do
> is advocate this as a sort of destination therapy.]{.underline}
>
> [MR. POIRIER: If you look at the valve dysfunction, the primary reason
> for the valve dysfunction was excessive pump chamber pressure, and
> that came about from several factors, one, outflow kinks, patient\'s
> high arterial pressure, any occlusions in the anastomosis, the
> anastomosis to the aorta was done with just a simple slit as opposed
> to removing material, there was a pressure drop across that
> area.]{.underline}
>
> [So, unlike the human body, that has only one pressure drop in the
> ventricle to the aorta, which is the aortic valve, these devices have
> many, many pressure drops, the anastomosis, the size of the graft, the
> outflow valve, any kinking, so there were many factors.]{.underline}
>
> [All of those are additive. The net result is the pump chamber
> pressure has to increase, which puts stress on the valve. We have
> taken great pains at improving that. We put the strain relief bond to
> reduce that pressure drop, we have instructed and written papers on
> patient management in terms of the anastomosis, how the device should
> be installed.]{.underline}
>
> [We have looked at changing, modifying the way the device is
> controlled to reduce the pump chamber pressure, so we have done many,
> many things to try to reduce pump chamber pressure, to increase the
> longevity of the tissue valves.]{.underline}
>
> [I would like to clarify one point. The in-vitro test does not
> evaluate the tissue valves. It is impossible to do a long-term test
> with tissue valves in mock circulatory loop because the valves become
> contaminated and the tissue deteriorates.]{.underline}
>
> [So, the valves are never tested. They are tested separately in a
> separate circulatory loop that can be kept in a sterile environment.
> So, the results of the in-vitro tests do not include the tissue valve
> durability, so there is a difference there.]{.underline}
>
> [I think that should answer some of your questions.]{.underline}
>
> [DR. LONG: A couple of other thoughts from a clinical point of view.
> The inflow valve failure problem with the HeartMate device is
> relatively new within the last couple of years. During its IP era,
> when it was a pneumatic-driven console with lower pressures, there
> were virtually no inflow valve failures.]{.underline}
>
> [It appears that a change in configuration of the inflow conduit to
> reduce bleeding has been associated with an increased risk that
> pressures inside the pump will lead to inflow valve failure. It\'s a
> new phenomenon. It appears to be correctable by the measures that Vic
> is introducing.]{.underline}
>
> [I guess the other issue of relevance is what are the consequences of
> that inflow valve failure. We don\'t have a lot of that, the bulk of
> that data within the REMATCH trial itself per se. From other
> experiences, we know the natural history of inflow valve failure is
> slow failure with patients who progressively increase in their heart
> failure, their pump goes up.]{.underline}
>
> [It may lead to a decrease in longevity of that pump, as it was
> alluded to this morning, but in the vast majority of experience, we do
> not experience catastrophic outcomes with these patients, and they can
> be managed medically over time, observed, and then finally committed
> to pump replacement.]{.underline}
>
> [DR. AZIZ: Obviously, the other issue, which is responsible both from
> morbidity and mortality, is sepsis. I accept that, I think as most of
> us, that that is clearly multifactorial. So, there are two
> questions.]{.underline}
>
> [One, was there a correlation between the albumin or pre-albumin
> levels and the incidence of sepsis?]{.underline}
>
> [DR. ROSE: To show you how ignorant we were of this problem, we
> didn\'t even collect prospectively albumins on the patients when we
> started the trial, obviously, highly relevant data and something we
> are trying to recreate retrospectively, but I think it is clear serum
> albumin is the best single predictor in the VA study of operative
> mortality for all patients having any kind of surgery regardless of
> what the reason was.]{.underline}
>
> [I do think that we paid much too little attention to perioperative
> nutrition in this trial. We had a symposium of investigators to look
> at just this subject shortly before the trial reached its endpoint,
> and I think going forward that nutritional management is going to be
> key in diminishing this frequency of infections.]{.underline}
>
> [DR. AZIZ: The other, which is probably more than a theoretical
> suggestion or it may be an etiological factor is the nature of your
> textured surface.]{.underline}
>
> [I think people from your own institution have very nicely shown that
> the new intima, although it actually may prevent thromboembolic
> events, does cause an elevation of PRAs in a T-cell separation and
> B-cell hyperactivity.]{.underline}
>
> [What role do you think that might have played or do you have any
> evidence that that could have also played a role in the genesis of
> sepsis?]{.underline}
>
> [DR. ROSE: I do believe there is firm evidence that these devices do
> modulate immune function, and, if anything, it seems that they
> up-regulate humoral responses and perhaps down-regulate cellular
> responses.]{.underline}
>
> [I don\'t think that that is unique to the textured surface. When we
> have looked at patients with smooth surface devices, we have seen
> similar perturbations, but I think there is certainly more than the
> possibility that these devices are, in themselves, immunosuppressant,
> and can lead to increased susceptibility to infection aside from the
> issues of access through the transcutaneous ports, and it is a very
> important set of issues for us.]{.underline}
>
> [DR. LONG: This is an extremely important part of the future for the
> field, and if you think about this as an issue-compromising outcome,
> thinking about it in three categories, one is what might the device
> do; two, what does the patient bring to bear, and three, how does
> management affect it, you have already alluded to the possibility that
> the device may play some role in terms of altering an immune system.
> Our general consensus is that that is probably a very low role
> relative to the other two at this point in time.]{.underline}
>
> [Patient factors, we think are substantial, and there is an analysis
> ongoing now trying to look at a subset that might predict risk of
> infection including nutritional factors. These patients in this group
> were absolutely dramatically different than any we had ever faced in
> the bridge to transplant group.]{.underline}
>
> [We thought bridge to transplant patients were sick because they were
> acutely decompensated with balloon pumps, drips and all sorts of other
> things. These patients would walk in, but be terribly cachectic, have
> lost 20, 30, 40 pounds over the last few months, terribly
> malnourished, as you know, from that, and immune
> compromised.]{.underline}
>
> [These are the kinds of patients we were dealing with here, and we
> believe that to be a very significant factor, patient-host issues that
> contributed to our infection rate.]{.underline}
>
> [It goes beyond that, into the third category, though, of management,
> and let me put a slide up.]{.underline}
>
> [\[Slide.\]]{.underline}
>
> [When we looked at a couple of centers that were responsible or that
> took on themselves extremely aggressive infection control efforts,
> which I will try to describe in a minute, we found that infection can
> be controlled, and we think this infers that management played a
> significant role in this process.]{.underline}
>
> [If you look at two centers here that did 16 LVADs relative to 52 for
> the rest, or 24 percent of the total LVADs done, with a median
> duration of use, even greater than the rest of them, so a longer time
> of exposure at which they could be more susceptible to infection, we
> find that in these two centers, we have zero percent of serious
> infection, 0.06 serious drive line or pocket infection, and zero
> serious pump housing inflow or outflow infection relative to the
> others that you see there.]{.underline}
>
> [This is certainly a small and not absolutely demonstrative that
> management does make a difference, but a strong inference that that is
> the case. So, out of the three categories of this very, very important
> topic, device probably plays a small role, patient factors in this
> patient population played an immense role, and management, we think
> plays very strong role, as well, and very significant room for the
> future in both of those latter two categories for
> improvement.]{.underline}
>
> [DR. EWING: Excuse me for a moment. I would like to remind the sponsor
> and the panel members that this is new information to the FDA, we have
> not reviewed this, and we would like to keep in consideration we are
> to be discussing material that is presented in the
> application.]{.underline}
>
> [DR. AZIZ: One other quick question. How many of the patients at two
> years had had the original device? In other words, how many patients
> who went on for a long period of time had had to have the device
> changed or something done technically?]{.underline}
>
> [DR. ROSE: A total of eight pump replacements as far as I know. Also,
> a number of patients who could have had their pumps replaced, who
> opted not to.]{.underline}
>
> [DR. LASKEY: Before we move on, Dr. Rose, your comments remind me of a
> small book I read as a surgical intern, written by Frannie Moore,
> about the metabolic control of the surgical patient, and I think it
> still remains true, perhaps more so.]{.underline}
>
> [It is my understanding that in a randomized trial by the toss of a
> coin, these predisposing factors should certainly sort themselves out
> in either arms, so there is something to be said here.]{.underline}
>
> [Moving on with the other panelists, Dr. Wittes, please.]{.underline}
>
> [DR. WITTES: First of all, I want to echo everybody\'s statement that
> the presentations, both in the panel pack and today, were very clear,
> and it helps us a lot when there is clarity.]{.underline}
>
> [I also want to just point out what a good thing it is that you
> randomized this study, because had you observed 75 percent mortality
> in your treated group, which is what you expected in the control, I
> don\'t think we would be here today.]{.underline}
>
> [I do see three main themes. One, of course, is the mortality, which
> has been already brought up in various ways. The other is the issue of
> device failure. The third is sepsis, which has been brought up, but I
> only have one extra thing to add.]{.underline}
>
> [Obviously the question of this very high mortality rate in the
> control group raises the question of who were these patients, and the
> device appears to have high risk, raising the concern of this device
> in a population of healthier patients.]{.underline}
>
> [I am just stating that, it is not really a question. It\'s a
> statement of concern. My own feeling is that death trumps nearly
> everything, so I am not all that concerned about Quality of Life and
> things like that. This may not go over so well around here, but it
> seems to me that when we have a big effect on mortality, that we have
> to sit up and take notice.]{.underline}
>
> [But I am troubled by the dearth of data at two years. I understand
> what happened, that you powered the study in a way that if you have 92
> deaths, you stop the study at 92 deaths, and because the mortality
> rate was so high, the deaths occurred before two years, so the
> follow-up didn\'t go as long as you planned.]{.underline}
>
> [I am not looking actually for statistical significance at two years,
> I am fine with a log-rank test over the period, but I would actually
> like to see more data at two, and there is 25 percent\--not 25
> percent, more than that\--I looked at the data through February, and
> there is still I think 20 patients in the treated group, in the device
> group, who are still censored, so there is data in the pipeline that
> will speak to two years.]{.underline}
>
> [What are your plans for follow-up of these patients?]{.underline}
>
> [DR. ROSE: Well, the trial is ongoing. We stopped enrollment and we
> reached the primary endpoint, and we did an analysis at the time of
> the enrollment. It is remarkable to me how\--it is not well
> appreciated this is now the largest series of long-term device
> patients ever as far as I know, and I think that there is a lot of
> additional useful information that will come to us.]{.underline}
>
> [We are funded by the NIH to continue to follow these patients, and we
> intend to follow them all for the duration of their lives. That is our
> intent, and we intend to keep reporting that as time
> passes.]{.underline}
>
> [DR. WITTES: The other thing, I just want to make a note about
> log-rank. I am very uncomfortable with the language about the log-rank
> being the area under the curve measure, because it is really not, and
> I think that it gives a very\--I mean the log-rank tests looks at data
> at the time of deaths, and it is not integrating area at all, and I
> just want to make sure that that is not the statement that you made,
> because it gives a very different picture.]{.underline}
>
> [DR. ROSE: What was the statement I made?]{.underline}
>
> [DR. WITTES: Well, I don\'t know who made it.]{.underline}
>
> [DR. ROSE: It probably was me.]{.underline}
>
> [DR. WITTES: I heard it several times. The first time I didn\'t pay
> any attention to it, but it came up a second time.]{.underline}
>
> [A question about sepsis. I may have misinterpreted the data in the
> panel pack, but it looked to me as if the number of cases in the two
> groups was the same, but the case fatality rate was higher in the
> device group.]{.underline}
>
> [So, my first question is, is that true, and the second question, if
> so, why?]{.underline}
>
> [DR. ROSE: Do you mean the mortality rate from sepsis?]{.underline}
>
> [DR. WITTES: Yes. If my first statement is correct, and I am not sure
> it is, but it was hard for me to find that, that the rate of sepsis is
> the same in the two groups, and we know that the mortality from
> sepsis, the split was 17-1 in the device versus the control. That
> would imply a higher case fatality rate.]{.underline}
>
> [So, the question is, what is it, why would that have been
> true?]{.underline}
>
> [DR. LONG: The overall sepsis rate, total rate was not different
> between the two groups, but when you look at device-associated sepsis,
> that led to a significant impact on adverse event that exceeded that
> in the medical management arm.]{.underline}
>
> [DR. WITTES: I don\'t think you are answering my question quite. What
> it seems to me it is saying is that somehow the sepsis, if you had
> sepsis in a device, your probability of living through that episode
> was much lower than if you were in medical management and had
> sepsis.]{.underline}
>
> [DR. LONG: That is correct.]{.underline}
>
> [DR. ROSE: The ratio of the incidence of sepsis in the device patients
> compared to OMM was 2. It was double in the device patients compared
> to the controls. I don\'t think that reached statistically
> significance in isolation, but it still was double.]{.underline}
>
> [DR. WITTES: But the death was 17 to 1.]{.underline}
>
> [DR. ROSE: Excuse me?]{.underline}
>
> [DR. WITTES: Wasn\'t it 17 to 1?]{.underline}
>
> [DR. ROSE: As a cause of death, it was significant.]{.underline}
>
> [DR. WITTES: Well, let me ask in a different way.]{.underline}
>
> [DR. ROSE: This is hot off the presses March 1st.]{.underline}
>
> [DR. WITTES: What?]{.underline}
>
> [DR. ROSE: This is March 1, 2002, data, so that difference was
> significant.]{.underline}
>
> [DR. WITTES: I am not interested in significance.]{.underline}
>
> [DR. ROSE: But another reason for that, though, the medically managed
> patients died from heart failure.]{.underline}
>
> [DR. WITTES: But the ones in medical management who got sepsis didn\'t
> seem to die of sepsis, is that right?]{.underline}
>
> [DR. ROSE: It may not have been the exact proximate cause of their
> death.]{.underline}
>
> [DR. LONG: One patient died of sepsis.]{.underline}
>
> [DR. ROSE: That was ascribed to sepsis.]{.underline}
>
> [DR. LASKEY: Are these not all adjudicated by the DSMB in terms of the
> cause of death?]{.underline}
>
> [DR. ROSE: By the M&M Committee, yes.]{.underline}
>
> [You are correct, there is one death attributed to sepsis. Whether
> that means that sepsis is worse in the device patients or heart
> failure is worse in the OMM patients and supersedes it, I don\'t
> know.]{.underline}
>
> [DR. LONG: Your observation is correct, that there are more deaths due
> to sepsis in the device group than there are in the medical management
> group.]{.underline}
>
> [DR. WITTES: Let me say it once more, though, because that is clear,
> but the other issue is, if the data as reported are correct, and I
> realize that you could have differential reporting in the
> classification, and so forth, then, it seems to say that if you are in
> a septic episode and you have the device, you are at much higher risk
> for death than if you have a septic episode and you are on medical
> management.]{.underline}
>
> [The relevance to me, and I obviously defer to all of you guys, is
> that that seems like it\'s a very high risk and maybe some of the
> discussion that came up before in terms of management of these
> episodes needs to be addressed.]{.underline}
>
> [DR. ROSE: I don\'t think it is surprising that sepsis in the presence
> of a large intravascular foreign body results in a higher mortality
> rate than in the other patients. I think that is part of the risk
> profile.]{.underline}
>
> [DR. LONG: Plus some of the patients who did get infected, LVADs
> underwent replacement in the face of sepsis and replacement, ended up
> with mortality. So, yes, we concur entirely with you.]{.underline}
>
> [This is an area of extreme concern for the field, as I discussed
> earlier, out of the three things that you look at in terms of
> etiology, device patient issues and management issues, we consider the
> latter two to be very substantial areas for targeting
> improvement.]{.underline}
>
> [DR. WITTES: The other issue has to do with patient reported outcomes.
