"UNITED STATES OF AMERICA"
1 UNITED STATES OF AMERICA FOOD AND DRUG ADMINISTRATION CENTER FOR DEVICES AND RADIOLOGICAL HEALTH MEDICAL DEVICES ADVISORY COMMITTEE CIRCULATORY SYSTEM DEVICES PANEL MEETING THURSDAY, MARCH 17, 2005 The Panel met at 8:00 a.m. in the Crystals Ballroom of the Hilton Washington, D.C., North / Gaithersburg, 620 Perry Parkway, Gaithersburg, Maryland, Dr. William H. Maisel, Chairperson, presiding. PRESENT: WILLIAM H. MAISEL, M.D., Chairperson BRENT A. BLUMENSTEIN, Ph.D., Consultant JEFFREY A. BRINKER, M.D., Consultant THOMAS G. BROTT, M.D., Consultant HENRY HALPERIN, M.D., Consultant NORMAN S. KATO, M.D., Consultant JOHN MARLER, M.D., Consultant MICHAEL C. MORTON, Industry Representative LINDA A. MOTTLE, M.S.M.R.N., CCRP, Consumer Representative RICHARD L. PAGE, M.D., Member JOHN C. SOMBERG, M.D., Member MYRON WEISFELDT, M.D., Consultant GERETTA WOOD, Executive Secretary FDA REPRESENTATIVES: RICHARD P. FELTEN, M.S. RONALD M. LAZAR, Ph.D., Advisor JULIE SWAIN, M.D., Advisor RON YUSTEIN, M.D. YIHUA ZHAO, Ph.D. NEAL R. GROSS COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. (202) 234-4433 WASHINGTON, D.C. 20005-3701 (202) 234-4433 2 SPONSOR REPRESENTATIVES: KEN COLLINS, MBBS RISTO O. ROINE, M.D., Ph.D. FRITZ STERZ, M.D., Ph.D. JOEL VERTER, Ph.D. NEAL R. GROSS COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. (202) 234-4433 WASHINGTON, D.C. 20005-3701 (202) 234-4433 3 A-G-E-N-D-A CALL TO ORDER......................................4 OPEN PUBLIC SESSION................................8 Dr. Terry Vanden Hoek........................9 Dr. Mary Ann Peberdy........................14 SPONSOR PRESENTATION: ALSIUS CORPORATION Dr. Ken Collins.............................26 Dr. Fritz Sterz.............................40 Dr. Risto Roine.............................48 Discussion..................................52 Dr. Joel Verter.............................69 FDA PRESENTATION Richard P. Felten...........................84 Dr. Julie Swain.............................88 Dr. Yihua Zhao.............................101 Dr. Ronald Lazar...........................119 Discussion.................................129 REVIEWS Dr. John Somberg...........................143 Dr. Thomas Brott...........................150 GENERAL COMMENTS.................................165 SPONSOR ADDRESSES EARLIER STATEMENTS.............188 FDA QUESTIONS TO PANEL Question 1.................................199 Question 2.................................213 Question 3.................................223 Question 4.................................226 Question 5.................................230 OPEN PUBLIC HEARING SESSION......................243 NEAL R. GROSS COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. (202) 234-4433 WASHINGTON, D.C. 20005-3701 (202) 234-4433 4 1 P-R-O-C-E-E-D-I-N-G-S 2 8:06 a.m. 3 CHAIRMAN MAISEL: Good morning. 4 I'd like to call to order this meeting of 5 the Circulatory System Devices Panel. Today's topic is 6 discussion of a premarket notification for the Alsius 7 Corporation CoolGard 3000/Icy Catheter system, 8 K040429. 9 Geretta? 10 EXECUTIVE SECRETARY WOOD: Before we begin 11 this morning, I have a couple of announcements. 12 Due to an emergency, Dr. Hallstrom was not 13 able to join us today. We have Dr. Brent Blumenstein 14 on the phone filling in for this morning. 15 Now I would like to read the conflict of 16 interest. 17 The following announcement addresses 18 Conflict of Interest issues associated with this 19 meeting and is made part of the record to preclude 20 even the appearance of an impropriety. 21 To determine if any conflict existed, the 22 Agency reviewed the submitted agenda for this meeting NEAL R. GROSS COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. (202) 234-4433 WASHINGTON, D.C. 20005-3701 (202) 234-4433 5 1 and all financial interest reported by the Committee 2 participants. The Conflict of Interest statutes 3 prohibit special Government employees from 4 participating in matters that could affect their or 5 their employer's financial interests. 