> I guess I have to confess I find them questionable in an open trial
> especially with huge differential mortality in the two
> groups.]{.underline}
>
> [I am comforted by the people who go from Class IV to Class I and II,
> but other than that, I think it is really hard to tease out what these
> mean.]{.underline}
>
> [DR. LASKEY: Dr. Domanski.]{.underline}
>
> [DR. DOMANSKI: I would kind of like to back off a little bit to a big
> picture and make sure that I really understand fully. I think, first
> of all, on the Quality of Life data, I guess I am taken with the
> fact\--I am sort of coming backwards to things that I think are more
> important\--but I think the small numbers, the unblinded nature of the
> trial, and so the potential for investigator bias, the potential for
> placebo effect, the small numbers, from my standpoint, make the
> Quality of Life data far less than compelling.]{.underline}
>
> [I share for different reasons Dr. Wittes\'s lack of interest in it
> actually, because I don\'t think it is terribly useful, but I may be
> wrong, and I am willing to accept an argument relative to
> that.]{.underline}
>
> [But I would like to come back to the mortality and also to the
> serious adverse events. It seems to me that if you look at death,
> there is a difference, certainly at one year. If you look at death
> plus serious adverse events as they have been defined, there is no
> difference, but I guess some of the serious adverse events strike me
> as not all that tremendously serious.]{.underline}
>
> [I mean extending hospital stay a bit is unfortunate, but I think that
> is one of them, and I guess that is not something that you live with
> long term even being rehospitalized, while it is a significant event,
> is not I think on a par with, for instance, a cerebrovascular
> accident.]{.underline}
>
> [While I don\'t think, in fact, I know these data weren\'t tabulated
> in this way. I guess things that do strike me as being irreparably
> serious adverse events are things like cerebrovascular
> accident.]{.underline}
>
> [So, if one were to look at death plus cerebrovascular accident, I
> wonder if you have a back-up slide that actually looks at that. If you
> don\'t with Kaplan-Meier, can we at least add them up and see what the
> difference is between the two groups, because that is in the
> submission, it is just not parsed that way.]{.underline}
>
> [I think if there weren\'t a difference, then, I start to wonder. So,
> that is Question 1 and I have a follow-up.]{.underline}
>
> [DR. ROSE: We don\'t have such a slide.]{.underline}
>
> [DR. DOMANSKI: Is it easy to add up? I know you can\'t get the
> Kaplan-Meier stuff this easily, but a reasonable approximation to it
> would be to look at one year at your deaths plus cerebrovascular
> accident rate. Do you have that for the two groups?]{.underline}
>
> [DR. ROSE: We have the raw data. Whether or not we can create freedom
> from death plus CVA at one time\--]{.underline}
>
> [DR. DOMANSKI: Because that is something I would really like to
> see.]{.underline}
>
> [DR. LASKEY: You mean death or.]{.underline}
>
> [DR. DOMANSKI: That\'s correct. That is what I mean by death plus CVA,
> that is what I mean, death or cerebrovascular accident. I am just
> curious because it seems to me that those are the two\--]{.underline}
>
> [DR. ROSE: I assume you mean cerebrovascular accident also
> with\--]{.underline}
>
> [DR. DOMANSKI: With a bleed, with an ischemic stroke.]{.underline}
>
> [DR. ROSE: With a permanent deficit.]{.underline}
>
> [DR. DOMANSKI: That\'s correct, or with a deficit that lasts beyond 24
> hours. I will spot you even the TIAs. I will even spot you the
> seizures. The reason I am so curious about it is that one is talking
> about, you know, if one asks whether something should be approved for
> use, one can reasonably ask whether it is demonstrated to be
> clinically very useful, and what you are talking about is taking
> people who are more or less at the end of their lives and saying maybe
> if I give you this device, I will give you a big operation, I will
> give you a big, expensive device, and I buy you a year of something,
> and it is not entirely clear to me what you have bought, all right, so
> there are a fewer of them dead at one year, but I wonder.]{.underline}
>
> [You know, if there were no difference between death or CVA, even at
> one year, then, I guess I would wonder what you have done. I still
> wonder a little what we have done doing it for one year, but that is
> the pith of the question.]{.underline}
>
> [DR. ROSE: I think it\'s an excellent question. It is something we are
> going to try to tabulate during the time that we are here. I want to
> make the point, though, with regard to the analysis of AE\'s of the
> two groups, that part of the design and reporting spotted the OMM
> group, worsening heart failure, as an AE. That was not considered to
> be an AE in the control group, had hospitalizations for it, you know,
> getting short of breath, need to be intubated, having to be
> hospitalized again, I think is a considerable adverse event when you
> have severe heart failure that was not totalled in the OMM group as
> adverse events.]{.underline}
>
> [If we were to do a fair comparison, we need to count everything from
> a patient perspective as an adverse event, not\--]{.underline}
>
> [DR. DOMANSKI: Why didn\'t you then?]{.underline}
>
> [DR. ROSE: Excuse me?]{.underline}
>
> [DR. DOMANSKI: So, why didn\'t you count it?]{.underline}
>
> [DR. ROSE: The sense was that this was tautologic, we knew that these
> patients had heart failure and they were going to die from it, so that
> the fact that they had exacerbations even of their severe heart
> failure was something that there was not much\--in retrospect, I wish
> we had.]{.underline}
>
> [DR. DOMANSKI: In order for me not to perseverate and hold the
> committee up, I would just like to, you know, again, just back off. I
> would like to see that tabulation, and I see the folks doing it over
> there, and I think the challenge that I would offer to the group that
> has to sit here and decide whether to approve it is whether or not one
> has done a clinically significant deed with this.]{.underline}
>
> [I have some concern about it even if the tabulation is in favor of
> the device. Certainly, if it\'s not, my concern would be raised. I
> think with that, I would pass it to the next person just while they
> are going ahead with that.]{.underline}
>
> [DR. LASKEY: Dr. Comerota.]{.underline}
>
> [DR. COMEROTA: Thank you. Also, I would like to extend my compliments
> to all the presenters for an excellent job. Many of my questions have
> already been addressed, so I will funnel them down to a couple
> comments and perhaps a couple questions.]{.underline}
>
> [Eric, in the manuscript, I think it was stated that there was no
> significant learning curve to this or that was a non-issue, but then
> also it was stated or the observation presented that in the patients
> enrolled in the last year, there was a 25 percent decline in mortality
> relative risk per year when survival was adjusted for date of
> entry.]{.underline}
>
> [Are those contradictory statements, so is there truly a learning
> curve or perhaps is there a change in patient care that resulted in
> this observation?]{.underline}
>
> [DR. ROSE: I do believe that there is a learning curve. I don\'t think
> REMATCH is a large enough trial powered to assess it. It was that
> difference of survival, adding a year to the date of enrollment we
> found did occur was not statistically significant.]{.underline}
>
> [When we tried to remeasure it again, it still does not reach
> statistical significance, but I think for anyone who gets involved in
> this field and starts doing it, the collective wisdom of the
> investigators I think is increased considerably during the course of
> this trial.]{.underline}
>
> [Also, I want to point out that before this, there was no experience
> of any large number with destination therapy. PREMATCH was a total of
> 21 patients. That was essentially the American experience, and it was
> only 11 patients that got devices, so the entire American surgical
> experience with destination therapy is now 79 patients.]{.underline}
>
> [I do think that there is a lot more to be learned at this
> point.]{.underline}
>
> [DR. LONG: Also, this is the first trial ever to look at a patient
> population of this age, which gives us a new learning insight, as
> well.]{.underline}
>
> [DR. COMEROTA: Correct, and that age issue obviously is unique to this
> trial.]{.underline}
>
> [DR. ROSE: Encouragingly, in patients that were younger than 60 years
> old in this trial, the one-year survival was 74 percent, which
> approaches outcomes at least at one year for the process of
> transplantation.]{.underline}
>
> [That is not to say that this is up to that, but that observation in
> that subgroup is a very encouraging observation.]{.underline}
>
> [DR. COMEROTA: That is a good segue to my next question. It was stated
> this morning that the mean time in your bridge to transplant group was
> about 29 days.]{.underline}
>
> [DR. ROSE: Right.]{.underline}
>
> [DR. COMEROTA: In those patients in the bridge to transplant group
> that exceeded the 29 days, that may have gone out to two months, have
> you looked at the survival curve in those patients and compared them
> to the survival curve in the REMATCH patients?]{.underline}
>
> [DR. ROSE: Meaning bridge to transplant patients with a longer
> hospital stay than\--]{.underline}
>
> [DR. COMEROTA: Well, the bridge to transplant patients that had their
> heart transplants delayed, so had the device implanted for a much
> longer period of time, and how did those early curves fit with the
> early curves for a similar time frame in the patients in the REMATCH
> study who were randomized to the device?]{.underline}
>
> [DR. EWING: I was just going to say that he could answer, I would
> recommend that he could answer the question, but you need to remember
> that we have not read the transplant the data. So, we can\'t tell you
> our opinion on that data.]{.underline}
>
> [DR. COMEROTA: Perhaps it is not an appropriate question for the
> purpose of the deliberation of this panel.]{.underline}
>
> [DR. ROSE: We have published on the subject of the long-term results
> of bridge to transplant patients, and there is an incidence of adverse
> events that I think is analogous to what we saw in the REMATCH
> data.]{.underline}
>
> [With regard to N\'s, though, that are out more than a year as a
> bridge, that N is pretty small as I remember.]{.underline}
>
> [\[Slide.\]]{.underline}
>
> [DR. ROSE: There it is. It is 104 patients.]{.underline}
>
> [DR. LASKEY: It is of interest, but not germane.]{.underline}
>
> [DR. COMEROTA: I would just echo my concern as to who this is
> indicated for. That question was raised, so obviously, it need not be
> addressed.]{.underline}
>
> [The concern in terms of the potential patient bias and the Quality of
> Life was also raised, and I think there is an enormous potential bias
> because those patients who were randomized to the device are going to
> get a great deal more attention than those that are randomized to
> ongoing medical care, feel, well, perhaps I am abandoned and I don\'t
> want to live like this, so I will just die.]{.underline}
>
> [Well, obviously, that bias is there, and my final comment was since
> most\--this is infection related\--since most of the infections were
> in the drive line tract, are there any specific recommendations coming
> from the manufacturers regarding how to manage this drive line
> infection?]{.underline}
>
> [DR. LONG: There are several issues that are very critical. The drive
> line does play an important part of that. One is the location of the
> drive line as it exits allowing for immobilization at the exit
> site.]{.underline}
>
> [One of the keys to success when we have looked at subsets within the
> REMATCH group, and again this is outside the data you have access to,
> but it will answer your question, is those who paid a great deal of
> attention to immobilization and proper exteriorization of the drive
> line had a very much lower rate of infection.]{.underline}
>
> [We also believe that the stiffness of the percutaneous lead has been
> a factor, and that is being addressed with a lead that is now being
> introduced that is more flexible and less prone to trauma at the exit
> site itself.]{.underline}
>
> [There are also measures being looked at in terms of antimicrobial
> impregnation. So, this is an area clearly that is very, very important
> for the future, that has to be considered strongly when you look at
> attempts to correct infection in this patient population.]{.underline}
>
> [DR. STEVENSON: If I can just interject, with regard to the issue
> about attention, we agree completely that we cannot eliminate the
> patient bias in terms of how they feel about having a device or
> not.]{.underline}
>
> [On the other hand, we controlled what we could, the frequency of
> clinic visits, the frequency of telephone contact was virtually
> exactly the same per patient month of follow-up in the two groups. We
> were very careful to try to achieve that.]{.underline}
>
> [DR. HEITJAN: I am Daniel Heitjan, the REMATCH statistician from
> Columbia University. I have no financial interest in Thoratec although
> they are paying my expenses to attend the meeting.]{.underline}
>
> [Dr. Domanski had a question about the stroke and death. Everyone who
> had a stroke died, so if you consider stroke or death an event, it
> doesn\'t change the event rates compared to the death rate. So, the
> death fractions are exactly the same.]{.underline}
>
> [DR. DOMANSKI: So, you had no non-fatal strokes.]{.underline}
>
> [DR. HEITJAN: I believe that is not the case, but they all eventually
> died. Some of them died from other causes, they may have died from
> sepsis or heart failure]{.underline}
>
> [DR. DOMANSKI: That is interesting. Okay. Got it.]{.underline}
>
> [DR. LASKEY: I mean we have to live by what they are adjudicated as.
> Isn\'t that the key question here, you had an independent committee
> that assessed etiology and causation, and so forth, so if I understand
> you correctly, every stroke was fatal\--]{.underline}
>
> [DR. HEITJAN: No. I believe the question was, Dr. Domanski\'s question
> was instead of considering an event death, let\'s say death or stroke
> as an event, does that change the picture at all, and the fact is that
> everyone who had a stroke in either arm died, although they didn\'t
> necessary die of stroke, they may have died of sepsis or other
> causes.]{.underline}
>
> [DR. DOMANSKI: Yes, but it might well change the time to event
> analyses.]{.underline}
>
> [DR. HEITJAN: That is correct. I have never computer the Kaplan-Meier
> curve death or stroke, and I don\'t think TCI or Thoratec has done
> that either. In principle, it could change it.]{.underline}
>
> [DR. DOMANSKI: What I was trying to get at with that question is I
> don\'t buy into the Quality of Life data in this study. Frankly, I
> don\'t think it is useful. But I also don\'t buy into the death plus
> serious adverse event rate as it is defined. I think that attacks the
> machine inappropriately because I don\'t think some of the serious
> adverse events are so serious.]{.underline}
>
> [So, what I was trying to do is pick out something that I knew was
> serious and look at it at that point, and I guess you have answered
> the question. The bottom line is that if we approve this device, and
> you can go to somebody and say at one year, if you are willing to pay
> for this, I can buy you less death at one year.]{.underline}
>
> [I don\'t think you can say that for any other time. I don\'t think
> you can say that for two years really, I don\'t think, but certainly
> at one year you can.]{.underline}
>
> [DR. KONSTAM: He hasn\'t really said that, because he hasn\'t told you
> when they died.]{.underline}
>
> [DR. LASKEY: We are getting out of sequence here, so we will have a
> chance to reapproach this again after everyone has had their first
> round. I think this is very, very fruitful, but we need to at least
> complete round one.]{.underline}
>
> [Have you at least delivered the totality\--]{.underline}
>
> [DR. HEITJAN: Yes.]{.underline}
>
> [DR. LASKEY: Thank you.]{.underline}
>
> [DR. COMEROTA: I have finished my comments, thank you.]{.underline}
>
> [DR. LASKEY: Dr. Nissen.]{.underline}
>
> [DR. NISSEN: I will try to keep us on time.]{.underline}
>
> [DR. LASKEY: Well, after you, we will take a break.]{.underline}
>
> [DR. NISSEN: Lynne, you characterized the medical treatment of these
> patients very well, but there is one thing I didn\'t see, and I may
> just have missed it in here, but AICD use. I would like to know about
> AICD use in this trial. What can you tell me about that?]{.underline}
>
> [DR. STEVENSON: If you want to wait a couple minutes, I can give you
> slightly more thorough, but as I recall, there were 15 ICDs in the
> medical management arm at the time of randomization. There were
> several put in after that. I would have to look up the
> data.]{.underline}
>
> [Of interest, though, I think we have got to get back to how sick this
> population is. In fact, five of the people who had ICDs and requested
> that they be turned off, so they would be allowed to die without any
> further ICD firings. So, I think this is not a population in which
> sudden death, in fact, is our major concern. We are more concerned
> with kind of the slow, miserable dying from heart
> failure.]{.underline}
>
> [DR. NISSEN: Let me just take issue with you on that. During the
> course of this trial, there was a lot of evolution of data on the
> benefits of implantable defibrillators, and remember now we are
> talking about very small numbers. We had seven patients alive at the
> end of two years in the LVAD group, and we had three patients alive in
> the medical group.]{.underline}
>
> [All it would have taken was survival of four additional patients in
> the medical group to have equalized the actual two-year mortality. I
> would argue that 15 patients, only 15 patients in implantable
> defibrillators represents a shockingly under-utilization of a therapy
> that has been shown to prolong life in these patients.]{.underline}
>
> [DR. STEVENSON: I actually have the correct number here. Fifteen had
> it at baseline, an additional 10 had it inserted, so that would be 25
> patients in that arm.]{.underline}
>
> [DR. NISSEN: It\'s a little closer.]{.underline}
>
> [DR. STEVENSON: Again, I would emphasize that none of the ICD trials
> have addressed Class IV heart failure at all. They have been
> specifically excluded from every ICD trial done. So, we, in fact, have
> no data that ICD would prolong survival in Class IV heart failure, and
> certainly even less concept that it would prolong meaningful survival
> in Class IV heart failure.]{.underline}
>
> [DR. NISSEN: Let me move on for the moment, but I do think that
> currently, patients with low ejection fractions are getting a lot of
> ICDs put in. Wouldn\'t you agree that today, more of these patients
> would arrive into the trial with an ICD in place?]{.underline}
>
> [DR. STEVENSON: They would arrive into it, but wouldn\'t necessarily
> get it if they didn\'t arrive with one.]{.underline}
>
> [DR. NISSEN: But I am just saying it is a low utilization for this
> type of population by contemporary standards.]{.underline}
>
> [DR. STEVENSON: I don\'t know. In fact, the patients referred to us
> for transplantation, approximately 15 to 20 percent have ICDs in,
> which would be very comparable with what you see here.]{.underline}
>
> [DR. NISSEN: I am also interested in understanding how New York Heart
> Association classification was determined and who assessed it. Let me
> tell you why I want to try to understand this. There is a divergence
> in the data with the best data being the NYHA classification for the
> device.]{.underline}
>
> [So, in the medical patients and in the surgical patients, who
> determine what their New York Heart Association classification was,
> how was that done?]{.underline}
>
> [DR. STEVENSON: At baseline, that was done by the cardiologists at the
> time of enrollment, and certainly I think all the baseline
> qualifications indicate that Class IV was appropriate at
> baseline.]{.underline}
>
> [DR. NISSEN: No, no, no, I am talking about during the course of the
> trial. There was an improvement in classification in the group that
> got the LVAD, and what I want to know is how was NYHA classification
> determined during the course of the trial.]{.underline}
>
> [MS. TIERNEY: I am Anita Tierney from the Data Coordinating Center. I
> have no conflict of interest with Thoratec.]{.underline}
>
> [We credentialed both the surgeons and the cardiologists at the
> beginning of the trial. The patients were seen on follow-up generally
> by both the surgeon and the cardiologist. It was one of the two who
> determined the Class IV heart failure or the class of heart failure
> during the duration of the trial.]{.underline}
>
> [DR. NISSEN: You understand why I am asking the question, and that is,
> that if I am a surgeon and I put an LVAD in a patient, and I am asked
> to assess whether their NYHA classification has improved, my answer
> may be very different from\--I mean I think I would have been much
> more comforted if you told me you had an independent person not
> involved in the trial, and I think it is how you should have done the
> trial, is someone not involved in the direct care of the patient
> should have interviewed them about their symptoms and determined their
> classification.]{.underline}
>
> [So, to me, this process really doesn\'t validate that aspect of the
> results.]{.underline}
>
> [DR. ROSE: But the Quality of Life aside from NYHA classification,
> which was not made by the patient, but is done by the clinician seeing
> them or the nurse clinician seeing the patient, the Quality of Life
> questionnaires themselves were not administered by the investigators
> themselves.]{.underline}
>
> [DR. NISSEN: No, but you see the data there is very limited and much
> weaker. The strongest data you presented on Quality of Life was New
> York Heart Association classification, and when I saw that, and I saw
> this big divergence between the Quality of Life questionnaires and the
> 6-minute walk, and all the things that might be quasi-objective, I
> said to myself I wonder if the surgeons weren\'t determining the
> Quality of Life, you know, the NYHA classification for surgical
> patients, and the medical people determining of medical patients, and
> didn\'t that, in fact, bias the assessment. So far, nothing is
> addressed.]{.underline}
>
> [DR. ROSE: Your point is well taken, and it very well may
> have.]{.underline}
>
> [DR. NISSEN: I think we really have to not consider that data to be
> valid for purposes of this study.]{.underline}
>
> [I guess the other question I had was, were any patients deemed
> Functional Class I if they were in the hospital, could you be
> Functional Class I and be hospitalized?]{.underline}
>
> [DR. ROSE: I would think not, but I don\'t feel like I can assert for
> sure.]{.underline}
>
> [DR. NISSEN: I guess at some point, if there is an answer to that, I
> would like to know that.]{.underline}
>
> [DR. PINA: You can have an infection and still be a Class I, you can
> still walk around and have an infection.]{.underline}
>
> [DR. NISSEN: Again, I think it would be just helpful to me to
> understand that.]{.underline}
>
> [The final question that I had was what was the mean time to internal
> device failure and what was the mean time to any device failure for
> this device in this trial. I saw the 3.4-year figure, but I would like
> to know what the mean time to internal device failure was for the use
> of the device in this trial.]{.underline}
>
> [DR. ROSE: Well, something is still changing because there are devices
> in place.]{.underline}
>
> [DR. NISSEN: Yes, but I mean all the other data you have given us,
> have given us as of a specific time.]{.underline}
>
> [MR. POIRIER: We have not calculated that.]{.underline}
>
> [DR. NISSEN: If it would be possible to determine that, it seems to me
> it would be useful to know, because if we are going to label the
> device, I mean if you are going to use a device, say, for an
> indication for a two-year period of time, it would be nice to know
> what the actual mean time to device failure is in actual clinical use
> as opposed to the data we heard from bench lab testing.]{.underline}
>
> [I mean you have that data now for a significant number of
> patients.]{.underline}
>
> [MR. POIRIER: We are going to try to do that calculation at
> break.]{.underline}
>
> [DR. LASKEY: Your timing is propitious.]{.underline}
>
> [I would suggest we break. I have 2:30. May we reconvene at 2:45.
> Thank you.]{.underline}
>
> [\[Break.\]]{.underline}
>
> [DR. LASKEY: Congratulations to all for keeping us on
> schedule.]{.underline}
>
> [We would like to continue on with Dr. Pina.]{.underline}
>
> [DR. PINA: I add my congratulations since I know how very difficult
> this is to do, and I think that for once we have data on probably the
> sickest group of heart failure patients that have ever been looked at
> or studied. I am amazed, as many of you are, at the incredible
> mortality rate of this population.]{.underline}
>
> [A lot of my questions have already sort of been answered, but I want
> to come back to the Quality of Life for a few minutes. Another recent
> trial of a lot less sick group of heart failure patients has equated
> their lack of worsening of Quality of Life, and there is a difference
> obviously between improvement in Quality of Life and lack of worsening
> to being out of the hospital.]{.underline}
>
> [So, my question is, in the patients whose Quality of Life was able to
> be assessed at multiple times, were those most likely to be the
> patients who were out of the hospital when those Quality of Life
> assessments were done?]{.underline}
>
> [DR. ROSE: The completeness of the patients surveyed Quality of Life
> data actually was much greater in the VAD patients compared to the
> OMM, and they also were the ones that spent more time in the hospital,
> so I don\'t think it is the issue of whether or not you are
> hospitalized that determines whether or not we had completeness of
> data.]{.underline}
>
> [We do have some data as to the reasons that we didn\'t have responses
> to the Quality of Life data. Those we have in a back-up slide, and we
> can show. Before, as they bring up the slide, most of that data that
> is missing is in the OMM group, and a typical reason was that they
> were too sick to want to respond to the questionnaire or to come in
> for a visit.]{.underline}
>
> [DR. PINA: You also wonder how much the depression of not having been
> chosen to get the device counted in it, because I also noticed that
> there were 12 patients who withdrew care in the medical treatment
> group or asked for withdrawal of care, and at least five of those were
> within 30 days of randomization, so you wonder how much the Beck would
> pick up the depression of not being chosen since I think there is the
> perception from patients that you are doing something to them rather
> than just sticking in an IV and sending them home.]{.underline}
>
> [DR. ROSE: I don\'t know if we have Beck data at 30 days, do we? I
> think the earliest that we had the follow-up was at three months, but
> your point is very well taken. I think there was in some patients a
> sense of letdown, but I would say also in some, there was probably a
> sense of relief.]{.underline}
>
> [DR. PINA: It depends upon how you look at it.]{.underline}
>
> [DR. ROSE: That\'s right, and patients have a range of subjective
> views, you know, going forward. Some are going to want to do this, and
> some are not, and the way it is perceived is either as a victory or a
> loss.]{.underline}
>
> [There is some element we found of cognitive dissonance in patients,
> you know, who would I got randomized to the better limb. That was
> their own perception. That was keeping them going with the sense that
> the process worked for me, and I got the better limb, and that could
> be either.]{.underline}
>
> [DR. PINA: Just in concept.]{.underline}
>
> [DR. ROSE: Yes.]{.underline}
>
> [DR. PINA: My other question relates to the implant element
> replacement of which there was really one patient alive, so it seems
> that that complication of the device failure seems to be the
> greatest.]{.underline}
>
> [How many of those were in the SNAP version versus the previous
> version?]{.underline}
>
> [\[Slide.\]]{.underline}
>
> [DR. ROSE: Apparently, there is 30-day data on Beck
> depression.]{.underline}
>
> [DR. STEVENSON: \[Off mike.\]]{.underline}
>
> [DR. EWING: I am sorry. Could you repeat that into the mike, so we can
> get it into the transcription.]{.underline}
>
> [DR. STEVENSON: Looking at the one-month score, in fact, the OMM arm
> was less depressed at one month than baseline, which suggests that the
> randomization outcome did not significantly increase their
> depression.]{.underline}
>
> [DR. ROSE: Going from 16 to 13 on the Beck compared to 16 to
> 10.]{.underline}
>
> [DR. PINA: It\'s a small change on the Beck, but
> nonetheless.]{.underline}
>
> [Do you have that data about the SNAP, how many of the device
> failures, the implant element failures were?]{.underline}
>
> [DR. ROSE: I don\'t believe we have that data immediately at hand, if
> it\'s obtainable. I think your point, though, about reoperation
> regardless of whether it was the VE SNAP or the other device is a
> highly risky procedure at this point, but again, the world experience
> now is 8 in REMATCH plus a small N, as well, in the bridge to
> transplant experience, it\'s a major reoperation.]{.underline}
>
> [DR. LONG: And that is an area that is subject to evolution in the
> management of that. While there were 7 out of 8 in the REMATCH trial
> that died with device replacement, there has been experience outside
> that now that suggests by doing it entirely extra-thoracic approach to
> device replacement, not doing a median sternotomy, you can see much
> better results. In fact, in one series, 6 out of 6 patients survived
> to do well with hospitalizations half of the length of their initial
> implant experience.]{.underline}
>
> [DR. PINA: I think two items that I know that we don\'t have the data
> for the submission, but the issue of malnutrition in this population,
> being unable to handle another invasive procedure added to whatever
> the immune response is.]{.underline}
>
> [I wonder if you looked at the women separate from the men, did the
> women have more septic complications? You have a very small number of
> women. My sense is that the women\'s immune response is very different
> particularly if they have had children.]{.underline}
>
> [DR. ROSE: We are in the midst of a multivariate analysis of all of
> the potential demographic factors, procedural factors, process issues
> for death and adverse events. My suspicion is that few of them will
> shake out as significant determinants just simply because the N is too
> small to make that judgment.]{.underline}
>
> [DR. PINA: That would be an interesting point to look at.]{.underline}
>
> [DR. ROSE: We are in the midst of the analysis. We do not have that
> data here.]{.underline}
>
> [DR. OSSORIO: First of all, I would also like to add my
> congratulations to those who sponsored and conducted this trial. It is
> really clear that you are certainly adding to the knowledge base that
> we have in this very important and under-studied area.]{.underline}
>
> [My first question has to do with DNR orders, particularly in the
> Medical Management population. It seems to me in looking through the
> case reports that a number of those people had DNRs, and that could
> certainly influence the time to death in the sense that those people,
> on their first event in which they had a DNR, and since most of them
> died of heart failure, this is going to influence the
> results.]{.underline}
>
> [So, I am wondering how many of those people had DNRs and in how many
> of the instances that was really relevant and how many of the people
> with the device had DNRs.]{.underline}
>
> [DR. STEVENSON: In terms of the medical arm, there were five patients
> during the index hospitalization who had DNR at some time during that
> hospitalization. I don\'t remember exactly, I believe two or three of
> them died, the other two went on to hospice, but this, in fact, is I
> think indicative of the overall feeling of patients with heart
> failure, which is that frequently, at some point, during a
> hospitalization, they decide there are certain things they don\'t want
> done again, whether that is intubation or defibrillation.]{.underline}
>
> [In many instances, however, DNR doesn\'t necessarily mean do not
> treat, it just means they don\'t want to be resuscitated, and the
> efficacy of resuscitation in this group when something happens in
> hospital, is in general the outcome is pretty poor.]{.underline}
>
> [DR. OSSORIO: I think that is right, but I think that could just add
> to a particular bias, which is that for those patients who are on
> medical management, they are not perhaps so interesting to medical
> staff, and there already is I think good evidence to suggest that
> resuscitation is not very effective in these patients, and physicians
> often just don\'t want to do it, right? So, the effort might be pretty
> slender on those who are just on medical management, whereas, those
> who have the device are much more interesting to the physicians around
> them, and the sort of effort put in to keeping them alive may be much
> greater, and also because the patients on the medical management arm
> were dying particularly of heart failure, where the DNR really is
> relevant as opposed to the ones who are dying of other things, like
> sepsis, where that is a little different issue because it is not a do
> not resuscitate, so that is why I was thinking that could have
> actually contributed to\--I guess I am wondering with respect to
> efficacy, whether the difference in time to death really can be
> attributed to the device as opposed to these other things that might
> be related to have the device in you or not.]{.underline}
>
> [DR. STEVENSON: First of all, it is only 5 of the 61 who requested
> DNR, so it is a small number during that hospitalization. With regard
> to the intensity of their therapy, certainly when a patient finally
> comes to a DNR decision, we begin focusing more on comfort issues than
> a prolongation of life.]{.underline}
>
> [In fact, however, that is what we are treating all the way along are
> comfort issues. With regard to the intensity of therapy in this
> population, I think all of the cardiologists involved felt extremely
> committed to provide the patients who got randomized to medical
> therapy with the optimal medical management that, in fact, we had
> promised them in that arm.]{.underline}
>
> [All I can say is that one has to at some level have some faith in the
> integrity of the investigators.]{.underline}
>
> [DR. OSSORIO: Oh, I am not actually questioning anybody\'s integrity.
> I think it is just a cognitive bias that ends up coming into
> play.]{.underline}
>
> [I would also like to sort of second, I guess, Dr. Domanski\'s
> interest in knowing the time to stroke, as well as the time to death,
> and in part because I do think that to assess efficacy, we have to
> decide, okay, whether the device, if used as intended, really produces
> clinically significant results.]{.underline}
>
> [That must mean something more than just keeping a warm body around,
> and so from my point of view, the Quality of Life measures really have
> a lot to do with understanding whether or not we have achieved
> something clinically significant and the sense of whether those
> adverse events were really\--how many of them were so adverse that
> they could really have quite a negative impact on somebody\'s Quality
> of Life.]{.underline}
>
> [I won\'t belabor the issue of the weakness of the Quality of Life
> data that we have, and I commend you for doing what you did because I
> know it is very hard to do, and there aren\'t baselines aren\'t out
> there, and so forth. I guess for me, I have a hard time really
> assessing whether we have achieved something clinically significant
> without those data.]{.underline}
>
> [That was just a comment.]{.underline}
>
> [Also, this is perhaps also a sort of seconding of something that has
> already been said, is that it seems to me that the indications, if
> this were approved, there would have to be something much more clearly
> stated about the indications for which it would be used and in which
> patients it would be indicated, because it seems that the
> reasonableness of the risks in a situation like this, where you have
> got patients who are very sick, the reasonableness of the risk depends
> on the situation the patient is facing.]{.underline}
>
> [Nobody is going to say that having this implanted in you is not very
> risky because it is. It is just that it may be worth it if your other
> alternative is even a more likely death. But if it were approved with
> very sort of slender guidance as to which patients were appropriate
> for this, it may be used in a much wider variety of patients than it
> was in this trial, people who are much less ill and perhaps have other
> alternatives, or in people for whom the reasonableness of the risks
> might not be as compelling as it might be in a case where somebody has
> no other alternatives.]{.underline}
>
> [Certainly, I would want to see more about that.]{.underline}
>
> [Also, in terms of sort of labeling and guidance, both the physicians
> and patients, I think particularly for patients, the manual was very
> technical for one thing, and it wasn\'t clear to me whether you did
> anything to assess patients\' understanding or whether they even read
> this manual, whether you did anything to assess their understanding of
> that, whether you did anything to assess their understanding of the
> training that they received, and, in particular, with respect I think
> to infection control, that might be very important.]{.underline}
>
> [Did you do anything to assess that?]{.underline}
>
> [DR. ROSE: I think one of the lessons that we learned in PREMATCH is
> that these patients are so sick, that the original Quality of Life
> battery that we had for them, they couldn\'t endure even those levels
> of measurement.]{.underline}
>
> [So, to say that we were in a position to test their cognitive
> function and say how much of the manual did you read and how did you
> score on a test, I hope the investigators would have done better on
> such a test than the patients would have, but it is not something that
> we added as a test to this.]{.underline}
>
> [I don\'t think there is any question that the labeling on this and
> beyond the labeling, the interaction between clinicians and patients,
> it is going to have to happen, and it does happen over this kind of
> therapy, is intense, very individual, and has to happen before a
> decision like this is made. If it is not, I don\'t think that a
> standard of care in general for a terminal patient is being met if
> those types of options are not being discussed.]{.underline}
>
> [Whether or not that is an issue that can be addressed in labeling, I
> personally doubt it. I don\'t think that is going to have the impact.
> I think the major issue is really whether or not the panel has faith
> enough in the community of physicians doing this that this type of
> discussion will indeed happen.]{.underline}
>
> [I am certain that this happens in heart failure programs and in
> transplant programs, which is the kind of group that we had doing this
> kind of study, I think it is reasonable to say, will that continue if
> it becomes more generalized to other types of institutions, for
> bridging, for example, centers had to be trained in the use of the
> device. I think it is perfectly reasonable to say that part of the
> training ought to be a patient education piece around what patients,
> you know, ought to be told in this context.]{.underline}
>
> [I think those are issues for going forward. We don\'t have data on
> the issue of how much they grasp. Unfortunately, I think they are not
> in a position to grasp as much, and there are profound ethical issues
> that that raises in people that are so helpless that often they are
> going by instinct rather than by analysis.]{.underline}
>
> [DR. STEVENSON: I would just like to address briefly your previous
> point, which I think is the most pertinent one in front of us, which
> is who are the best patients to benefit from this therapy, and there
> is no easy answer to this.]{.underline}
>
> [For this trial, in addition to the criteria we had here, which were
> really very general, there were gatekeepers, there were three of us,
> one of whom reviewed every single case and often made recommendations
> for further therapy before randomization, particularly early in the
> trial.]{.underline}
>
> [Our best precedent may be looking at what happened with cardiac
> transplantation. Over the experience, we gradually assembled a set of
> contraindications and indications for cardiac transplantation.
> Regardless of how rigorous these were, however, they really could not
> employed except in the context of people with extensive
> experience.]{.underline}
>
> [I don\'t think one can come up with a labeling set of indications
> that could be delivered divorced from the concept of expertise in the
> clinical hands of the physicians advising the patient. So, this is
> clearly a major issue, there are no easy answers, but we certainly can
> rely on some of the lessons that we learned from
> transplantation.]{.underline}
>
> [DR. OSSORIO: I also had just one other question, which has to do with
> recruitment of people into this study. I noticed that 90 percent of
> the patients in the study were white. It seems to me that if this goes
> out onto the market, well, at the very least we know that there is a
> higher rate of diabetes and serious complications from diabetes in
> people of color, and there may be other reasons why people of color
> are less likely to get transplants in general, at least with
> kidneys.]{.underline}
>
> [So, it may be that there would be a disproportionate number of people
> of color who might actually be at least potential patients for this
> kind of a device supposing they could get it paid for.]{.underline}
>
> [Do you think that there is a problem? Do you think that if is widely
> used among people of color that there would be any
> differences?]{.underline}
>
> [DR. STEVENSON: I think at this point, based on at least in the
> medical management, you know, 61 patients, and 68 in the VAD arm, we
> clearly have tremendous amounts to learn about all the different
> subgroups.]{.underline}
>
> [Minority enrollment in this trial, in fact, is very comparable to
> what happens in most NIH trials in which minorities are
> under-represented, a specific focus of the NHLBI at this point, but we
> all recognize that there is a lot of information that will come in the
> future as well get more experience with this.]{.underline}
>
> [DR. OSSORIO: I am finished.]{.underline}
>
> [DR. DeWEESE: Thank you for the excellent presentation. One quick
> question. Of the patients who did not receive the implant, how many of
> them had DNRs before they had their procedure?]{.underline}
>
> [DR. STEVENSON: That was five during the initial
> hospitalization.]{.underline}
>
> [DR. DeWEESE: No, the five were for those who did not get the
> implant.]{.underline}
>
> [DR. ROSE: I think I misunderstood the question. The people who did
> have the device?]{.underline}
>
> [DR. DeWEESE: Yes. Did any of them have DNRs prior to the
> procedure?]{.underline}
>
> [DR. ROSE: Prior to procedure, I don\'t believe any of them had\--the
> procedure itself in many respects, you could consider a
> resuscitation.]{.underline}
>
> [DR. DeWEESE: That is what I wondered.]{.underline}
>
> [DR. ROSE: But late in the course of the trial, there were patients on
> device with complications that made that conclusion. We certainly were
> committed to them enough to want to resuscitate them, though,
> perioperatively.]{.underline}
>
> [DR. DeWEESE: Infection is a real problem obviously, 17 out of 65,
> about 25 percent. How about in the studies to bridge, how many of
> those developed infections?]{.underline}
>
> [DR. ROSE: Those rates are comparable in the bridging experience with
> this type of implantable VAD.]{.underline}
>
> [DR. DeWEESE: That would argue against what you said, that the cause
> of death might be due to malnutrition.]{.underline}
>
> [DR. ROSE: Well, the rescue from infection in the bridge patients,
> though, is transplantation, where if you can suppress the infection
> and get a donor heart, you can take the infected device out and put a
> biologic replacement in instead, which is a definitive solution in
> general to the problem of infection. That is not an option for
> patients here.]{.underline}
>
> [DR. DeWEESE: Device failure was listed as a cause of death was only
> two patients, I think, or none in one of your slide, two patients in
> Table 14, a summary of the cause of death. There were only two who
> were attributed to device failure?]{.underline}
>
> [DR. ROSE: Two devices which could not generate a cardiac output. That
> was the strict definition of device failure. Can you bring up that
> slide, my causes of death slide?]{.underline}
>
> [\[Slide.\]]{.underline}
>
> [Three deaths in patients perioperatively at the time of device
> replacement for a component failure of the device. For example, if
> these there are a bearing failure and the patient were being pumped
> pneumatically, which this device allows, as opposed to using the
> electric pump, you can see those.]{.underline}
>
> [There were three patients who died at the time of operation or a VAD
> replacement, where using a strict definition of the pump is not
> pumping was not the case because the device in which a component had
> failed was still working well enough to sustain the patient to get to
> the point of being able to replace it in the operating
> room.]{.underline}
>
> [But these are devices in which we knew it did not pump and that the
> pump was explanted and it was found to have failed. That was the
> strictest definition of VAD failure.]{.underline}
>
> [We showed you before there were device malfunctions.]{.underline}
>
> [DR. DeWEESE: I know there were a high percentage of
> that.]{.underline}
>
> [DR. ROSE: One definition, you could say that inflow valve
> insufficiency is device malfunction, that generally allowed time
> enough to replace it. By some constructs, you might say that is a
> device failure because you need to replace the device, but these are
> the malfunctions, 70 were confirmed, as we said, 50 external
> components, 20 internal, the controller most commonly followed by the
> inflow valve.]{.underline}
>
> [Actually, the mechanism of failure in the in-vitro studies was
> something that we saw rarely in the trial.]{.underline}
>
> [DR. DeWEESE: But the cause of death was 6 device failures, is that
> correct?]{.underline}
>
> [DR. ROSE: The nomenclature that the M&M committee has used is root
> cause of death, and, yes, it is more than you two patients, I think
> you could say it is probably in the range of 6 or 7, the root cause of
> death was pump failure and the need to replace it.]{.underline}
>
> [DR. DeWEESE: How about the patient who refused another procedure
> where it had failed? Where was his death put?]{.underline}
>
> [DR. ROSE: How did we adjudicate that? This is a patient who is a
> candidate for device replacement because of an inflow valve, for
> example, failure, and then elects not to have the reoperation. How was
> that death classified? The cause of death would be, what? That is what
> Dr. DeWeese is asking.]{.underline}
>
> [DR. DeWEESE: That\'s all right. There could be an additional. We are
> getting more. How about the patient who went ahead and had the implant
> and died postoperatively within three or four days?]{.underline}
>
> [DR. ROSE: Those are these three here. We are looking to see what that
> death was classified as ultimately. Actually, those may be the LVAD
> dysfunctions. One of these is a pump that is turned off. There are two
> deaths from heart failure in the VAD group, and that is where those
> are.]{.underline}
>
> [DR. DeWEESE: I just wanted to clarify. I had the impression that
> there were none, there are 6 or 7.]{.underline}
>
> [DR. ROSE: Yes, in that range.]{.underline}
>
> [DR. DeWEESE: The other is a question about the air venting. Did that
> cause any infection problems? I know it is not touching the blood, but
> did the passageway for the air venting get infected or
> not?]{.underline}
>
> [DR. ROSE: Well, to know whether or not the channel for infection was
> either through the air vent or around the periphery of the drive line,
> I don\'t know that we could discern. One of the air embolism events,
> though, was in a lining rupture that resulted in air embolization with
> communication with the outside world.]{.underline}
>
> [The hypothetical you raised, that specific patient was classified as
> LAD dysfunction.]{.underline}
>
> [DR. DeWEESE: Thank you.]{.underline}
>
> [DR. KLOCKE: Eric, like everyone else, I recognize this is a landmark
> study, and I do want to express my admiration for the people who
> conducted the study and the way in which it was
> conducted.]{.underline}
>
> [In the discussion, I still find myself most focused on the infection
> issue. I sense and realize that you are also. Frankly, you have
> demonstrated a temporary survival benefit that clearly, by 30 months
> or something, has essentially closed.]{.underline}
>
> [My concern is, I am trying to assess and would appreciate your
> comment on whether the continuing infection is perhaps the dominant
> role in that. That is, you have made so many advances with the pump
> and everything else, but it seems to me that that is perhaps the
> biggest unsolved issue, and that at least gives me the most pause in
> trying to decide how far are we ready to go forward.]{.underline}
>
> [I think the slide you had up there, in the first 40 deaths, there
> were 17. That is 40 percent, and actually, as I read through the
> individual patient summaries, and obviously, the care is remarkable,
> but I have the impression and realize how adjudication of deaths goes
> on, but it seems to me that infection, continued serious infection
> played a prominent role in many of the cases where it was not a
> primary cause of death, for instance, if a VAD had to be removed
> because of infection and the died of perioperative bleeding, I have no
> quarrel with the classification.]{.underline}
>
> [So, I am troubled by that, and I presume from the course that the
> infection business wasn\'t just in the first 30 days. In terms of the
> Kaplan-Meier curves, that had to be a continuing problem over time,
> and I don\'t know if you have any data. Those are the first 40 deaths.
> I realize you have more. I am not sure if things have been
> adjudicated, but there are now 65 deaths, if I understand correctly,
> in the LVAD group.]{.underline}
>
> [DR. ROSE: No, there are still 18 ongoing.]{.underline}
>
> [DR. KLOCKE: Good. So, there are 50 deaths.]{.underline}
>
> [DR. ROSE: Right.]{.underline}
>
> [DR. KLOCKE: So, in the first 40, it was 40 percent, and I guess the
> infection rate is continuing on.]{.underline}
>
> [DR. ROSE: Right.]{.underline}
>
> [DR. KLOCKE: Jim asked you about the bridge to transplant. I guess I
> would have liked to hope that with the benefit in LV function, which I
> am sure the LVAD patients got, that apparently, that benefit in
> overall, even those these were terribly sick patients, but that
> benefit apparently is not sufficient to reduce the infection
> problems.]{.underline}
>
> [So, that is the one that I am sort of left struggling with the most,
> and I sense that you are.]{.underline}
>
> [DR. ROSE: I think we are struggling, but I don\'t think we are in the
> dark at this point as to what it is that we need to deal
> with.]{.underline}
>
> [DR. KLOCKE: Okay.]{.underline}
>
> [DR. ROSE: As I said, malnutrition was not something that was even on
> the investigator\'s radar screen when we began this, because our
> assumption was that if you fix the cardiac output, the nutritional
> depletion of these patients would reverse itself.]{.underline}
>
> [I think it is clear to us at this point that that is not the case,
> that simply restoring an adequate cardiac output in a nutritionally
> depleted patient may not be enough, and there was no particular
> attention paid to preoperative nutrition, as well.]{.underline}
>
> [DR. KLOCKE: I hear you, and I guess in the bridge to transplant
> patients, the same nutrition issue occurs?]{.underline}
>
> [DR. ROSE: Except for the sense that the entry criteria here was
> initially that you had to be sick with heart failure for three months,
> which actually I hope in the labeling will not be there because that
> allows an awful long interval for people to really waste
> away.]{.underline}
>
> [DR. KLOCKE: I hear you. I guess the question I am sort of left with
> is how strong is the information we have at the moment to think that
> the current infection rate, which I see at this stage as the dominant
> limiting factor, and we have ideas how to address it, but we have
> limited experience in addressing it successfully.]{.underline}
>
> [DR. ROSE: I want to sing Jim Long\'s praises. There are two centers
> in the trial that have taken that on as a very specific area of
> interest, and they have offered a lot of guidance to us, and now with
> a small, but very encouraging experience with us, I think will become
> a model for the rest of those of us involved in the
> field.]{.underline}
>
> [As well, I think the drive line in the VE was too rigid, and is a
> source of contamination because the inflexibility of the drive line
> would crack the junction between the device and the skin, which a
> softer drive line, which the newer iterations have, we believe will
> also help deal with this.]{.underline}
>
> [DR. KLOCKE: I am confident that you will and we will go out and we
> will solve it. I guess the problem that we have is at this point in
> time, where do we stand in terms of having satisfactory evidence to
> approve the request that has been made to us. That is really what I am
> struggling with.]{.underline}
>
> [DR. ROSE: The issue there is that even in spite of all the infections
> and all the other adverse events, there is still a highly significant
> statistically valid survival benefit to the device, so in spite of all
> these troubles, these people are still living longer, and for those of
> us who do believe the Quality of Life, they are feeling better, as
> well.]{.underline}
>
> [That, I think is the overwhelming evidence, and I think the very
> reasonable expectation that these results are the floor of what we are
> going to be able to achieve going forward.]{.underline}
>
> [DR. LONG: Some evidence of that is a shift in infection rates between
> the precursor to this trial, which is called the PREMATCH trial, and
> the REMATCH trial, and there was a very significant reduction in
> infection between those two with efforts to try to improve
> management.]{.underline}
>
> [Now, that is limited in its data, but is one more inference that
> management plays a significant role in helping control this. In
> essence, in considering the etiologies of this, it is device related,
> patient related, or management related, and our sense is that it would
> be unfair for us to place the burden of this entirely on the
> device.]{.underline}
>
> [There is a very substantial portion of this that is related, in fact,
> to management and to the patient especially in that early upfront
> period while we have so many comorbid factors ongoing. A very
> important topic, though.]{.underline}
>
> [DR. LASKEY: Mr. Dacey.]{.underline}
>
> [MR. DACEY: I want to salute everybody involved with this because I
> don\'t think, at least when you get out in the general population,
> that people will fully capture in their daily lives how much the
> landscape is changing and how much work that you are doing is
> contributing to that change.]{.underline}
>
> [When I first read over this material, the first thing that occurred
> to me was is this a heart prosthesis, because if it is, this also is a
> change in landscape and understanding.]{.underline}
>
> [If my prosthetic leg malfunctions, I can still hop around, I can use
> crutches. If a heart prosthesis malfunctions, then, it is a much more
> serious problem. I know you understand that, but speaking as a
> consumer, as a representative of the consumer, trying to capture these
> ideas in ways that are very understandable to them is part of my
> mission.]{.underline}
>
> [Also, I see this remarkable change, both quantitatively and the
> velocity of change in the body of knowledge especially around
> something like CHF. There is a few of us in this room who remember
> this, which was the ACPR guideline for heart failure, which is only
> eight years old. This is just eight years. That is not a long time
> really, yet, in some people\'s eyes, it is an eternity.]{.underline}
>
> [But at the end of the algorithm for end stage, refer for evaluation
> for heart transplant, and now you have got to add a couple more steps.