6 However, the Agency has determined that 7 participation of certain members and consultants, the 8 need for whose services outweighs the potential 9 conflict of interest involved is in the best interest 10 of the Government. Therefore, a limited waiver has 11 been granted for Mr. Halperin for his interests 12 related to the issues before the Panel that could 13 potentially be affected by the Panel's 14 recommendations. The limited waiver allows him to 15 participate in the review and discussion, but excludes 16 him from voting. Copies of this waiver may be obtained 17 from the Agency's Freedom of Information Office, Room 18 12A-15 of the Parklawn Building. 19 In the event that the discussions involve 20 any other products or firms not already on the agenda 21 for which an FDA participant has a financial interest, 22 the participant should excuse him or herself from such NEAL R. GROSS COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. (202) 234-4433 WASHINGTON, D.C. 20005-3701 (202) 234-4433 6 1 involvement and the exclusion will be noted for the 2 record. 3 With respect to all other participants, we 4 ask in the interest of fairness that all persons 5 making statements or presentations disclose any 6 current or previous financial involvement with any 7 firm whose products they may wish to comment upon. 8 ACTING CHAIR MAISEL: Thank you. 9 At this point I'd like to have the Panel 10 members introduce themselves. I am William Maisel, 11 cardiologist at Brigham and Women's Hospital in 12 Boston. 13 And why don't we start on my right with 14 Dr. Yustein? 15 DR. YUSTEIN: I'm Ron Yustein. I'm the 16 Acting Critical Deputy Director for FDA's Office of 17 Device Evaluation. 18 MS. MOTTLE: Linda Mottle, Director of 19 Clinical Research at GateWay in Phoenix. Consumer 20 rep. 21 DR. MARLER: John Marler, a neurologist 22 with the National Institute of Neurological Disorders NEAL R. GROSS COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. (202) 234-4433 WASHINGTON, D.C. 20005-3701 (202) 234-4433 7 1 and Stroke. 2 DR. BRINKER: Jeff Brinker, Interventional 3 cardiologist, Johns Hopkins. 4 DR. PAGE: Rick Page, cardiologist, 5 University of Washington. 6 EXECUTIVE SECRETARY WOOD: Geretta Wood, 7 Exec Sec. 8 DR. BROTT: Thomas Brott, neurologist, 9 Mayo Clinic. 10 DR. SOMBERG: John Somberg, Professor of 11 Medicine and Pharmacology, Rush University, Chicago. 12 DR. HALPERIN: Henry Halperin, I'm an 13 electrophysiologist at Johns Hopkins Hospital. 14 DR. KATO: Norman Kato, cardiothoracic 15 surgery, private practice, Encino, California. 16 DR. WEISFELDT: Myron Weisfeldt. I'm Chair 17 of the Department of Medicine at Johns Hopkins. My 18 background is in cardiology. 19 MR. MORTON: I'm Michael Morton. I'm 20 employed by Medtronic. And I'm the industry 21 representative. 22 CHAIRMAN MAISEL: Dr. Blumenstein? Dr. NEAL R. GROSS COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. (202) 234-4433 WASHINGTON, D.C. 20005-3701 (202) 234-4433 8 1 Blumenstein, can you hear us okay? I'll take that as 2 a no. 3 DR. BLUMENSTEIN: I'm having a very hard 4 time hearing. I heard some better than others. 5 CHAIRMAN MAISEL: Can you introduce 6 yourself, please? 7 DR. BLUMENSTEIN: I'm sorry. Was I asked 8 a question? 9 CHAIRMAN MAISEL: Can you introduce 10 yourself? 11 DR. BLUMENSTEIN: Yes. My name is 12 Blumenstein. I'm a consultant working independently 13 living in Seattle, Washington. 14 CHAIRMAN MAISEL: Thank you. 15 At this point I'd like to open the public 16 hearing session of today's meeting. Both the Food and 17 Drug Administration and the public believe in a 18 transparent process for information gathering and 19 decision making. To assure such transparency at the 20 open public hearing session of the advisory committee 21 meeting, FDA believes that it is important to 22 understand to understand the context of an NEAL R. GROSS COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. (202) 234-4433 WASHINGTON, D.C. 20005-3701 (202) 234-4433 9 1 individual's presentation. For this reason FDA 2 encourages you, the open public hearing speaker, at 3 the beginning of your written or oral statement to 4 advise the Committee of any financial relationship 5 that you may have with the sponsor, it's product, or 6 if know its direct competitors. 7 For example, this financial information 8 may include the sponsor's payment of your travel, 9 lodging or other expenses in connection with your 10 attendance at the meeting. 