> There is no reference there to bridge to transplant.]{.underline}
>
> [Then, also, on the patient handbook, and I know this is a work in
> progress, there was a time in patient education and information where
> the pass of distribution of information, words on paper, was enough to
> satisfy legal requirements, informed consent requirements, and I have
> heard very reassuring words today from the professional perspective
> there is a great deal of intensity at trying to work with patients,
> because these are very, very sick patients. I have known some of
> them.]{.underline}
>
> [But as we know, if you are going to get people to the point where
> they understand, and it is not just the patient, it\'s the family,
> it\'s the caregivers, it\'s the people around them who have to take
> care of them, they have to have skill training.]{.underline}
>
> [When this was published, 24 pages of fifth grade text, now we are
> seeing 50- and 100-page technical documents that are being given out
> to satisfy this requirement. There is no substitute for that one on
> one, and I know you know that.]{.underline}
>
> [I hope if this should be approved and moves out across the country,
> that all the colleagues involved understand it, as well.]{.underline}
>
> [Finally, as I end my four years on this panel, there is just one
> editorial comment I would like to make. Having been an advocate for
> the subject of Quality of Life for such a long time, going back a very
> long time, and maybe my age is showing, but I sure wish we could find
> another term.]{.underline}
>
> [I know you have to test and measure it, but it has become a marketing
> term also, and I sure would hope to see it convert to a marketing term
> within the context of this subject. I understand all the methodology
> involved, SF-36, and the well life expectancy model and the general
> health policy model, and I have worked with them, and it\'s a daunting
> task, and it\'s horribly subjective.]{.underline}
>
> [You are at the cutting edge of some new work here also, and for this
> I salute you. So, in summary, my perspective says you have got a heart
> prosthesis, and it is part of a process that is going somewhere, and I
> don\'t know fully yet where that \"where\" is, but I salute your
> effort.]{.underline}
>
> [DR. ROSE: Thank you very much, appreciate it.]{.underline}
>
> [DR. LASKEY: Mr. Morton.]{.underline}
>
> [MR. MORTON: Thank you. Thank you, Bob. Thank you, Dr.
> Laskey.]{.underline}
>
> [Just to follow up, Mr. Dacey, on your comments about this being a
> heart prosthesis, I would like to bring up something that was
> discussed during the break, and something that is of interest to me,
> and that is, we have heard several comments that the device, as
> presented to us, does not have an end of pump life indicator on
> it.]{.underline}
>
> [I would respectfully like to remind the panel that many other heart
> prostheses and critical devices also do not have an end of device life
> indicator, and I would ask us not to view that lack of such an
> indicator for this device as a negative, but review it as tested,
> designed, and presented to us today.]{.underline}
>
> [That ends my comments.]{.underline}
>
> [DR. KNAPKA: I am supposed to be representing the patients, and as a
> heart patient myself, I do have a defibrillator, a pacemaker like Vice
> President Cheney, you know, both waiting for them to go
> off.]{.underline}
>
> [I just have to make several comments. I think from a patient\'s
> standpoint, strictly not so much as a scientist, just as a patient, I
> would probably be scared.]{.underline}
>
> [We talked a lot about first effects and then Quality of Life, and to
> me this was kind of contradictory because it was saying with this
> implant or with this device, there is all these adverse effects, and
> then we say, well, this is improved Quality of Life, and to me, that
> is a little contradictory.]{.underline}
>
> [I mean maybe when you first start, and as you said, you are very
> sick, and you are glad to have something, but you go through all these
> adverse effects, and then maybe that last year, maybe the Quality of
> Life is good, maybe there is a balance there.]{.underline}
>
> [Now, that being said, I think it is good that many, many of us
> patients would be very glad to have another two years, praying that
> there is a new development that is going to help us. So, from that
> standpoint, I think again this becomes a very, very individual
> decision.]{.underline}
>
> [I know I was very sick, and quite frankly, I didn\'t care if I lived
> or not, so maybe in that case, those people, they don\'t want to live,
> and that is their choice, but I think it is good that people have a
> choice to maybe have two more years, and, gee, maybe NIH is going to
> come to something that is really going to be top-notch, and I will
> live the next hundred years, which may or may not, probably not,
> because even some of the people that Jesus saved died, too, you
> know.]{.underline}
>
> [\[Laughter.\]]{.underline}
>
> [DR. KNAPKA: I would like to just make one other comment about the
> patient handbook, and I would agree it is very technical, but I think
> if I were a patient reading it the first time, every other page there
> is warning, caution, that would just make me more scared, and I think
> if you redo it, and I think it is very honest, don\'t get me wrong, I
> think it is very honest, but I think some of these maybe could be
> tuned down, and I would agree that probably there should be a training
> session with the physician and the patient rather than just hand it,
> you know, here is your handbook. It is really highly technical, and I
> don\'t think most people would know.]{.underline}
>
> [I got a lot out of it. The other one thing that surprised me, and
> again I am going to talk a little bit as a scientist, and not as a
> patient, but this issue came up that there wasn\'t much until now,
> much concern about the management, the 20 different centers that were
> involved, they all seemed to have different management this and this,
> and to me, that is Statistics 101. You identify all your variables and
> measure. I am a little disappointed in that because to me, management
> of any disease, any experiment is very important, and I would think
> that would be, as I say, that is Stat 101. You identify your variables
> and start considering it.]{.underline}
>
> [Thank you very much.]{.underline}
>
> [DR. LASKEY: Thank you, sir.]{.underline}
>
> [I think before we get on with the nitty-gritty, I think there has
> been additional food for thought and some people have some follow-up
> questions, so I would like to limit that to perhaps five minutes per
> person, also, with the hope that maybe some of the information that
> was requested before the break is available.]{.underline}
>
> [Janet.]{.underline}
>
> [DR. WITTES: I actually have one other thing that I think we haven\'t
> really addressed very much, and that is the distribution of time to
> critical failure. What we have is information about estimated mean and
> estimated median time to failure, but not a distribution of
> time.]{.underline}
>
> [I wonder if you have that both in vivo, especially in vivo, but also
> in vitro, so not just the point estimates of failure.]{.underline}
>
> [MR. POIRIER: We don\'t have all our data here. We will be looking at
> it, and we can certainly get that information back to you, but we
> don\'t have the data that we can come up with any mean time to
> failures in the clinical environment.]{.underline}
>
> [Also, I think FDA frowns upon look at clinical data for reliability
> because it is uncontrolled. Every patient is different. If you look at
> reliability, you really want to look at a controlled environment where
> you control the parameters, and you can compare one device to another.
> You cannot do that clinically.]{.underline}
>
> [So, that is why we have not made those calculations because FDA
> frowns on that.]{.underline}
>
> [DR. LASKEY: Mike.]{.underline}
>
> [DR. DOMANSKI: No.]{.underline}
>
> [DR. LASKEY: Dr. Konstam.]{.underline}
>
> [DR. KONSTAM: I have just a few things that I want to touch on that I
> don\'t think we have gone into at any length. One is some help about
> indications for use, what patients are we talking about is one topic,
> and the other topic is, Eric, you mentioned training, and I am going
> to want to pick your brain about what ideas you had for
> that.]{.underline}
>
> [With regard to indications, I guess I have got some deep concerns on
> both sides of utilizing this device in patients who are not as sick as
> you have in this study given the mortality that you see with the
> device at two years, we had better be reserving the use for patients
> who are really sick, really have a very, very limited life
> expectancy.]{.underline}
>
> [I am worried about the other side, too, but, first, let me ask you
> about that one. How would you propose this indication be written, so
> that we are sure that patients who get it have a very limited life
> expectancy?]{.underline}
>
> [DR. STEVENSON: Well, as I said before, this is probably the most
> pertinent question that I think some of us are focused on at the
> moment. I would suggest that we perhaps add language that says
> \"refractory to all current standard therapy,\" and in addition,
> including the proviso that patients be ineligible for cardiac
> transplantation implies, in fact, that they will be evaluated for
> cardiac transplantation by people who are accustomed to do
> that.]{.underline}
>
> [I am hopeful that perhaps including both of those, refractive to all
> currently accepted therapy and ineligible for cardiac transplantation
> may, in fact, help us to get to the severity of illness here, but I
> agree it is a major challenge.]{.underline}
>
> [DR. KONSTAM: Do you think that will do it or do you think you would
> want to be a little bit more rigorous at defining what that
> means?]{.underline}
>
> [DR. STEVENSON: It is exceedingly difficult to be more rigorous. I
> think judging from our experience with cardiac transplantation, we can
> certainly put in some of the constraints that we put in for
> transplantation, we can think about that.]{.underline}
>
> [If we look at the indications for entry into this trial, Class IV, EF
> under 25 percent, peak VO~2~ less than 12, we all know plenty of
> patients like that who, in fact, would not have a 75 percent, two-year
> mortality. So, I think those may be helpful, but they are not adequate
> yet to get the severity.]{.underline}
>
> [DR. KONSTAM: I don\'t think we are going to wordsmith it now, but
> certainly there are guidelines for indication for transplant, and I
> just leave it with the comment now that I think that if we are going
> to approve this, I think it will, in my mind, require some work to
> define, to make sure that patients who don\'t have, based on what we
> see here, an extremely limited life expectancy, don\'t get this
> device. Let me just say that, and say we are going to need to work on
> that.]{.underline}
>
> [The other side of it is a more societal question of putting it in
> people with comorbidities or advanced stage, and that can be more
> difficult to deal with.]{.underline}
>
> [Let me just ask, because it is sort of interesting, one of the entry
> criteria here was comorbidities. I mean that was a permissive entry
> criteria. You had to not be a candidate for transplant. That is one of
> the ways you could not be a candidate for transplant.]{.underline}
>
> [So, it certainly didn\'t exclude patients with, quote
> \"comorbidities,\" but do you want to comment about what type of
> patients and what type of comorbidities you would not want to see
> receiving this device clinically?]{.underline}
>
> [DR. STEVENSON: At this point, I don\'t think I want to list them for
> the record. I think we all agree that there are a number of organ
> system degrees of failure that we would not want to see. For instance,
> part of the success of the bridge to transplant program has been, in
> fact, that people have to be eligible for transplant to get into the
> bridge, and I think that some of those criteria, for instance, in this
> one, you couldn\'t have a creatinine over 3.5 to get into this
> trial.]{.underline}
>
> [I think that we will end up with some organ system function
> parameters, and I would, in fact, propose that hepatic function be a
> very important factor in here, but I don\'t want to actually suggest
> specifics at this point.]{.underline}
>
> [DR. KONSTAM: Who is going to do that, though, do you think that is
> something the panel is going to be able to do?]{.underline}
>
> [DR. STEVENSON: I think this is going to be a work in progress along
> with the patient manual, will be how indications should be specified,
> and I think it is impossible to divorce it from the people who, in
> fact, will be evaluating these patients, and I think that those should
> be people with expertise in evaluating end-stage heart failure. I
> don\'t think there is any way we can write something out here that we
> could give to someone in the community and have them make this
> decision.]{.underline}
>
> [DR. KONSTAM: Okay. The other big concern I have is who is going to be
> putting these in. Let me just preface it by stating the obvious, that
> the results that you have here with\--I guess I can\'t get away from
> it\--a less than anticipated survival rate in the treatment group,
> nevertheless were achieved with extremely expert investigators, all of
> whom I guess had experience with this device as a bridge, I assume, so
> maybe I could just open that to your comments.]{.underline}
>
> [How do we assure ourselves that we are going to have this device used
> by clinicians who are capable of achieving at least this same degree
> of success with it?]{.underline}
>
> [DR. ROSE: I think the best way to assure that that is happening is
> with postmarketing surveillance, to know, we can all want that to
> happen, but I don\'t see how you can know that without doing
> it.]{.underline}
>
> [DR. KONSTAM: You wouldn\'t propose some kind of a certification
> process, a training program?]{.underline}
>
> [DR. ROSE: Absolutely. Aside from that, even for bridging, the use of
> these devices requires mandatory training for centers, and even
> retraining for centers in the use of this device, and all of them now
> I would expect are going to participate in the ISHLT registry of
> devices, as well, which is the community\'s attempt to\--]{.underline}
>
> [DR. KONSTAM: Not to take too much time on this, because I think this
> is a concern to me, and may be to other people on the panel, could you
> just expand a little bit, what might be the nature of a training
> program that people might have?]{.underline}
>
> [DR. ROSE: It is generally two to three days of going to an expert
> center where a device will be implanted in an animal typically, or two
> animals, as well as didactics. We teach several of these courses at
> Columbia, and there is a curriculum, a syllabus, indications, process
> of management to the patients, and the ability to participate in an
> animal implant with experts in device insertion is all part of the
> course.]{.underline}
>
> [Frankly, after the course, there is often a lot of dialogue, as
> well.]{.underline}
>
> [DR. KONSTAM: What about patient experience, what about actually
> assisting or participating in actual patient operations?]{.underline}
>
> [DR. ROSE: Why don\'t you speak to that for the bridging.]{.underline}
>
> [MR. POIRIER: In the bridging program, we made the determination right
> upfront that no one would be allowed to use this device without going
> through a formal training session. The training session consists of
> two parts.]{.underline}
>
> [One is that we have a training center, and Columbia is one, where the
> physician and his team go to Columbia for two to three days, they
> implant the device in two different animals, they go through all of
> the issues in terms of patient management, patient care, patient
> selection, all of those things.]{.underline}
>
> [In addition to that, the company sends to the specific hospital that
> wants to use this, a team to train the nurses and the people who will
> take care of these patients, go through the operation of all of the
> systems with the engineering people on site, so that everyone is
> thoroughly trained.]{.underline}
>
> [There are manuals, operating manuals, patient manuals, a whole
> variety of different manuals that are used in this training. So,
> nobody will touch this device until we are convinced that they are
> adequately trained.]{.underline}
>
> [DR. KONSTAM: And in terms of other elements at the site, you know, in
> terms of the heart failure care or the ability to select patients, any
> thought about that? Should it be limited to certain sites or only
> certain surgeons?]{.underline}
>
> [MR. POIRIER: One of the advantages that we have is this is a
> close-knit community, everyone talks to each other. If there are any
> questions, people call each other and discuss it, and we have a whole
> network of people willing to do that.]{.underline}
>
> [If there are any issues on patient selection, there are many people
> who will discuss that. I think the physicians here will back that
> up.]{.underline}
>
> [DR. KONSTAM: Thanks.]{.underline}
>
> [DR. PINA: But I think you have to extend that a little bit
> differently, because up to now you are bridging classes, which I am
> familiar with, have been for transplant centers because that has been
> the approval, and now if a community hospital wants to put this device
> in, if it gets approval, they are going to be able to do
> it.]{.underline}
>
> [My worry goes even before the surgical expertise of the people that
> are putting it in, it is the people who are treating the heart
> failure, and what we don\'t want to see in the heart failure
> community\--and I am sure Lynne would echo this\--is people being
> inappropriately treated for heart failure, and not being offered the
> therapy that sometimes is tough to do, but if you are persistent about
> it, you can get people on therapy, for example, beta blocker
> use.]{.underline}
>
> [It may be simpler to say, well, look, we now have this device
> approved. So, I think that Lynne\'s point about somebody not being a
> transplant candidate means that they must have gone through some
> process of being looked at as a transplant candidate, for whatever the
> reason, comorbidity, age or whatever.]{.underline}
>
> [That is my bigger concern even before, because I think you can train
> a good surgeon to do this and gather experience, but I want to go one
> step before this.]{.underline}
>
> [MR. POIRIER: We agree with that, we agree with Lynne. Don\'t think
> that there is going to be an avalanche of implants tomorrow. That
> won\'t happen.]{.underline}
>
> [DR. PINA: But that is something that has got into your training
> thinking beyond what you have done now.]{.underline}
>
> [MR. POIRIER: Yes, of course.]{.underline}
>
> [DR. PINA: I know your programs right now, and they are
> terrific.]{.underline}
>
> [MR. POIRIER: I mean as a company, we are concerned with that more
> than you are, because the results will be detrimental, and that will
> hurt us. So, obviously, we don\'t want that to happen. We will be very
> careful on how we let this out, and we will be very careful who gets
> it, and we will make sure that the people who are being evaluated are
> being evaluated properly.]{.underline}
>
> [We have a long track record of that. We have not been careless. I
> have been involved with this for 35 years.]{.underline}
>
> [DR. LASKEY: We are not impugning your integrity either, but the
> nature of the marketplace is also a wild animal at times. That is our
> concern, it is always our concern with these devices. It is not all up
> to you always.]{.underline}
>
> [DR. LONG: Clearly, responsible dissemination is utterly essential. We
> would agree with controlling that and making sure that there is
> excellence involved in this, especially until such time as it is
> appropriate to expand the volumes with adequate
> experience.]{.underline}
>
> [I would like to add one other comment about the patient populations
> that this is appropriate for. While we agree that this is a very
> high-risk patient population that should be receiving these devices,
> it would be unfortunate to constrain this field to serve up only
> patients that are very high-risk patients and patients who bring a
> burden, not because of the device, but because of their comorbidities
> to the process, so that we don\'t have the opportunity to improve the
> outcomes with these patients based on that particular
> feature.]{.underline}
>
> [DR. LASKEY: Nevertheless, we need to evaluate what we have in front
> of us. I understand you, and it would be wonderful if we had a
> distillation of what the gatekeepers went through, but we don\'t have
> that, and that is what we need, and I think that is what many of us
> are concerned about, is that that thought process has not been
> codified, it has not been translated into scalable
> covariates.]{.underline}
>
> [We have no idea who these patients are except for the fact that there
> was a 7 to 1 ratio between looking t them and putting them into this
> protocol, and that is not necessarily a generalizable study
> result.]{.underline}
>
> [DR. COMEROTA: I would just echo Marvin\'s concern about indications,
> and I think inclusion criteria are one element that probably will be
> easier to identify than exclusion criteria, and I think it is fair to
> say that this panel would be very uncomfortable with defining that,
> and that is something that definitions need to be made and then
> brought to this panel.]{.underline}
>
> [I think many of those issues have been already enumerated, and some
> of them being societal, age, and are there going to be cutoffs, as
> well as other comorbidities.]{.underline}
>
> [I will just leave that as a comment.]{.underline}
>
> [DR. NISSEN: I must tell you that I am terribly disappointed in your
> inability to provide mean time to failure data. Let me tell you why.
> We have a device here that if I read Dr. Swain\'s review, failed in 20
> of the 68 patients with an internal failure, not an external
> component, but an internal component, that is a 30 percent failure
> rate.]{.underline}
>
> [Now, for us to counsel patients about whether they ought to undertake
> such an operation without being able to say to them, look, if we put
> this device in you, it has a mean time to failure of 12 months, and
> you didn\'t know that within an average of 12 months, you are likely
> to require replacement of the device, we have to know
> that.]{.underline}
>
> [The in-vitro testing data doesn\'t tell us that. Only the in-vivo
> data tells us that. So, I think that we must know how long we can
> expect this device to function for in order for patients to make an
> educated decision about whether they want to undergo an
> implant.]{.underline}
>
> [I am told the FDA is not interested in such data, I don\'t know if
> that is true or not true, but I am certainly interested in knowing how
> reliable is the device in a clinical in-vivo setting.]{.underline}
>
> [Can anybody give me any insight into that? I would certainly
> appreciate it.]{.underline}
>
> [DR. ROSE: I think to argue that there is no insight from this based
> on the survival data is just not correct. I think that patients, while
> they may be interested in failure rates and detailed failure rates, I
> think that most patients want to know even more how long can I expect
> to live.]{.underline}
>
> [That, unquestionably, I do believe we have very firm data about, firm
> enough that I think it is reasonable for a physician to make a
> recommendation or to advise a patient as to whether or not it should
> be considered.]{.underline}
>
> [Without the approval of this body, those choices can\'t be made out
> in the public, and I think it is time based on this data set, that
> those choices be available to patients. The additional data, I think
> is desirable from the point of view of helping elucidate these issues,
> but from the point of there being critical to making a decision or
> not, as to whether or not this belongs out there for patients to
> benefit from is a separate question.]{.underline}
>
> [DR. ZUCKERMAN: Dr. Laskey, can I just provide a point of agency
> clarification on this reliability issue? I think the clinical question
> posed by Dr. Nissen is an extremely important one, and while the
> sponsor may have gotten the impression in the past that certain
> reliability calculation wasn\'t called for, et cetera, I don\'t think
> that that would be our current position.]{.underline}
>
> [In fact, I am going to ask Dr. Berman to better explain what we were
> trying to convey to the sponsor. It is also the reason why we do have
> panel discussions like this one, just to better clarify what are the
> pertinent issues to, one, look at the device, and two, better capture
> information in our labeling.]{.underline}
>
> [DR. BERMAN: There may be a misapprehension of a misunderstanding. We
> would not accept reliability data from an animal study to demonstrate
> long-term reliability for a device. That is, typically, in the past,
> people have done eight cows for three months, and that does not
> demonstrate long-term device reliability in patients, it just
> doesn\'t, and we don\'t like that, and we tell people we won\'t accept
> that. We do want to see bench testing, there is no
> question.]{.underline}
>
> [We will certainly look at reliability data, data of rates of
> occurrence of different kinds of device malfunctions rate, time to
> occurrence of different types of malfunctions, and so on, as observed
> in a clinical trial. We will not accept that as the only data. We do
> want to see formalized bench testing.]{.underline}
>
> [Mr. Poirier is quite correct. Patient data is somewhat uncontrolled.
> You don\'t know under what conditions the device had a problem. There
> were at least one or two instances in the REMATCH trial in which there
> was what appeared to be a device problem, but which we, in discussion
> with the sponsor, agreed was not, it was a patient problem. The device
> is not responsible for what the patient misuses.]{.underline}
>
> [So, to correct the misapprehension, yes, we want to know what
> happens, what is observed during the clinical trial, no, it is not by
> itself entirely sufficient, but it is very important, as in this case,
> to look at bench testing and how the clinical trial proves out that
> the bench testing was adequate or perhaps not completely
> adequate.]{.underline}
>
> [DR. NISSEN: One other question. I will ask the sponsor to comment on
> that. The other relates to the fact that the most common reason for
> not being eligible for transplantation is being over the age of 65.
> You suggested that there might have been some differences between how
> people did according to age.]{.underline}
>
> [So, I would be very interested in understanding whether there was a
> difference in the over-65 category. I know it was most of the
> patients. You suggested that the under-65 did particularly well. Is
> the converse also true, if you were over 65, did you tend to do quite
> poorly with the device? Is that is the case, doesn\'t that speak
> somewhat to labeling?]{.underline}
>
> [DR. ROSE: We had three prespecified age strata in the survival
> analysis. One was less than 60, another was 60 to 69, and the other
> was above 69. In all of the age strata, there was a survival benefit
> of the LVAD arm. Only in the 60 to 69 group was that benefit
> statistically significant, but that was also the largest group, so I
> think it was reasonably powered to answer that question.]{.underline}
>
> [The younger age stratum that I described, that difference was not
> different compared to the others. I think as we accumulate more
> experience, that those kinds of data are going to be critical to
> deploying this kind of device.]{.underline}
>
> [DR. AZIZ: Just a suggestion and a question. Would it be reasonable to
> suggest that initially, at least for the next year or so, that the
> implantations only be done at centers that do
> transplantation?]{.underline}
>
> [DR. ROSE: Excuse me?]{.underline}
>
> [DR. AZIZ: That do heart transplantation rather than letting every
> community hospital be using this device.]{.underline}
>
> [DR. ROSE: I personally think that dissemination to community
> hospitals at this point is not the way to go. I am open to argument.
> In particular instances, there may be a strong reason as to why a
> particular institution that doesn\'t do transplantation ought to have
> this available as an option, but in the early get-go, I think it is
> probably the wrong way to go.]{.underline}
>
> [DR. AZIZ: The other thing, I know that obviously, our discussion is
> related to this particular device, but I do believe that I think other
> devices have been used for long periods of time particularly in
> Europe. I don\'t have the numbers. I think the Quality of Life at
> least for those devices, the patients have done quite
> well.]{.underline}
>
> [DR. PINA: One small point. We learn from clinical trials whether the
> trials are positive, negative, or neutral, and I think as you look at
> the demographic data, which you apparently have not done right now,
> you may be able to come up with a risk profile for the patient who
> would be more likely (a) to have sepsis, the patient would be more
> likely to develop a CVA, looking at, say, vascular
> disease.]{.underline}
>
> [I would be particularly interested in you looking at the body mass
> index, which you can probably calculate if you have the height and the
> weight\--]{.underline}
>
> [DR. ROSE: We have that data.]{.underline}
>
> [DR. PINA: \--and get some sense of muscle mass. I mean it\'s a very
> gross sense of muscle mass to look at the rate of\--if you don\'t have
> albumin or pre-albumins\--to look at the rate of complications based
> on the muscle mass or nutritional status.]{.underline}
>
> [DR. OSSORIO: I have two questions. One goes to the informed consent
> issue, and you had mentioned that these patients are so ill that it is
> not as though they are sitting around reading manuals or
> whatever.]{.underline}
>
> [Did you do anything particular in this trial to try to ensure that
> the informed consent was adequate? I am asking that question because I
> am trying to think about generalizing that, and thinking about perhaps
> unusual or special things that could be done in a non-research
> context, but that could help.]{.underline}
>
> [DR. ROSE: Oddly enough, I think one of the confirmatory issues around
> informed consent is the fact that the ratio of screened patients
> compared to enrolled patients was so high. I don\'t think that we
> pulled any punches with regard to describing to patients what it is
> that was entailed here. Clearly, a large number of patients said with
> regard to a device, \"I am not interested.\"]{.underline}
>
> [So, if anything, I think we bent over backwards and here the issue
> was clinical equipoise. We had the appropriate degree of equipoise in
> our posing these issues to patients.]{.underline}
>
> [Early on, I think there were questions around\--I remember the first
> investigators\' committee, there was still question as to whether or
> not this was an ethical randomization. I think we came to that
> conclusion particularly reassured when the DSMB looked at the first
> cut of data and just said to us, \"Keep working.\"]{.underline}
>
> [That was enormously encouraging to us, so I think that we did have a
> reasonable degree of informed consent for the trial. I think the
> nature of informed consent though now, if the device is approved, is a
> different issue with a lot of other considerations, particularly the
> issue of concerns around overselling the device, and also I think it
> reasonable to have concerns around underselling it, too, that patients
> who could benefit from it, as you mentioned before, patients of color
> that could benefit from it, that don\'t necessarily get
> it.]{.underline}
>
> [I think on both sides, we need to be particularly vigilant, and that
> is a challenge to us.]{.underline}
>
> [DR. OSSORIO: Another question, which I don\'t know if this is exactly
> a fair question, this is more for general information. Obviously,
> there are a lot of real societal concerns about investing tremendous
> amounts of resources extending to very, very end of life.]{.underline}
>
> [Did you and your company have any kind of an ethics discussion or
> particularly an ethics discussion about this that helped you to decide
> that it was a good thing to move forward with this kind of a trial as
> opposed to some other kind?]{.underline}
>
> [DR. ROSE: I don\'t work for Thoratec. The company I work for is
> Columbia University.]{.underline}
>
> [DR. OSSORIO: Right.]{.underline}
>
> [DR. ROSE: At my company, yes, we have considerable discussions around
> the ethics of doing this kind of dissemination. I think at the other
> end of the spectrum, though, can a society as successful and
> productive as ours, afford not to do this ethically, I think is as
> good a question as whether or not we shouldn\'t.]{.underline}
>
> [DR. LASKEY: Dr. DeWeese.]{.underline}
>
> [DR. DeWEESE: I have no additional comments. I would hope that your
> group would be able to provide a definition as has been asked for of
> just who would be accepted, but with your experience, and then it
> could be evaluated by the panel, if necessary, at a future date, and
> carried out.]{.underline}
>
> [DR. KLOCKE: I am sure you will do it. I guess I would encourage you
> to, if you could, one was saying codified, but you pointed I think
> correctly that the LDS in the Minnesota experience I understand with
> infection, which I have been focused on, appears to be different, and
> certainly anything you could do to codify that, to extend it to a
> larger group of patients if that really is a reasonable answer to the
> infection problem, it would be useful to, if the technology spreads,
> to be sure that other people don\'t go through the same learning curve
> that you have been forced to go through.]{.underline}
>
> [DR. LASKEY: Thank you. If there are no further questions, thank you,
> gentlemen, very much for a very persuasive and articulate
> presentation.]{.underline}
>
> [I am going to ask that the sponsors step back from the table at this
> point, so that we can go through the questions again.]{.underline}
>
> **[Panel Recommendations]{.underline}**
>
> [DR. BERMAN: I am going to read into the record the questions we would
> like the panel to consider as they deliberate their decision for this
> PMA supplement.]{.underline}
>
> [1. The bench testing performed to assess device reliability did not
> account for all observed clinical conditions, in particular, higher
> than expected pressure in the pump chamber and higher than expected
> beat rates. Accordingly, the observed times to device failure and/or
> device malfunction seen in the clinical study are less than those
> predicted by the reliability model. As well, there is no reliable
> end-of-pump-life indicator. Please discuss the clinical implications
> of the observed reliability.]{.underline}
>
> [2. Are the device failure and malfunction rates and their time to
> occurrence appropriate for a device intended for use for destination
> therapy?]{.underline}
>
> [3. Given the Kaplan-Meier survival curves and the fact that 7 device
> patients and 3 control patients, as of February 02, had survived to 24
> months, have enough patient data been reported to demonstrate a
> clinically meaningful survival benefit?]{.underline}
>
> [4. The New York Heart Association, the Quality of Life, and the
> functional testing results are not consistent. From these data, can we
> determine that there is a clinically meaningful improvement in
> functional status?]{.underline}
>
> [5. This device demonstrated an increase in median survival time and
> showed an overall difference in survival. However, this benefit
> diminished at two years and was associated with serious adverse events
> and hospitalizations throughout the course of the study. Do the
> benefits of this device outweigh its risks?]{.underline}
>
> [6. One aspect of the premarket evaluation of a new product is the
> review of its labeling. The labeling must indicate which patients are
> appropriate for treatment, identify potential adverse events with the
> use of the device, and explain how the product should be used to
> maximize benefits and minimize adverse events.]{.underline}
>
> [6(a). Please discuss the appropriateness of the proposed indications
> for use for this device, which reads:]{.underline}
>
> [\"The HeartMate VE LVAS is indicated for use as a bridge to
> transplantation in cardiac transplant candidates at risk of imminent
> death from nonreversible left ventricular failure. The HeartMate VE
> LVAS is also indicated for use in patients with end-stage left
> ventricular failure who are ineligible for cardiac transplantation.
> The HeartMate VE LVAS is intended for use both inside and outside the
> hospital.]{.underline}
>
> [6(b). Does the labeling accurately inform patients of the risks of
> the device?]{.underline}
>
> [6(c). Does the labeling adequately inform patients of the expected
> duration of use for this device?]{.underline}
>
> [6(d). Are there any other issues of safety or effectiveness not
> adequately covered in the labeling?]{.underline}
>
> [7. Based on the clinical data provided in the panel pack, do you
> believe that additional clinical follow-up or postmarket studies are
> necessary to evaluate the long-term effects of this device? If so, how
> long should patients be followed, and what endpoints and adverse
> events should be measured?]{.underline}
>
> [DR. LASKEY: At this, Dr. Zuckerman, would you like some consensus
> opinion on each to these? I can tick these off with the help of my
> colleagues, so, please, feel free to correct me if I am misquoting or
> misparaphrasing, any of you.]{.underline}
>
> [For Question No. 1, on device reliability, I think we have
> established the fact that we would like to see more data on device
> reliability, that what we have seen to date indicates that in the
> clinical arena, the reliability falls short of the predictions made
> from theoretical and in-vitro testing, and that we would like to see,
> as requested by two of the panelists, the distribution of the times to
> failure, not just the medians and the means, but all the data
> points.]{.underline}
>
> [Your colleagues, please feel free to contribute.]{.underline}
>
> [Is that helpful, Bram, am I touching on the high points
> here?]{.underline}
>
> [DR. ZUCKERMAN: Yes.]{.underline}
>
> [DR. LASKEY: With respect to Question No. 3\--]{.underline}
>
> [DR. DOMANSKI: Could I just ask a question about that? That could also
> be after, that is the postmarket period also or could be if we choose
> to approve this?]{.underline}
>
> [DR. LASKEY: Yes, I am simply rehashing.]{.underline}
>
> [Mike, can you go to Question 3, data analysis?]{.underline}
>
> [DR. DOMANSKI: Shouldn\'t we talk about 2? I am not sure we really
> addressed 2.]{.underline}
>
> [DR. LASKEY: I am sorry.]{.underline}
>
> [Are the device failure and malfunction rates and their time to
> occurrence appropriate\--but we needed to see more data up to this
> point, is that not correct? Dr. Nissen wanted to see means and medians
> to failure. A number of us would like to see the actual distribution
> of all the points, not just those two.]{.underline}
>
> [DR. KONSTAM: I agree, but I think we could discuss No. 2 based on
> best case of what we think we are seeing, that is, a device that lasts
> on the average about three years in vitro and appears to be somewhat
> shorter than that in the trial. This is asking the judgment question
> of whether\--I mean that is how I interpret it\--whether that is an
> appropriate level of reliability for destination advice.]{.underline}
>
> [DR. DOMANSKI: I guess the question I have is if you are going to do
> that, again, do you feel like there is not enough data in to consider
> this application, or can that be done by the FDA staff after
> approval?]{.underline}
>
> [DR. COMEROTA: Wouldn\'t it be simpler to define destination? If the
> definition was one year of additional life versus four years of
> additional life, would the answer be clearer, and then the gray area
> gets in the 2 1/2 to 3?]{.underline}
>
> [The real crux of the matter is what is the destination.]{.underline}
>
> [DR. NISSEN: I guess what I was trying to get at here is that as I
> understand it, the patients lived an average of around 400 days, and
> during those 400 days of life, approximately 30 percent of the devices
> had an internal failure that could not be fixed without another
> operation.]{.underline}
>
> [That gives me some flavor for what the durability of the device is in
> a clinical setting, so I would be prepared to answer the question. I
> think I would answer it as no, that it is not reliable enough for
> destination therapy, it is reliable enough for a bridge to transplant,
> but in this application, my answer would be no.]{.underline}
>
> [DR. DOMANSKI: That is a fundamental question about whether or not
> this thing is going to be approved.]{.underline}
>
> [DR. LASKEY: We are overlapping with voting now, so I think many of
> these issues will be more black and white as each member gives the
> reasons for yea or nay. So, that ultimately may be the answer to many
> of these questions.]{.underline}
>
> [DR. DOMANSKI: Yes, but I don\'t know that we have a consensus that
> you can give the FDA on No. 2 right now is the point.]{.underline}
>
> [DR. LASKEY: Then, let the record reflect that there is no consensus
> perhaps due to the wording or perhaps due to the issue
> itself.]{.underline}
>
> [I think Question No. 3, we are all uncomfortable looking at 7 versus
> 3, nevertheless, the P-values are statistically significant. My
> question to this question, is a clinically meaningful survival
> benefit, can it be viewed in isolation? It needs to be viewed in
> relationship to the associated complication rate. So, yes, we have
> demonstrated a survival benefit, but is it clinically meaningful if it
> confers a hazard of adverse events, as well?]{.underline}
>
> [Does the rest of the committee share that sentiment?]{.underline}
>
> [DR. WITTES: I don\'t think that the first clause and the second
> clause match, and I am having trouble with this because the problem is
> not only that there is only 7 and 3 at 242 months. It\'s that there is
> a lot of censored data. So, it\'s not as if we had all 68 patients and
> we knew that the rate is 7 and 3. Then, we would have a good estimate
> of two-year survival rate.]{.underline}
>
> [The problem I think\--I mean there are several problems\--but one is
> that there is data in the pipeline that we don\'t know yet, and so I
> would like for you guys to reword that question to effect
> that.]{.underline}
>
> [DR. LASKEY: That would indicate that not enough patient data has been
> reported then.]{.underline}
>
> [DR. KONSTAM: Can we take a step back? I think there is a core
> question that probably it might be worthwhile to sort of have the
> panel reflect on, that seems to me to come through as you work through
> these.]{.underline}
>
> [It relates to reliability and it relates to this Question No. 3. That
> is the very essence of what REMATCH shows, and is the REMATCH result
> clinically significant, yes or not, and to me it all circles around
> whether if you have a statistically significant effect and apparently
> clinically very relevant effect at one year, but for the sake of
> argument, let\'s say that we are all lost at two years, because we
> don\'t have very reliable data at two years, and there are concerns
> about the reliability of the device at two years.]{.underline}
>
> [If that is what we have, is that a clinically meaningful result, and
> before you get into the adverse effects, yes or no. I think, to me,
> from my point of view, I would love to hear the panel sort of try to
> reach a consensus about that.]{.underline}
>
> [DR. KLOCKE: I think Marvin stated it. I would have to vote
> no.]{.underline}
>
> [DR. DOMANSKI: Well, I don\'t agree with that. I think a year means
> different things to different people, and governments rise and fall in
> a year, our grandchildren are born, you know, it means different
> things to different people, and I think putting it on the market and
> letting people make their own decision is more to the
> point.]{.underline}
>
> [The fact is that the job of this panel isn\'t to make major societal
> decisions about resources are allocated. Our job here is limited to
> saying is it safe and effective, and, you know, I think the thing is
> safe and effective to extend life by one year.]{.underline}
>
> [DR. KONSTAM: Since I posed the question, I guess I will weigh in. I
> happen to agree with Mike. I think that there are major societal
> questions that are hit upon by this application and I have to keep
> reminding myself that those questions are not before us, that the
> questions before us, and I think Mike sort of stated it, is this
> device safe and effective, and if you accept the core finding of the
> study\--I mean one can challenge it, I mean I heard some challenges
> about whether there could be some bias introduced because some
> patients had the device and maybe were not DNR, and this sort of
> thing, that might be worth asking\--but if one accepts the basic core
> finding that there is a highly significant prolongation of life even
> though it may well disappear at two years, I guess I cannot make a
> value judgment that that is not something we should offer to the
> patient.]{.underline}
>
> [DR. KLOCKE: I would understand and would agree with that, and could
> imagine circumstances in individual cases where someone has a daughter
> who is getting married in four months and wants\--I mean I would
> certainly do that. On the other hand, I think, Marvin, at least for
> me, it depends on the meaning of the term \"clinically significant,\"
> and I think that actually, I find it difficult, although I understand
> the survival data, it seems to me that the data we have indicate that
> the window may well be closing, although you don\'t know that until
> the data are in, but I also have to judge that in terms of the full
> complement of the device, the prolongation of life at the expense of
> increased adverse events, which I think really is correct, and so
> it\'s a judgment business, which I personally have no problem that
> reasonable people would differ.]{.underline}
>
> [But I don\'t think in this circumstance, if I were dealing with one
> patient, I am the advocate for that patient, and I certainly would do
> everything I could, but I think \"clinically significant,\" and I
> don\'t mean to consider it in a societal text or anything else, in the
> overall best medical judgment case, separate from society, separate
> from cost, there may be a clinically significant benefit, but I am not
> convinced at this point.]{.underline}
>
> [DR. NISSEN: I would like to weigh in on this one, too. Let me say
> that, first of all, I really do think this was a valiant effort on the
> part of everybody involved to try to make this work, but I don\'t
> think it worked very well, and I don\'t think it was a clinically
> meaningful enhancement to survival.]{.underline}
>
> [I want to point out to the committee several things that we have
> heard today. Thirty percent of the patients that got the LVAD never
> made it out of the hospital, 27 percent had a serious neurological
> event, 31 percent had sepsis. Overall, 64 of the 68 patients had a
> serious adverse event.]{.underline}
>
> [So, if you said, well, we can extend your life by a year and we can
> avoid really large numbers of major morbidity and mortality, and we
> can improve your quality of life, then, I think it would be
> meaningful, but the Quality of Life data is very inconsistent as we
> have all talked about.]{.underline}
>
> [There is not really any solid evidence that that was the case, and I
> think the fact that so many people didn\'t get out of the hospital, so
> many devices failed during the course of the study, means that it was
> a good idea, but the device is not good enough to yet turn this thing
> loose on a population of people who undoubtedly are likely to be not
> as good at using it as the investigators in this trial.]{.underline}
>
> [So, I think that if we are going to let the genie out of the bottle,
> let the genie out of the bottle for a device that really works well,
> and I don\'t think this device worked well.]{.underline}
>
> [DR. COMEROTA: I guess I need to make a comment. I don\'t necessarily
> agree with you, Steve, because if you take it on face value, these are
> exceedingly ill patients, there will be an operative mortality from a
> large operation, that we need to accept, and I think most of us
> probably do.]{.underline}
>
> [The bottom line is if we are focused at two years and beyond, I think
> there is discomfort, but the discomfort should be lessening with the
> updated data that we are presented, obviously, not quite statistically
> significant, but more convincing.]{.underline}
>
> [The bottom line is at one year, there is a significant increase in
> survival, and there is no device failure at one year, which we can
> accept. There must be improvement at the device level, and there will
> be. I thin the quality of life does parallel the findings in the
> improvement in the New York Heart Association functional class
> although we have to accept the possibility and the probability of