11 Likewise, FDA encourages you at the 12 beginning of your statement to advise the Committee if 13 you do not have any such financial relationships. If 14 you choose not to address this issue of financial 15 relationships at the beginning of your statement, it 16 will not preclude you from speaking. 17 Is there anyone in the audience who wishes 18 to address the Panel this morning? Yes, sir? 19 DR. VANDEN HOEK: Hi. Good morning. My 20 name is Dr. Terry Vanden Hoek. I'm an Associate 21 Professor of Medicine at University of Chicago and in 22 practice as an emergency medicine attending there. NEAL R. GROSS COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. (202) 234-4433 WASHINGTON, D.C. 20005-3701 (202) 234-4433 10 1 My conflicts of interests that I should 2 declare today is Alsius is paying for my expenses 3 today. I get no other salary support from Alsius or 4 any other cooling device funding. 5 My research funding is from the NIH and 6 Department of Defense for study of mechanism of post- 7 resuscitation injury after cardiac arrest and 8 hemorrhagic shock. 9 I was asked to speak today regarding the 10 ILCOR recommendations that were published in 2003 in 11 Circulation. And these recommendations were the 12 result of consensus meetings by professionals from six 13 continents, seven professional organizations that 14 included cardiologist, neurologist, critical care, 15 anesthesiologists, emergency medicine, physicians as 16 well as nursing staff that practice in the critical 17 care and emergency medicine setting. 18 And what's remarkable is that there were 19 worksheet presentations that were done and a number of 20 forums represented. All of the weight of the evidence 21 for the use of therapeutic hypothermia for selected 22 patients after cardiac arrest. NEAL R. GROSS COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. (202) 234-4433 WASHINGTON, D.C. 20005-3701 (202) 234-4433 11 1 And what the conclusion was that the 2 American Heart Association had already recognized that 3 hypothermia may play some role after cardiac arrest. 4 And if you read the guidelines in 2000 what they say 5 is that hemodynamically stable patients who develop a 6 degree of hypothermia spontaneously after cardiac 7 arrest should not be actively warmed. And there was 8 already a recognition back then that hypothermia could 9 be tolerated and, in fact, may be beneficial but at 10 that time we didn't have the evidence to suggest that 11 they should be actively cooled in certain groups of 12 patients. 13 After the evidence had been presented at 14 multiple forums in which specialists could 15 participate, critique the evidence, the decision was 16 made to issue an advisory statement between the 17 guidelines, which were published in 2000 and will be 18 coming out this year, which is an unusual event and I 19 think reflects the consensus among the specialists 20 that we needed to say something because the weight of 21 the evidence suggested that there was actually 22 something we could do for cardiac arrest patients that NEAL R. GROSS COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. (202) 234-4433 WASHINGTON, D.C. 20005-3701 (202) 234-4433 12 1 improved survival. And that was to cool subsets of 2 patients to 32 to 34 degrees for 12 to 24 hours. 3 And we issued that advisory statement in 4 the summer of 2003. 5 The thing I want to emphasize to the Panel 6 is how remarkable it is that we actually have anything 7 that can improve survival from cardiac arrest. It's 8 an extremely lethal disease. The mortality rate is 95 9 percent. It is remarkable that we have even one 10 randomized controlled trial that shows any evidence of 11 improved survival benefit, not only to hospital 12 discharge but actually to six months survival. 13 The fact that those patients can actually 14 go back and work at last part time and live 15 independently is extraordinary. 16 I think that the fact that you can develop 17 a consensus amount that many physicians from that many 18 continents is also quite remarkable. 