> bias, but they are parallel.]{.underline}
>
> [With that said, and a significance at one year an device failure at
> one year, can we justify not approving it with the definition of the
> indication thrown in.]{.underline}
>
> [DR. LASKEY: I am not sure we can approve this device only for one
> year, though.]{.underline}
>
> [DR. DOMANSKI: Actually, it is not a matter of approving it for only
> one year. I mean one doesn\'t usually put into an approval the
> survival data of any of the devices we put out.]{.underline}
>
> [DR. DeWEESE: I think that we have good evidence that it does increase
> survival rate albeit it maybe only at one year at this time, but I
> think that there is going to be improvement in this device. I think
> this is something that we are going to have eventually, and I think
> this group that has presented this and the group that worked with
> them, should continue to do it, and I would hope we would support them
> to do this and make the advances that are necessary to make it a
> little better maybe.]{.underline}
>
> [DR. LASKEY: Maybe we could get just a little bit of help since we
> have really answered Question 4, as well, here, but Dr. Zuckerman, you
> might try and frame for us where the FDA is going with respect to
> changing definitions of survival benefit.]{.underline}
>
> [This is clearly a very different relative risk reduction or reduced
> hazard ratio than we are used to thinking about, and the general rule
> of thumb has always has been the sicker the patient, the more dramatic
> you want to see the relative risk, or it is always the sickest who
> \"benefit the most.\"]{.underline}
>
> [What is that the Agency has in mind with respect to a meaningful
> survival benefit if 25 percent is not enough or 33
> percent?]{.underline}
>
> [DR. ZUCKERMAN: Can we go back to question 3, Dr. Berman.]{.underline}
>
> [When we look at our definition of \"reasonable assurance of safety
> and effectiveness,\" we need to be able to demonstrate clinical
> utility. As indicated in the opening presentations, clinical utility
> for this type of device in this type of population hasn\'t been
> previously perhaps well defined.]{.underline}
>
> [Consequently, we are looking for some panel consensus, if possible,
> as to what a clinically meaningful survival benefit might be - is it
> what we see at one year, is it a difference in the median survivals
> for the two-patient populations, even though the survival curves might
> come very close together at two years?]{.underline}
>
> [We don\'t have a priori a predefined definition, and we are looking
> for some help here. The fact that this is a gray area isn\'t
> surprising, but maybe you can poll panel members again to see if there
> is some more of a consensus.]{.underline}
>
> [DR. LASKEY: I will poll them once again. I would like to also suggest
> one more index of survival benefit, which is how much longer the
> patient is going to live, how many more days or months of life can one
> expect with this treatment, and I think that needs to sometimes be
> added to this clinically meaningful survival benefit in addition to a
> P-value. I think if we knew how many more days a patient had, that
> would answer the question that I think Dr. Rose posed to us, which was
> how much longer do I have.]{.underline}
>
> [DR. KONSTAM: Let me just give my reflection on this. I come at it the
> other way, which is that I see a dramatic statistical effect, a large
> number for risk reduction, a substantial augmentation in median
> survival, and a very low p-value.]{.underline}
>
> [So, the effect is pretty dramatic in my mind. Again, to me, I
> compartmentalize the issue of adverse events, so I think Steve\'s
> points are very cogent and need to be addressed by the panel, but I
> think maybe separately.]{.underline}
>
> [To me, it is I think logically useful to first just go through the
> exercise of whether you think that there is a clinically meaningful
> effect on survival, yes or no, and to me I think there is a very
> dramatic effect on survival, and the question is do we feel that that
> is negated by the fact that we don\'t see it at two
> years.]{.underline}
>
> [This is to me the way I frame the question for myself, and I come
> away saying who am I to say that those findings are not important just
> because I don\'t see it in two years. You know, I am not the patient
> really being potentially presented with that choice.]{.underline}
>
> [I guess in terms of the survival effect, I am impressed with it, and
> I can\'t talk myself out of that.]{.underline}
>
> [DR. LASKEY: I am not sure we are any closer to a consensus. We keep
> going around and around. I must say as a clinician, I find it hard to
> divorce survival from the quality that goes along with that survival,
> and when there are so many infections and strokes and
> re-ops.]{.underline}
>
> [It just can\'t be viewed in isolation. Statistically, it can, but
> clinically, we take care of the whole organism.]{.underline}
>
> [Janet.]{.underline}
>
> [DR. WITTES: I would look at it as at one year, I am coming in, trying
> to make a decision about whether to have this implant or not, then,
> the relevant data it seems to me, if I don\'t have it, then, my chance
> of being alive in a year is a quarter, and if I do have it, my chance
> of being alive in a year is a half, and that to me seems like a big
> difference.]{.underline}
>
> [I don\'t care about two years, I am talking about disease where my
> imminent death is\--so, it seems to me that then what I personally
> would weigh, given those data, and I am comfortable with those data,
> the p-value for me tells me that those data are pretty robust, I am
> comfortable with those numbers.]{.underline}
>
> [So, then I would play into am I willing to take all these other risks
> to give me this benefit of mortality. My personal feeling, and I think
> as a panel member, that we shouldn\'t make that decision for other
> people, that I would say yes, it demonstrates a clinically meaningful
> survival benefit.]{.underline}
>
> [People may not choose it, but I would say yes.]{.underline}
>
> [DR. DeWEESE: When I first read this, I thought that the persons who
> had had a number of adverse events, it would discourage them and make
> them feel they should not have done what they did, and then I find
> that an equal number of people who were controls and had the procedure
> said that they wanted to withdraw.]{.underline}
>
> [I would have thought there would have been a much higher withdrawal
> rate from those who had the procedure, had it, when they are looking
> back, had they been that person.]{.underline}
>
> [DR. NISSEN: One comment. I personally cannot separate survival from
> quality of life, and I will tell you why. Let\'s just take, for
> instance, for a moment, that you had a therapy that could prolong
> survival by one year, but all the patients were in a vegetative state
> during that period of time.]{.underline}
>
> [Would you call that a clinically meaningful survival
> advantage?]{.underline}
>
> [DR. WITTES: No.]{.underline}
>
> [DR. NISSEN: Just so we all are on the same page here, I think it is
> one thing to say there is a statistical effect on survival, and the
> other is to say there is a clinically meaningful effect, and I think
> the word \"clinically meaningful\" to me implies that there is some
> quality of life.]{.underline}
>
> [DR. DOMANSKI: What little data we have on Quality of Life, and, you
> know, I don\'t think much of the Quality of Life data in this trial,
> not because of any fault of the investigators, but because of just the
> nature of the study, but what little we have suggests, in fact, that
> although not absolutely consistently across things, it has
> improved.]{.underline}
>
> [Much of the chemotherapy we give is little more than chemical last
> rites in a setting where the patients know they are not going to get
> much benefit from it, so people do choose it.]{.underline}
>
> [Here, they have an opportunity to choose some benefit.]{.underline}
>
> [DR. KNAPKA: Again, talking from a patient that was in this condition,
> given like 30 days to live, and this sort of thing, I don\'t think a
> panel can make a decision whether one year or two years is
> significant. There is just no way anybody can make this decision
> unless you have been there.]{.underline}
>
> [I think we probably need, if we feel very confident that this device
> will give the majority of people, and we realize that the tests we are
> looking at, these are real sick people, kind of a last
> resort.]{.underline}
>
> [I think this is one of the problems. There is a lot of these new
> devices and new chemicals that it is usually used on patients as a
> last resort, but I think we are arguing whether a year or two years is
> a significant amount of life, we will never come to that decision. It
> ha got to be a patient\'s decision, and I can\'t make that for
> anyone.]{.underline}
>
> [DR. OSSORIO: I just want to weigh in on the side that says clinically
> meaningful survival is something more than just statistically
> lengthened life. I want to weigh in on that side because I think that
> once you do, things begin to unravel here a bit, which is
> unfortunate.]{.underline}
>
> [DR. KONSTAM: I just want to clarify what I said earlier. I guess I
> was segmenting the issues, and to me I think it is worthwhile
> segmenting the issues. I took Question No 3 really just to address the
> one-year versus two-year issue, and really that is what I spoke
> to.]{.underline}
>
> [I certainly concur with everybody else, but I do think it is worth
> getting past that and just looking at that issue in isolation if for
> no other reason for its logical value.]{.underline}
>
> [I certainly, however, would not stop there. I certainly concur that
> if we were extending life, but people were in a vegetative state, I
> would say now, okay, the numbers are okay, but forget it. So, I
> certainly agree with that.]{.underline}
>
> [So, the next question, I think the next logical question is okay,
> life is extended if you accept that, and is it meaningful. Well, I
> have trouble saying that we have not extended meaningful life here. If
> you look at six months, for example, in the LVAD group, you have 8
> patients who are classified as New York Heart Association Class I, and
> 19 patients classified as Class II.]{.underline}
>
> [The corresponding numbers in the medical management group is zero and
> 2 patients. Now, I agree that this statistical analysis of the Quality
> of Life comparison is extremely problematic, but to me, comparing the
> Quality of Life in the two groups is much more important if you have
> most of the patients alive.]{.underline}
>
> [If you have one limb that is 75 percent dead after one year, to me
> the question changes. The question becomes is the clear extension of
> life very problematic because very, very few of the patients are
> having meaningful life, and a best I can read into this, not having
> the patients in front of us, I see significant, clinically
> significant, in my mind, numbers of patients who are doing pretty
> well.]{.underline}
>
> [This really gets back to the comments that were made earlier, who are
> we to say it is not appropriate to offer that to patients. So, I agree
> it is a several-step process, and I wasn\'t up to that step yet, but I
> don\'t think you can look at this and say well, we are keeping
> everybody alive, but they are vegetative. There seem to be people who
> are doing pretty well here.]{.underline}
>
> [DR. LASKEY: I am sure Steve used that more for hyperbole than for
> reality, but it certainly makes the point, and I think certainly what
> we are all grappling with is we can easily deal with the easiest thing
> to do here is to interpret the p-value, as Janet has said, and say
> that there is a significant effect demonstrated here.]{.underline}
>
> [However, we are clinicians, and I think that there is this nagging
> feeling that many of us can\'t get past when a survival benefit is
> associated with risks of bleeding or risks of sepsis or risks of
> stroke, and so on, and so forth, which is identical to the end of life
> chemotherapy issue, as well, and I am not sure there is a meaningful
> answer to that one either.]{.underline}
>
> [I am not sure that we can give you an answer to your question yes or
> no. I think you have heard the deliberations and the really assiduous
> thought process that we have put into this. This is a different
> category of patient, this is a different proposal here.]{.underline}
>
> [DR. WITTES: Several of you have said that I responded to the p-value,
> and I want to make it clear what I was responding to. I was responding
> to the difference in the magnitude of survival at one year, the 50
> percent versus 25 percent, which I was interpreting.]{.underline}
>
> [You know, you may not agree with the interpretation as an important
> difference. What I said about the p-value was that the p-value made me
> believe that that difference was likely to be real, but I was not
> reacting to, and I think it is important for you guys to know
> statisticians tend not to react to the p-value by itself, it is the
> magnitude of the difference.]{.underline}
>
> [DR. ZUCKERMAN: The fact that there isn\'t one clear-cut answer is
> okay. This is a difficult question that FDA has struggled with. Would
> it be fair to summarize, though, that panel members come to this
> question with different prior beliefs, and there is a range of answers
> as to whether or not a clinically meaningful difference has occurred
> at one year and throughout the course of the study?]{.underline}
>
> [DR. DOMANSKI: And you are going to get a quantitative estimate of
> that balance when they vote yes or no in terms of
> approval.]{.underline}
>
> [DR. ZUCKERMAN: Right. It just underlines the need therefore for a
> control in this study to better assess that risk-benefit
> profile.]{.underline}
>
> [DR. LASKEY: I think we really have beat up Question 4.]{.underline}
>
> [DR. ZUCKERMAN: Before going on to Question 5, though, can you just
> give us a quick summary for the record?]{.underline}
>
> [DR. LASKEY: I think I can summarize the panel\'s feeling as saying
> that, number one, it is recognized and accepted among the heart
> failure community that measures in NYHA, 6-minute walks, et cetera, et
> cetera, don\'t always correlate. Number two, they are soft endpoints.
> Number three, unless they are blinded in their ascertainment, it is
> even more difficult, and the potential for bias is always there when
> you have unblinded observers assessing soft endpoints.]{.underline}
>
> [I think we would all like to read into this an improvement in
> functional status, but it is hard with those caveats.]{.underline}
>
> [DR. OSSORIO: I guess for me this is the crux right here. If people
> can\'t do better than this, I think we are in real trouble. I people
> should be expected to do better than this in terms of measuring
> something about whether or not there is a functional improvement or
> whether there is some kind of decent functioning going on in people\'s
> lives after they have had this intervention because what patients do
> care about is, you know, if what somebody cares about is I want to see
> my child\'s wedding or my grandchild\'s birth or whatever, if you
> can\'t recognize your child or your grandchild, it doesn\'t really
> matter, you know, that you are alive at that point.]{.underline}
>
> [There are ways of assessing these things. They may not be in the
> cardiology community, they may not be as widespread, but there are
> ways of assessing these things, and I think people ought to be
> expected to do it.]{.underline}
>
> [DR. DOMANSKI: I don\'t think that is an entirely fair analysis,
> though, because, you know, these people did go through the whole
> battery of things. There are certain things that are peculiar to an
> unblinded study where you put a device in.]{.underline}
>
> [DR. OSSORIO: I know.]{.underline}
>
> [DR. DOMANSKI: I think if you say that, then, you ought to offer some
> indication of how you think they could have done it better, because I
> think they did what they could, but it is the nature of the beast that
> makes it difficult to assess, so I don\'t buy into that
> statement.]{.underline}
>
> [DR. NISSEN: Mike, how about just having somebody who is not the
> operating surgeon ask the question about what your functional class
> is. I mean to me, you know, I can\'t think of a lower standard to
> apply than to have the person who actually did the operation asking
> the patient whether they feel better or not. That is about as bad a
> data as you can possibly generate.]{.underline}
>
> [DR. LASKEY: That perhaps will be recommendations for further study
> design.]{.underline}
>
> [DR. DeWEESE: Where did we have that evidence that the surgeon got
> that information? Was that in anything we received?]{.underline}
>
> [DR. NISSEN: That is what we are told, to ask the question, and that
> was the general gist of the answer.]{.underline}
>
> [DR. DOMANSKI: Since that is raised factually, is that really true,
> because actually, I didn\'t know that.]{.underline}
>
> [DR. OSSORIO: That question was asked.]{.underline}
>
> [DR. DOMANSKI: I took it at face value. Is that what they said?
> Okay.]{.underline}
>
> [Could I ask them to clarify that for us, please? Could I ask them to
> come back to the table and answer that question?]{.underline}
>
> [DR. LASKEY: The question being, so we are clear for the record, how
> was NYHA classification assessed and by whom.]{.underline}
>
> [DR. ROSE: We didn\'t specifically state that surgical patients should
> not be evaluated for NYHA class by the surgeon or the operating
> surgeon, and I can\'t say that there are data that don\'t reflect
> that. I think knowing how these clinics and follow-up function, the
> overwhelming majority of patients were assessed by the cardiologists
> who were following them or the nurse clinicians who were following
> them, as well.]{.underline}
>
> [So, to think that this reflects, this improvement in NYHA class
> reflects some enormous blinding on the part of the surgeons doing this
> at some level is an insult I think to the participants in the
> study.]{.underline}
>
> [DR. LASKEY: The panel abjectly apologizes for any sense of insult. It
> wasn\'t meant to be an insult, but I think that the answer is that the
> investigators and/or their associates obtained this information. We
> certainly didn\'t mean to insult them.]{.underline}
>
> [DR. NISSEN: As opposed to an independent third party. I mean, look, I
> mean you asked if there could have been better methods, and the answer
> is that it would have been extremely easy to have a non-participating
> person do the assessment of functional classification, and that would
> have been the proper approach from a trial design point of view, and
> that was not what was done.]{.underline}
>
> [DR. DOMANSKI: I think there are some other things, though, that came
> in. It wasn\'t just NYHA. NYHA class is tough, because don\'t forget,
> there is a big placebo effect. I mean if you bury one of these things
> in somebody\'s chest, they want to feel better.]{.underline}
>
> [So, I would be worried about that, as well, in terms of unblinding,
> but I think there were also, you know, they did the SF-36, you know,
> they did a bunch of things and stuff.]{.underline}
>
> [DR. KONSTAM: I completely agree with the points that were made, but I
> still keep coming back to the fact that the control group had so many
> dead people in it, so the issue really changes. I mean if you had 90
> percent survival in both groups, you would really want to know which
> group is doing better.]{.underline}
>
> [When three-quarters of the control group is dead by a year, I think
> the question changes. The question becomes one, which is much more
> difficult to answer, which is how is the treatment group doing, and do
> we have a sense that they are all vegetative, do we have a sense that
> they are all hospitalized, or do we have a sense that at least a
> sizable number of them are actually doing okay, and looked at it that
> way, you know, I think the data are adequate for me to say, you know,
> there are sizable numbers of patients that at least at six months and
> a year are doing okay.]{.underline}
>
> [DR. LASKEY: And that you can\'t be doing well if you are
> dead.]{.underline}
>
> [DR. KONSTAM: You can\'t be doing well if you are dead.]{.underline}
>
> [DR. LASKEY: No. 5. I think we have been grappling with the
> denominator here, that is, the benefit as it relates to Question No. 3
> and the data analysis and the magnitude of the clinically meaningful
> survival benefit, that being the denominator of the risk-benefit
> ratio.]{.underline}
>
> [Do we need more discussion about the presence of risk or do we need
> to focus in on the magnitude of this risk and how it relates to that
> ratio?]{.underline}
>
> [We all agree that there is risk with this device. Where is this
> ratio, is it closer to zero or closer to 1, I guess is what you need
> to know.]{.underline}
>
> [DR. BERMAN: I think the panel has discussed this question along with
> the others.]{.underline}
>
> [DR. LASKEY: Okay.]{.underline}
>
> [DR. PINA: Let me bring up one point that hasn\'t been brought up, and
> it is part of the protocol, and that is the issue of cost, which has
> not even entered into any of the data that we have, but the expense
> even on a surviving family member may be some of the risks that have
> to be assumed other than just the physical risk.]{.underline}
>
> [So, I think that is something we need to keep in the back of our mind
> even though that is not part of the data that we have.]{.underline}
>
> [DR. ZUCKERMAN: Again, Dr. Laskey, for Question No. 5, the question is
> do the benefits of this device outweigh its risks. Is there any
> consensus at this point from panel members?]{.underline}
>
> [DR. LASKEY: What I am hearing at this point is I don\'t think there
> is consensus, you may see consensus or lack thereof with voting in
> several minutes, but I think right now we have aired the concerns
> about both the numerator and the denominator, and their relative
> weight will be reflected in how people vote.]{.underline}
>
> [DR. KLOCKE: I would answer that as possibly, but not clear to me at
> this point.]{.underline}
>
> [DR. LASKEY: Labeling. I think it is fair to say we have had an
> extensive discussion about the nature of this patient population. What
> is missing is how the investigators got there and how that translates
> into more detailed information in the IFU, I am not convinced that we
> have heard that.]{.underline}
>
> [DR. BERMAN: Is it fair to say that the panel thinks there needs to be
> more details or more specific indications?]{.underline}
>
> [DR. OSSORIO: Yes.]{.underline}
>
> [DR. PINA: Yes. I think in the patient booklet, where there is a whole
> series of warnings, and I understand what Eric said, that a lot of
> these patients are not exactly going to be reading this great detail,
> but the relatives will be, and the spouses very often do, that all the
> complications that have been found in the study need to be enumerated,
> so that the patient is well informed and the spouse is well informed
> about all the risks, and that is not in there.]{.underline}
>
> [DR. COMEROTA: Which includes those who are indicated for the
> procedure, as well as those who are not indicated for the
> procedure.]{.underline}
>
> [DR. KONSTAM: Can I just make sure that the point is made and see if
> other people agree, that based on what we see in the REMATCH study,
> this device should only be indicated for people who are severely ill
> and with an extremely limited life expectancy.]{.underline}
>
> [Now, there were some comments on that made both sides, but I think
> based on what we see in the survival data at two years, and those of
> us who think it is acceptable or not acceptable, nevertheless, most of
> the patients in the device group are dead at two years, and therefore,
> I cannot imagine doing anything other than approving this device for
> patients with an extremely limited life expectancy without this
> device.]{.underline}
>
> [Now, how you get there is for further discussion, but I think that
> would be the sense that I would want to inject into it.]{.underline}
>
> [DR. DeWEESE: I would agree.]{.underline}
>
> [DR. LASKEY: Does the labeling accurately inform patients of the
> risks, well, there were certainly conspicuous warnings and cautions,
> and so forth, which relate to I think mechanical malfunction. I am not
> sure what the data are there on the risks of infection and bleeding,
> and so forth.]{.underline}
>
> [DR. PINA: It\'s not in there.]{.underline}
>
> [DR. OSSORIO: Along with accurately informing about risk, if there are
> things that patients can do to minimize those risks or their family
> members and people who are helping them if they happen to go home,
> those things ought to be in there, too.]{.underline}
>
> [DR. KONSTAM: I would say that this cuts to the heart. We talked
> earlier about patient choice. If we wind up approving this, I think
> some of us are going to say we are doing it because we think there
> should be an option for the patient, but if it\'s an option for the
> patient, here, really more than any other application for anything I
> have ever seen, we really have to take pains to inform the patient of
> what he or she is getting himself into and what kind of adverse events
> have been observed over the two years of this study.]{.underline}
>
> [You know, here is one where I don\'t mind scaring the patient, to
> tell you the truth, because of the degree of uncertainty that we have
> and what we have seen in this trial. I think a good deal needs to be
> done with this document to make sure patients adequately get a sense
> of that.]{.underline}
>
> [DR. PINA: I think also, in all fairness to the sponsor, they probably
> haven\'t seen these kinds of complications because this is a sicker
> group than I have ever seen LVADs in, because most of these patients,
> we would not transplant, and therefore, we would have not have
> VADed.]{.underline}
>
> [So, I think in all fairness, this is probably their first experience
> with this very, very sick cohort where these complications were
> arising. This isn\'t the usual.]{.underline}
>
> [MR. MORTON: One point of clarification I would make is I have heard
> the panel refer to letting the genie out of the bottle, and that is a
> connotation of something that is out of control, and labeling is very
> much a way that release of this device could be
> controlled.]{.underline}
>
> [I know that on devices of this type, the FDA and the sponsor work
> together to very clearly define what the training program is going to
> be and what the release program is going to be, so I would like us to
> move away from the genie out of the bottle image.]{.underline}
>
> [DR. LASKEY: Fair enough.]{.underline}
>
> [Does the labeling inform patients of the expected duration of
> use?]{.underline}
>
> [DR. WITTES: It needs more.]{.underline}
>
> [DR. LASKEY: Very good, Janet. Needs more.]{.underline}
>
> [DR. KONSTAM: I would be fairly draconian about this. I think that the
> panel has some serious, at this point, lack of information and
> uncertainty about the duration of this device, and I think that
> somehow again, I think the patient needs to be informed of
> that.]{.underline}
>
> [I think the comments that\'s in the proposed wording is simply that
> sometime in your life, you might expect to have to have this replaced.
> Well, I mean that sort of begs a lot of the issues that we have raised
> like there is no indicator of end of life, number one, so what is the
> implication of that.]{.underline}
>
> [Secondly, how many patients do we have now experience with, who have
> had successful reimplants and alive? I think there is one such patient
> who has had reimplant and are alive. Maybe there is more than one.
> Two? Okay, two. That is a very, very, very, very small experience, and
> to have that reflected by a comment that says at some point you might
> have to have this changed really strikes me as pushing
> it.]{.underline}
>
> [So, that wording really has to be rethought, and I think based on
> what we see right now, it should be made very blunt that we don\'t
> fully know the expected life expectancy of this, and somehow these
> points needs to be brought out.]{.underline}
>
> [DR. LASKEY: No. 7, PMA, postmarketing. I think we all would agree
> yes. There is a need for additional clinical follow-up specifically,
> and there is certainly a need for more appropriate risk stratification
> for who will benefit or who won\'t.]{.underline}
>
> [DR. ZUCKERMAN: Can you comment on what the major questions would be
> to answer in any sort of postmarket experience?]{.underline}
>
> [DR. PINA: Let me start out by again expressing my concerns about the
> internal device malfunction and the lack of knowing when it is going
> to malfunction, and I think the company has experience in the bridging
> group with perhaps the same problems, and all these other variations
> have been made, like the SNAP, the different wiring system, and I
> think we need a body of data on internal pump malfunction with all the
> advances and all the improvements that the company has made. I don\'t
> think we have that, and I certainly haven\'t seen it.]{.underline}
>
> [DR. DOMANSKI: One thing you will gain with your postmarket
> surveillance is you will gain a sense of the time course of the
> different types of complications - patient complications, device
> complications, and so forth, with this device, and then other ones
> that come along.]{.underline}
>
> [So, actually, I think the postmarket surveillance in this case could
> be quite useful, particularly as the device evolves or devices like it
> evolve.]{.underline}
>
> [DR. KONSTAM: Can I add one other thing, I guess to come back to, I
> had raised earlier, is the question of anticoagulation. I just would
> like to see going forward some consideration of potential
> anticoagulation regimens.]{.underline}
>
> [I don\'t know what that would be right now, but we are seeing, to me,
> a higher than expected number of what I consider thromboembolic
> events, and I don\'t understand all the bleeds, but I think that that
> should be addressed with some postmarketing research.]{.underline}
>
> [DR. LASKEY: Certainly, first of all, with collection of information
> to get a better idea of the rate because it is entirely possible the
> rate may be higher in real life than in the trial settings. So,
> additional ascertainment of endpoints. Okay.]{.underline}
>
> **[Open Public Hearing]{.underline}**
>
> [DR. LASKEY: I would like for the last time today to open the forum
> for public hearing.]{.underline}
>
> [Is there anyone in the audience who wishes to address the panel on
> this topic?]{.underline}
>
> [\[No response.\]]{.underline}
>
> [DR. LASKEY: If not, then, I will close the public hearing and request
> that the sponsor come forward and give us your final
> sentiments.]{.underline}
>
> **[Sponsor Comments]{.underline}**
>
> [MR. MIDDLEBROOK: Certainly, all aspects of the study have been
> discussed thoroughly here today, and we just want to thank all the
> panelists for their insight and their analysis.]{.underline}
>
> [As a company, we are committed to, as Vic said, continuously improve
> this product, and if we look at our experiences from the bridge to
> transplant, generally speaking, our results have improved from the
> time when we did the clinical trial. We would hope that that
> improvement would be seen here as we look at this nascent
> therapy.]{.underline}
>
> [Again, I would like to thank the panelists, the FDA, and certainly
> all of our presenters.]{.underline}
>
> [Thank you.]{.underline}
>
> [DR. LASKEY: Thank you.]{.underline}
>
> [I would like to ask Dr. Ewing to read the voting
> options.]{.underline}
>
> **[Panel Voting]{.underline}**
>
> [DR. EWING: The panel recommendation options for premarket approval
> applications are the Medical Device Amendments to the Federal Food,
> Drug, and Cosmetic Act as amended by the Safe Medical Devices Act of
> 1990, allows the Food and Drug Administration to obtain a
> recommendation from an expert advisory panel on designated medical
> device premarket approval applications that are filed with the
> Agency.]{.underline}
>
> [The PMA must stand on its own merits and your recommendation must be
> supported by safety and effectiveness data in the application or by
> applicable publicly available information.]{.underline}
>
> [Safety is defined in the Act as, \"Reasonable assurance based on
> valid scientific evidence that the probable benefits to health under
> conditions of intended use outweigh any probable risk.\"]{.underline}
>
> [Effectiveness is defined as, \"Reasonable assurance that in a
> significant portion of the population, the use of the device for its
> intended uses and conditions of use, when labeled, will provide
> clinically significant results.\"]{.underline}
>
> [Your recommendation options for the vote are as follows:]{.underline}
>
> [Approval if there are no conditions attached. Approvable with
> conditions. The panel may recommend that the PMA be found approvable
> subject to specified conditions, such as physician or patient
> education, labeling changes, or a further analysis of existing data.
> Prior to voting, all of the conditions should be discussed by the
> panel.]{.underline}
>
> [The third option is not approvable. The panel may recommend that the
> PMA is not approvable if: the data do not provide a reasonable
> assurance that the device is safe, or if a reasonable assurance has
> not been given that the device is effective under the conditions of
> use prescribed, recommended, or suggested in the proposed
> labeling.]{.underline}
>
> [Following the voting, the Chair will ask each panel member to present
> a brief statement outlining the reasons for their vote.]{.underline}
>
> [DR. OSSORIO: May I ask for a point of clarification?]{.underline}
>
> [DR. LASKEY: Yes.]{.underline}
>
> [DR. OSSORIO: That very last thing that you just said, under the
> proposed labeling. Now, we have all made quite a number of suggestions
> about what we think ought to go on the labeling, so when we are
> voting, are we voting assuming that those suggestions would be
> incorporated, or are we voting based on what we have right now in this
> packet?]{.underline}
>
> [DR. EWING: If the panel feels that to be approvable, then, the
> changes in labeling would be necessary, then, that could be approvable
> with conditions.]{.underline}
>
> [DR. LASKEY: It is your prerogative, Dr. Konstam, to make a
> motion.]{.underline}
>
> [DR. KONSTAM: I move approvable with conditions.]{.underline}
>
> [DR. LASKEY: And they would be?]{.underline}
>
> [DR. KONSTAM: I have a bunch.]{.underline}
>
> [DR. LASKEY: First, we need a second.]{.underline}
>
> [\[Second.\]]{.underline}
>
> [DR. LASKEY: You have a second, so you might want to delineate the
> conditions.]{.underline}
>
> [DR. KONSTAM: I have a bunch of conditions, and I think they have all
> been touched upon. One is additional analysis of existing data. The
> two that occur to me are revisiting the whole question of reliability,
> bringing data up to date, and getting a clear indication of
> reliability at two years.]{.underline}
>
> [Secondly, that analysis that Mike Domanski had suggested of time to
> death or stroke be looked at to be certain that it is at least
> consistent with the observation with regard to survival. So, existing
> data would be one.]{.underline}
>
> [Secondly, the indications for the device be much more extensively
> delineated particularly to denote a population with a very limited
> life expectancy without the device implanted.]{.underline}
>
> [Third, that there be fairly rigorous criteria for implantation from
> the perspective of both the surgeon and the facility at which it would
> be done to be certain that both patient selection and expertise in the
> procedure and in patient follow-up meets a high level of
> acceptability.]{.underline}
>
> [Fourth, that there be a significant amount of postmarketing work be
> done surveying patients in whom these are implanted as least out to
> two years with analysis of reliability and analysis of all of the
> other adverse effects that we saw here and their rates.]{.underline}
>
> [I had mentioned earlier I would include in that some kind of
> consideration of the need for anticoagulation.]{.underline}
>
> [Finally, that there a lot of work go into a detailed set of
> information for the patients that really, as best as can be
> accomplished, delineates for the patient what the tradeoff is that he
> or she is getting himself into with this.]{.underline}
>
> [DR. LASKEY: There are five conditions then, and we need to vote on
> each one separately. Can we have some discussion amongst the panel
> members about Dr. Konstam\'s first condition, which is the requirement
> for more data analysis from the current data set?]{.underline}
>
> [DR. NISSEN: Could I understand this, does that mean that it would not
> be approvable until the data is analyzed, is that what you are saying?
> I am not sure I know what you mean by that.]{.underline}
>
> [DR. KONSTAM: Well, I guess I would want to ask the Agency what the
> options are in that regard.]{.underline}
>
> [DR. ZUCKERMAN: You are making a recommendation whereby potentially
> the device is approvable if these conditions are met.]{.underline}
>
> [DR. DOMANSKI: But I thought that what you meant was that these
> analyses would take place over time. You know, if you don\'t think
> it\'s approvable until they meet it, that is different than saying we
> are going to do postmarket surveillance after.]{.underline}
>
> [DR. KONSTAM: Let\'s take the one that you suggested, the analysis of
> time to death or stroke. You made a compelling argument for
> that.]{.underline}
>
> [DR. DOMANSKI: I think that is fine. I think that is an easy one for
> them to come in with, and I think the numbers of events are such that
> that is not going to be a land mine in the field for them, but that is
> something they can go over with FDA staff, so that is fine. They are
> not going to have a problem with that.]{.underline}
>
> [I will just finish discussing the question. I would suggest that they
> not be forced to go out and gather new data.]{.underline}
>
> [DR. KONSTAM: What I meant with regard to the reliability is more
> detailed analysis of existing data.]{.underline}
>
> [DR. EWING: If you do not believe that there is sufficient information
> currently here, then, it would make more sense to vote not approvable,
> if you are talking about you need the results of current
> analysis.]{.underline}
>
> [DR. KONSTAM: At least what I had intended was pretty much along the
> lines that Mike was suggesting. I do think that the first part of that
> is the analysis of death or stroke. I would like the Agency to hear my
> sense that I am assuming, Mike is assuming that that analysis will not
> radically change the overall survival analysis, and if it did, if it
> looked like all of a sudden it was substantively different\--and I
> don\'t know how to advise you better than that\--then, I would
> reconsider my approval. I don\'t know how to convey that.]{.underline}
>
> [DR. DOMANSKI: I have a suggestion. I will tell you what I really
> think. I think the number of events is not going to be sufficient to
> make much difference, and I would leave that out, delete that from
> your motion, and let the FDA just look over the entire application,
> because this is a recommendation, and not put this in as some kind of
> a firewall. I can\'t imagine it would, and the FDA is going to look at
> this thing. I just don\'t want to see them disapproval over something
> like that.]{.underline}
>
> [DR. KONSTAM: I think we are saying the same thing. I think the Agency
> has the prerogative of looking at the data and say you know what, I
> mean they can do whatever they want with it. They don\'t have to
> accept our final vote, so I guess we are saying the same
> thing.]{.underline}
>
> [DR. DOMANSKI: One way of doing this would be to structure the
> recommendations on things that need substantive change. I mean the FDA
> is going to go over this whole application again, but there really are
> some substantive things that they have to do.]{.underline}
>
> [The panel wants different labeling, so they are recommending
> that.]{.underline}
>
> [DR. LASKEY: He has put five recommendations, five conditions on the
> table for his recommendation. We need to either take them apart or
> just whittle that down to one or two. Can we try and do that, so we
> get a coherent, articulate vote?]{.underline}
>
> [DR. KONSTAM: Let me then clarify. I guess I would still stick to my
> first one, but I am not basing approvability\--]{.underline}
>
> [DR. LASKEY: The first one being\--just so we are all on the same page
> here\--is additional data analysis as pertain to device reliability
> and?]{.underline}
>
> [DR. KONSTAM: And analysis of time to death or stroke.]{.underline}
>
> [DR. LASKEY: Time to death or stroke in the current data
> set.]{.underline}
>
> [DR. COMEROTA: And the purpose of that is not for device approval, but
> better judgment on the basis of physicians and patients in the future
> upon whether their decision should be to move ahead with their own
> decisionmking or not, more informed consent on the patient\'s
> part.]{.underline}
>
> [DR. LASKEY: Yes, it is to be added to the labeling, is that correct?
> Okay.]{.underline}
>
> [Enough discussion on that condition? Shall we vote? Voting on these
> two conditions to Dr. Konstam\'s motion for approval, the first
> condition being additional data on device reliability and additional
> data on time to death or stroke.]{.underline}
>
> [DR. WITTES: Analysis.]{.underline}
>
> [DR. LASKEY: Analysis, yes, of the current data set.]{.underline}
>
> [DR. OSSORIO: Can I ask for a point of clarification? Could we vote,
> say yes on the various amendments, and at the end, still vote no on
> the motion?]{.underline}
>
> [DR. LASKEY: Yes.]{.underline}
>
> [DR. EWING: For the first condition, we need to go around the room,
> start with Dr. Wittes, please.]{.underline}
>
> [DR. WITTES: I am going to vote no. I think it should be a
> recommendation. I don\'t see it as a condition.]{.underline}
>
> [DR. DOMANSKI: So, this isn\'t framed as a recommendation, is that
> right?]{.underline}
>
> [DR. EWING: This is the first condition of approval.]{.underline}
>
> [DR. DOMANSKI: I will vote yes to that, fine, do the
> analysis.]{.underline}
>
> [DR. KONSTAM: I vote yes.]{.underline}
>
> [DR. COMEROTA: I vote yes.]{.underline}
>
> [DR. NISSEN: Either we need more data or we don\'t need more data, and
> since I would like to see more data, I am not sure whether voting yes
> is going to let us look at more data before we make a decision, so I
> am going to abstain. I mean either we need these data in order to make
> a decision or we don\'t. I think I need these data in order to make a
> decision. Lacking those data, I don\'t think the amendment helps
> me.]{.underline}
>
> [DR. AZIZ: Yes for Dr. Aziz.]{.underline}
>
> [DR. PINA: Yes.]{.underline}
>
> [DR. OSSORIO: Yes.]{.underline}
>
> [DR. DeWEESE: Yes.]{.underline}
>
> [DR. KLOCKE: Yes.]{.underline}
>
> [DR. EWING: Thank you. I will tabulate that that is 8 yes, 1 no, 1
> abstain. The condition carries.]{.underline}
>
> [DR. LASKEY: Are you happy with the distillation of the
> conditions?]{.underline}
>
> [DR. ZUCKERMAN: Yes.]{.underline}
>
> [DR. LASKEY: Any discussion on Dr. Konstam\'s recommendation for
> additional clarification or new indications for use? Do we need to go
> through that?]{.underline}
>
> [DR. PINA: No, I think we have discussed that pretty well, and it may
> merit some other meeting at some point to sit down and really go
> through, and the Agency can do this, to go through the patient
> population that, in fact, would be eligible for this.]{.underline}
>
> [DR. EWING: Okay. We can take a vote although Dr. Domanski has stepped
> out. We will come back to him.]{.underline}
>
> [Dr. Wittes.]{.underline}
>
> [DR. WITTES: Yes.]{.underline}
>
> [DR. KONSTAM: Yes.]{.underline}
>
> [DR. COMEROTA: Yes.]{.underline}
>
> [DR. NISSEN: Yes.]{.underline}
>
> [DR. AZIZ: Yes.]{.underline}
>
> [DR. PINA: Yes.]{.underline}
>
> [DR. OSSORIO: Yes.]{.underline}
>
> [DR. DeWEESE: Yes.]{.underline}
>
> [DR. KLOCKE: Yes.]{.underline}
>
> [DR. EWING: That is almost unanimous for No. 3, the conditions for
> clarification of indications of use, clarification of the patient
> population indicated and excluded.]{.underline}
>
> [The next was the postmarket study.]{.underline}
>
> [DR. KONSTAM: No, the next is criteria for use both in terms of the
> operator and the site be clarified to be certain of high quality in
> patient selection and in performance.]{.underline}
>
> [DR. LASKEY: And training and experience.]{.underline}
>
> [DR. KONSTAM: But it is a little bit more than training. Training
> and\--]{.underline}
>
> [DR. PINA: Setting standards?]{.underline}
>
> [DR. KONSTAM: Setting standards for both the operator and the
> site.]{.underline}
>
> [DR. LASKEY: So, what you would like to see the Agency receive is a
> document outlining the criteria for credentialing, if you
> will.]{.underline}
>
> [DR. KONSTAM: Right, and the spirit is that it be fairly
> rigorous.]{.underline}
>
> [DR. PINA: And could I add that it is not just limited to surgeons,
> but also to cardiologists taking care of this patient
> population.]{.underline}
>
> [DR. KLOCKE: And could I ask that it include the group\'s best
> recommendations at that point in terms of infection control in
> relationship to the issues that I have been talking
> about?]{.underline}
>
> [DR. KONSTAM: That is fine with me.]{.underline}
>
> [DR. AZIZ: Do you want to restrict it to transplant
> centers?]{.underline}
>
> [DR. KONSTAM: Well, I held back from saying that. Maybe it is worth
> some additional discussion on the part of the panel about how far we
> want to go and what we mean. I mean I would be happy with limiting it
> to transplant center if other people on the panel would.]{.underline}
>
> [DR. LASKEY: I think in deference to Mr. Morton who raised the point
> that we really should not concern ourselves with how this device is
> used or abused, we just need to go forward in good faith and outline
> criteria for training and experience of these centers and individuals,
> realizing it is a system as much as people.]{.underline}
>
> [DR. KONSTAM: I thought he was saying that it is these very processes
> of labeling and training that give us a comfort level that we are not
> \"letting the genie out of the bottle\" by doing these
> things.]{.underline}
>
> [MR. MORTON: Thank you. That is true. Again, from my experience on a
> device of this type, it is a collaborative process with the Agency of
> exactly what the training program is going to be and exactly how the
> release will happen.]{.underline}
>
> [DR. NISSEN: I am glad you all have faith that nobody ever uses
> devices off label.]{.underline}
>
> [DR. ZUCKERMAN: I think the issues from the Agency perspective are,
> one, two, consider Dr. Konstam\'s motion that the training program be
> rigorous and looked at by FDA. The second part is that potentially, as
> a postmarket requirement, one can look at how new sites are brought up
> to speed, et cetera, but there are two parts, and Dr. Konstam is first
> just asking about the review of a training program.]{.underline}
>
> [DR. KONSTAM: Did you want more specification to that or do you feel
> like leaving it as clear as we have is sufficient?]{.underline}
>
> [DR. ZUCKERMAN: Why don\'t you try restating it, so that then we can
> have a vote.]{.underline}
>
> [DR. KONSTAM: I think the spirit of what I would like to convey is
> that this device be implanted in centers and by individuals who are
> highly trained and specialized in the management of patients with
> end-stage heart failure both from the perspective of patient selection
> and surgical procedure, and perioperative management and long-term
> management. I guess that is really what I meant now.]{.underline}
>
> [DR. ZUCKERMAN: Are you asking FDA to review the company\'s training
> program as a condition of approval?]{.underline}
>
> [DR. KONSTAM: Yes.]{.underline}
>
> [DR. LASKEY: That is fairly straightforward. Do you want to just do a
> hand vote?]{.underline}
>
> [DR. EWING: Sure.]{.underline}
>
> [DR. LASKEY: All in favor of this condition?]{.underline}
>
> [\[Show of hands.\]]{.underline}
>
> [DR. EWING: I believe that is unanimous. Is that correct?