19 The other thing I want to emphasize is 20 that we think there is great promise in the use of 21 hypothermia but we have a long ways to go. Surface 22 cooling has its own limitations. It could take eight NEAL R. GROSS COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. (202) 234-4433 WASHINGTON, D.C. 20005-3701 (202) 234-4433 13 1 hours to cool a patient. Based on the animal data 2 that's available and some human trials, we think that 3 if we can cool faster, the benefit may be even more 4 profound. And certainly we don't have all the answers 5 yet. Cooling studies such as has been done by Clifton 6 in the study of traumatic brain injury, the onset of 7 cooling was much longer, took longer to cool his 8 patients than it did in the HACA trial. 9 The Cool MI trials, the cooling certainly 10 was not done for 12 to 24 hours. And those are 11 actually what would be considered Level 7 studies when 12 we present our worksheet. Because those were studies 13 of cooling for other diseases. 14 So I would like to take any questions. 15 Right now I have to get back to a study section for 16 the NIH. 17 CHAIRMAN MAISEL: We're going to go 18 through all the public speakers and we'll do a 19 question session at the end if any of the Panel 20 members have questions. 21 Thank you very much. 22 DR. VANDEN HOEK: Okay. Thank you. NEAL R. GROSS COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. (202) 234-4433 WASHINGTON, D.C. 20005-3701 (202) 234-4433 14 1 CHAIRMAN MAISEL: Is there anyone else who 2 wishes to address the Panel this morning? 3 DR. PEBERDY: Good morning. My name is 4 Mary Ann Peberdy. I'm an Associate Professor of 5 Medicine and Emergency Medicine at Virginia 6 Commonwealth University in Richmond. And I'm a 7 cardiologist by background. 8 I receive grant support from Medivance for 9 the participation in the RESCUE trial. And my 10 expenses to attend today's meeting will be paid by 11 Alsius. 12 Intellectual disclosures are that I am an 13 unpaid volunteer for the American Heart Association 14 and a member and past char of the Science Advisory 15 Board for its National Registry of Cardiopulmonary 16 Resuscitation, which is an in-hospital database that 17 currently houses data on over 60,000 in-hospital 18 cardiac arrest resuscitation events. As the current 19 vice chair Research for NRCPR, I am responsible for 20 developing a dataset for post resuscitation care that 21 will include the induction of mild hypothermia in that 22 dataset. NEAL R. GROSS COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. (202) 234-4433 WASHINGTON, D.C. 20005-3701 (202) 234-4433 15 1 The purpose of my comments today is to 2 provide this Panel with a description of the current 3 practice of providing mild hypothermia to survivors of 4 cardiac arrest. My comments are based, in part, from 5 the data on NRCPR o n information obtained from its 6 participants, from users groups and focus groups, on 7 communications with other clinicians and scientists 8 both individually and as part of the Guidelines 2005 9 Conference, and on my personal experience as 10 Chairperson of my hospital's Resuscitation Committee, 11 and the primary physician responsible for providing 12 this therapy at my hospital. 13 The national and international scientific 14 community strongly recommend treatment with mild 15 hypothermia for subsets of comatose survivors of out- 16 of-hospital cardiac arrest. Despite the science and 17 the current guidelines, hypothermia is under utilized 18 in the United States. 19 Dr. Abella and his colleagues at the 20 University of Chicago recently published an article in 21 Resuscitation citing the survey results of the 22 practice of providing post-resuscitation hypothermia. NEAL R. GROSS COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. (202) 234-4433 WASHINGTON, D.C. 20005-3701 (202) 234-4433 16 1 Out of 265 responders, only 13 percent had admitted to 2 using hypothermia following a cardiac arrest. 3 While some of this may be due to the fact 4 that it often takes a decade or more to translate 5 science into clinical practice, a third of the 6 responders stated that the reason for not using 7 hypothermia was that the current cooling methods were 8 technically too difficult or too slow and imprecise. 9 Less than five percent of U.S. hospitals participating 10 in NRCPR currently provide hypothermia. Many admit to 11 believing that the therapy should be provided, but 12 find the current protocols to burdensome to perform. 