> Okay.]{.underline}
>
> [DR. LASKEY: As I recall, the last condition was\--]{.underline}
>
> [DR. KONSTAM: There were two more.]{.underline}
>
> [DR. LASKEY: Sorry.]{.underline}
>
> [DR. KONSTAM: Next was the postmarketing, and then the final one was
> information for patients.]{.underline}
>
> [DR. LASKEY: Let\'s take the first. Maybe I misunderstood. The
> information requested from postmarketing surveillance would
> be?]{.underline}
>
> [DR. KONSTAM: Well, we talked about it before, I think developing a
> sizable body of experience at least out to two years, tracking patient
> survival, tracking complications, tracking device reliability and
> durability. There may be others people want to add to
> that.]{.underline}
>
> [DR. COMEROTA: Marv, would you be comfortable in extending that to
> death since a large percentage of those who have lived two years, died
> shortly thereafter? I would like to see it extended out to
> death.]{.underline}
>
> [DR. KONSTAM: Sure, so indefinitely.]{.underline}
>
> [DR. COMEROTA: Yes.]{.underline}
>
> [DR. KONSTAM: To death, yes.]{.underline}
>
> [DR. COMEROTA: Well, death is rather definite.]{.underline}
>
> [DR. KONSTAM: Definitely.]{.underline}
>
> [DR. LASKEY: Marv, given the limited capability of the Agency to do
> these kinds of surveillance, what would you recommend that they focus
> on, that they require?]{.underline}
>
> [DR. KONSTAM: You mean in terms of duration of follow-up or in terms
> of what they are looking at?]{.underline}
>
> [DR. LASKEY: More what they are looking at.]{.underline}
>
> [DR. KONSTAM: I think the things that I listed shouldn\'t be too
> onerous. I mean patient survival, device survival, and major
> complications, at least the major complications as were demonstrated
> in this study.]{.underline}
>
> [DR. PINA: Implantation rate.]{.underline}
>
> [DR. KONSTAM: That is device survival.]{.underline}
>
> [DR. LASKEY: This is all in the form of a registry, or are you
> recommending the conduct of an additional trial, if you
> will?]{.underline}
>
> [DR. KONSTAM: Well, I wasn\'t recommending a randomized
> trial.]{.underline}
>
> [DR. DeWEESE: Can\'t we just ask for what they have done in the first
> two years? That is what we want them to do, we want to get the same
> information we had before.]{.underline}
>
> [DR. WITTES: We are asking for less, I think, than what they did in
> the first two years. It seems to me we are talking about a
> registry.]{.underline}
>
> [DR. ZUCKERMAN: At this point, Dr. Konstam, perhaps you can help us
> with what major questions you would like to see answered in a new
> cohort experience, and then the Agency and sponsor can work together
> on what type of trial design might be optimal, but if we can first
> define the questions.]{.underline}
>
> [DR. KONSTAM: I would like to know the life expectancy after
> implantation. I would like to know reliability and longevity of the
> device. I would like to know the frequency of the major complications
> that were identified in this trial, and I guess I would add to it and
> ask for some discussion or comments, you know, some indication of
> patient function, some indication that patients are doing well, and I
> don\'t know if people want to discuss what that should look like, but
> something more than that they are just alive.]{.underline}
>
> [DR. AZIZ: Also, I think it would be important when a patient dies,
> that the device be examined by one center specifically, so any valve
> problems or any motor problems could be documented, because I think
> just because the patient dies, there may be different reasons, maybe
> sepsis. I think the devices must be examined and
> explanted.]{.underline}
>
> [DR. PINA: I would like to echo the functional capacity assessment
> because there are a lot of data on functional capacity and bridge to
> transplant, and that is well published and well known. So, I would
> like to see how this compares.]{.underline}
>
> [DR. KONSTAM: I also again would like to see something explored with
> regard to anticoagulation. I guess I don\'t want to make that more
> definitive right now except to say that I would like some sort of
> study proposed in the next six months, say, to explore\--]{.underline}
>
> [DR. LASKEY: You need a handle on the rates.]{.underline}
>
> [DR. KONSTAM: My feeling would be that we already have from the data
> set in front of us, evidence that there is an excessive rate of
> thromboembolic events, more than anticipated. That is my
> interpretation of the data. Maybe there will be some differences of
> opinion on that.]{.underline}
>
> [DR. COMEROTA: I thought they were less for a totally implantable
> prosthetic without anticoagulation.]{.underline}
>
> [DR. KONSTAM: Less than what?]{.underline}
>
> [DR. COMEROTA: Less than anticipated.]{.underline}
>
> [DR. DOMANSKI: I have a sort of process problem with that, and the
> process problem is this. We are approving this. All of the data that
> have come in here, have come in without the
> anticoagulation.]{.underline}
>
> [Now, we are approving the device, and you are trying to mandate a
> study that basically send them off label to do some anticoagulation. I
> don\'t think we can do that. I mean I think it is a good research
> study to do, but I think somebody ought to apply to NIH. I don\'t
> think we should be asking the sponsor to try to do something that is
> off label.]{.underline}
>
> [DR. COMEROTA: It is part of the condition, what you are saying, it
> would be appropriate to document that platelet inhibitors, what
> anticoagulants the patients are on, and monitor the outcome as a
> registry.]{.underline}
>
> [DR. KONSTAM: That\'s fine. If there is no objection, I would amend it
> to say that special attention should be placed in the postmarketing
> survey to examine rates of thromboembolic events with an eye toward
> considering subsequent investigation based on what events rate is
> seen.]{.underline}
>
> [DR. LASKEY: I think that is fine in concept, but there is not going
> to be a DSMB, there is not going to be adjudication committee. This
> may be a tough one. I agree with you it is important, but it could be
> an under- or an over-estimate unless somehow it is ascertained
> appropriately or accurately.]{.underline}
>
> [DR. KONSTAM: Can\'t the FDA\--]{.underline}
>
> [DR. LASKEY: You need to make that recommendation clearly in this
> condition.]{.underline}
>
> [DR. ZUCKERMAN: Yes, in the condition of approval, you can also ask
> that an independent CEC, similar to the original randomized study,
> continue to look at events to better clarify what are actual
> rates.]{.underline}
>
> [DR. KONSTAM: I could live with that.]{.underline}
>
> [DR. LASKEY: The registry\'s requirements are getting
> longer.]{.underline}
>
> [DR. KONSTAM: That\'s fine. I don\'t have any objection. That doesn\'t
> bother me.]{.underline}
>
> [DR. LASKEY: Are we all clear on what we are voting on then for
> Condition No. 4, which is the recommendation to the Agency in terms of
> establishing a registry for purposes of postmarketing surveillance to
> assess rates of\--]{.underline}
>
> [DR. KONSTAM: \--survival, device failure, and major adverse events
> including thromboembolic events.]{.underline}
>
> [DR. LASKEY: All in favor?]{.underline}
>
> [\[Show of hands.\]]{.underline}
>
> [DR. EWING: So, everyone except for Dr. Wittes?]{.underline}
>
> [DR. WITTES: I am going to abstain.]{.underline}
>
> [DR. LASKEY: And your last condition was the instructions for the
> patient information pack?]{.underline}
>
> [DR. KONSTAM: Yes, that the patient information package
> really\--]{.underline}
>
> [DR. LASKEY: Serious buffing up.]{.underline}
>
> [DR. KONSTAM: Yes, make clear the risks and what the patient is
> getting into.]{.underline}
>
> [DR. LASKEY: So, rates of adverse events and certainly perhaps the
> addition of some help rewriting it. It is highly technical, I will
> agree.]{.underline}
>
> [Can we vote on that?]{.underline}
>
> [DR. AZIZ: The device once it\'s explanted, should be sent to a
> center.]{.underline}
>
> [DR. LASKEY: I like that idea. I don\'t know how you can mandate\--
> you mean explanted\--]{.underline}
>
> [DR. AZIZ: When the patients die.]{.underline}
>
> [DR. LASKEY: Well, when they die, doesn\'t that require consent or
> permission? I don\'t know if you can mandate that.]{.underline}
>
> [DR. DOMANSKI: I wonder if they are not getting those devices back
> anyway. Maybe we could ask them that, because that may be an easy one
> actually. Are you getting them back?]{.underline}
>
> [MR. MIDDLEBROOK: Yes, we do like to get the devices back, and we do
> take them apart and disassemble them, and we do an analysis on them.
> We collect that data and analyze it periodically.]{.underline}
>
> [DR. LASKEY: Can you require that, though?]{.underline}
>
> [MR. MIDDLEBROOK: I don\'t think it can be required because they
> refuse to return it, and we can\'t mandate that.]{.underline}
>
> [DR. AZIZ: That is really the only way, if these devices are going to
> be in for a long time.]{.underline}
>
> [DR. LASKEY: I would agree. I can see a family just refusing
> permission.]{.underline}
>
> [DR. AZIZ: That is a different issue, but I think all efforts should
> be made, because that is the only way, if these devices are in for
> four years or three years, we are going to learn
> something.]{.underline}
>
> [DR. LASKEY: I would agree. Should that be in the patient package
> then?]{.underline}
>
> [DR. DOMANSKI: I think it is great to inform. I was actually part of a
> trial where we did that once. I would stop short of informing them
> about what should go on at their autopsy. That probably is
> unreasonable.]{.underline}
>
> [DR. LASKEY: So, voting on the condition for the modification of the
> patient information package as currently written.]{.underline}
>
> [DR. KONSTAM: Let me just add to that, that based on what we see right
> now, there should be some indication of the limited present life
> expectancy of this device.]{.underline}
>
> [DR. LASKEY: Full disclosure.]{.underline}
>
> [All in favor?]{.underline}
>
> [\[Show of hands.\]]{.underline}
>
> [DR. EWING: That is unanimous for the last condition presented so
> far.]{.underline}
>
> [DR. LASKEY: That\'s the end of Dr. Konstam\'s list.]{.underline}
>
> [I shudder to ask this question, but are there any other
> conditions?]{.underline}
>
> [\[Laughter.\]]{.underline}
>
> [DR. LASKEY: No. Well done.]{.underline}
>
> [DR. EWING: I would like for the panel members to go around now and
> just state their vote for approvable with conditions. We might as well
> start with Dr. Wittes again.]{.underline}
>
> [DR. WITTES: Yes.]{.underline}
>
> [DR. DOMANSKI: Yes.]{.underline}
>
> [DR. KONSTAM: Yes.]{.underline}
>
> [DR. COMEROTA: Yes.]{.underline}
>
> [DR. NISSEN: Do you want yes or no, or do you want
> explanations?]{.underline}
>
> [DR. EWING: I want a yes or no first.]{.underline}
>
> [DR. NISSEN: No.]{.underline}
>
> [DR. AZIZ: Yes.]{.underline}
>
> [DR. PINA: Yes.]{.underline}
>
> [DR. OSSORIO: No.]{.underline}
>
> [DR. DeWEESE: Yes.]{.underline}
>
> [DR. KLOCKE: Yes.]{.underline}
>
> [DR. EWING: So, that is 8 yes and 2 no.]{.underline}
>
> [DR. LASKEY: If each panel member could take 60 seconds to defend
> their position.]{.underline}
>
> [DR. WITTES: A short essay, right?]{.underline}
>
> [DR. LASKEY: Well, short.]{.underline}
>
> [DR. WITTES: To me, the data showed convincingly a sizable benefit,
> mortality at one year, but the device is risky, and so I believe the
> patients and their families should be informed of the likely risks and
> the time course of those risks.]{.underline}
>
> [DR. DOMANSKI: I think they demonstrated safety and efficacy per the
> statutes.]{.underline}
>
> [DR. KONSTAM: I think that survival was extended. I didn\'t hear any
> disagreement about that. I think there were sizable numbers of
> patients who it appears from the data set were doing fairly well with
> a very, very high percentage of mortality in the control
> group.]{.underline}
>
> [I am concerned about the adverse events that were seen. I am
> concerned about the durability of the device and the fact that there
> was such low survival at two years, but that was not enough to negate
> the basic underlying finding of efficacy in terms of
> survival.]{.underline}
>
> [DR. COMEROTA: We have a treatment that doubled survival in one year
> with no device failure. There is an accompanying body of data that
> shows substantial improvement in the functional status of the patients
> albeit it that has come under some criticism.]{.underline}
>
> [There was a parallel increase in quality of life.]{.underline}
>
> [DR. NISSEN: I think this is a very promising therapy for heart
> failure, but this device is not ready, and I find it hard to accept a
> device that during an average duration of survival of 400 days had a
> 30 percent internal failure rate.]{.underline}
>
> [The reason I am so concerned about that is that we all know the
> impact of approving a device, is there is a trickle-down in the device
> to patients very quickly beyond the group of patients studied in a
> trial like this, and labeling does not protect patients from
> that.]{.underline}
>
> [That trickle-down would be less concerning to me if the device were
> reliable, but the problem is it is not, and so if you put this device
> in patients that have a 92 percent risk of dying in two years, it is
> not too bad a bargain. If you put this device in patients that are a
> little bit less sick, now what you have done is replaced good medical
> therapy with not such good surgical therapy.]{.underline}
>
> [So, I think getting the device reliability up to a higher level of
> reliability would be essential for this to be a meaningful advance in
> the clinical treatment of such patients.]{.underline}
>
> [I think that that can be done, and I think it will be done, and I am
> concerned that based upon the outcome in 67 patients with a very high
> device failure rate, I do think we have opened Pandora\'s Box, and I
> don\'t want to be the purveyor of doom and gloom, but I think this
> will be a decision that many people in the medical community will come
> to regret.]{.underline}
>
> [DR. AZIZ: I think that device therapy as an alternative to
> transplantation is going to be here to stay. I echo some of the
> comments of my colleague that I think the device should be carefully
> monitored. I think it does have a fairly high incidence of malfunction
> or dysfunction.]{.underline}
>
> [I think at one year, clearly, it works well, but I think it will be
> very important in the postmarket surveillance to watch that carefully,
> that this really does not get out of hand.]{.underline}
>
> [DR. PINA: I share Dr. Nissen\'s concerns about the device falling
> into the hands of people who are ill equipped to use them, and who are
> not going to apply proper medical therapy to the advanced heart
> failure patient. However, that does not negate the survival number at
> one year, which was their endpoint, and they have met it, and
> therefore, I don\'t think that we can sit here and say no, do not
> approve it.]{.underline}
>
> [I do share some of the very concerns that Dr. Nissen has expressed,
> and I think we have couched this with a lot of conditions, and I am
> hoping and really hoping beyond hope that the company will take this
> to heart and apply it only to those populations that need it, and put
> it in centers where people do know what they are doing, and try to
> control the trickling-down effect which we have already seen with
> other devices.]{.underline}
>
> [DR. OSSORIO: While I was impressed by the survival numbers, I am
> still not convinced that there is real clinical significance, and
> until I see more and better data, and I feel very torn about this and
> knowing that other people had already voted in a way that it would be
> approved with these conditions, it left me open to express my feeling
> that this really should have come to us a little bit later where there
> were more data for us to evaluate.]{.underline}
>
> [I think the number of conditions that were put on this actually was
> part of what convinced me that a lot of the other panel members feel
> strong discomfort about what was before us today. I think we should be
> voting to approve or not based on what we have seen before us, what we
> could evaluate.]{.underline}
>
> [We don\'t have I think adequate Quality of Life measures to evaluate.
> We don\'t have adequate description of what kind of training and
> labeling there is going to be to evaluate. So, I voted
> no.]{.underline}
>
> [The other thing is that part of our assessment of safety has to be an
> assessment of whether the harms have been reduced as well as they
> could be, and I think that is where the adverse events data, and so
> forth, call into some serious questions with respect to the standards
> that we are supposed to be applying.]{.underline}
>
> [DR. DeWEESE: I am convinced by the survival information. I feel
> confident that the final group deciding these things will be sure that
> these are performed in transplant centers by capable people, and that
> it will be limited to people who cannot be transplanted.]{.underline}
>
> [DR. KLOCKE: My question is that the long-term beneficial effect of
> this device will depend crucially on the degree to which the current
> incidence of adverse events can be reduced. If it can\'t be reduced,
> the data we have will still stand, but my hunch is that after a
> period, that clinical acceptance will be in fact limited, and if the
> genie does get out of the bottle, we make go through a period, as we
> did with transplant, where we have a disappointing experience because
> the genie out of the bottle.]{.underline}
>
> [That will be unfortunate, but it will be transitory, but I believe
> that the key event for this long term is the degree to which we can
> improve further on the incidence of adverse events.]{.underline}
>
> [DR. OSSORIO: Can I say one more thing?]{.underline}
>
> [DR. LASKEY: Yes.]{.underline}
>
> [DR. OSSORIO: I also just wanted to say that part of the reason I am
> very torn about this is because in other contexts, in the cancer
> context, I have dealt a lot with patients who are really at the end of
> life, and I think it is very important for us not to be making value
> judgments as to whether or not one year is long enough.]{.underline}
>
> [If I really believed the data, or it\'s not that I don\'t believe the
> data, if I really had enough data to convince me, then, I would have
> voted for approvability, but giving patients additional choices,
> especially additional choices with lots of uncertainty, is also a
> burden to them.]{.underline}
>
> [It is not merely a benefit to have a lot of choices. It also adds
> then responsibilities to their lives, decisions they have to make,
> which we have data on the fact that these decisions are very stressful
> for people to make.]{.underline}
>
> [So, I don\'t want it to seem as though I am insensitive to the needs
> and desires of patients, but I think it is not always doing anybody a
> favor to give them an option where we can\'t tell them enough about
> it, and we can\'t tell them the kinds of things they would like to
> know to help them make their decision.]{.underline}
>
> [DR. LASKEY: Mr. Dacey or Mr. Morton, any final thoughts?]{.underline}
>
> [If not, I would just like to reopen for one last time the public
> forum. Are there any public comments?]{.underline}
>
> [\[No response.\]]{.underline}
>
> [DR. LASKEY: If not, then, I thank all participants, in particular the
> presenters, for their participation and for their
> endurance.]{.underline}
>
> [I close this portion of our panel meeting.]{.underline}
>
> [\[Whereupon, at 5:50 p.m., the proceedings were recessed, to be
> resumed on March 5, 2002, at 8:00 a.m.\]]{.underline}

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