13 A few hospitals have even reported that 14 after developing their protocols and implementing the 15 hypothermia system, that after doing their first 16 patient the case was so difficult, messy and 17 burdensome that they abandoned this therapy 18 completely. 19 My personal experience mirrors that of 20 others. Our hospital has been performing hypothermia 21 for over a year, and I am intimately familiar with our 22 cases. NEAL R. GROSS COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. (202) 234-4433 WASHINGTON, D.C. 20005-3701 (202) 234-4433 17 1 The induction, maintenance and reversal of 2 mild hypothermia is not only difficult to perform 3 accurately and consistently, but is tremendously time 4 and resource consuming. Without a device specifically 5 to provide and control mild hypothermia clinicians are 6 currently left with whatever is cold and available to 7 them for quickly decreasing body temperature. This may 8 include infusing large amounts of icy saline, lavaging 9 gastric contents with ice, packing the patient in ice 10 bags which can range anything from traditional ice 11 packs to large hefty trash bags filled with ice cubes 12 and placing the patient on a cooling blanket 13 traditionally used for the purposes of reducing fever 14 rather than the induction and maintenance of mild 15 hypothermia. 16 Although these methods of treatment are 17 quite basic and without need for regulation, that does 18 not necessarily equate with them being safe and the 19 quickest and a most effective way to provide this 20 therapy. 21 Clinicians often use a combination of 22 these methods to induce the quickest time to target NEAL R. GROSS COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. (202) 234-4433 WASHINGTON, D.C. 20005-3701 (202) 234-4433 18 1 temperature. Thus, cooling from inside out and 2 outside in. 3 Almost all of the patients are packed in 4 ice that moves and leaks and creates an inconsistent 5 temperature control and winds up with the patient 6 being in a soaking wet bed. The inability to control 7 the depth of hypothermia within a reasonable degree of 8 predictability leads to overshoot with respect to the 9 target temperature. Well over half of the patients 10 with induced hypothermia in our institution, a place 11 where that pays particular attention to how we deliver 12 this therapy, have patients with temperatures that 13 fall below 33 to 34 degrees at sometime during their 14 therapy, which could place the patient at risk for 15 further complications from imprecise treatment. The 16 resulting actions to try and rewarm the patient to a 17 more acceptable level of mild hypothermia leads to a 18 ping-pong effect with the patient having temperature 19 curves that swing up and down requiring cooling and 20 reheating for almost the entire duration of the 21 protocol. Rather than a consistent predictable 22 temperature curve for cooling, maintenance and NEAL R. GROSS COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. (202) 234-4433 WASHINGTON, D.C. 20005-3701 (202) 234-4433 19 1 reversal, the typical patient is subject to jagged 2 fluctuations in body temperature. 3 In addition to this, the ice packs or 4 cooling blankets invariably leak leading to a very 5 electrical unstable patient lying in a puddle of 6 water. Many of us have commented that we have been 7 quite lucky to not have patients refibrillate and 8 require defibrillation in this setting. The dangers 9 of defibrillation are obvious. 10 The multiple staff carrying for these 11 critically ill patients often have their hands full in 12 providing immediately necessary medical therapies and 13 appropriately find it unreasonable to be expected to 14 change a bed one, two or even times during duration of 15 this protocol. 16 Attempting to provide this therapy by 17 these means is, for lack of a better term, a 18 thermalregulatory nightmare and potentially even 19 electrically dangerous. 20 As both scientists and clinicians we can 21 all agree that there is still much to be learned about 22 how to best deliver this therapy, the time frame to NEAL R. GROSS COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. (202) 234-4433 WASHINGTON, D.C. 20005-3701 (202) 234-4433 20 1 initiate cooling, the depth and duration of 2 hypothermia, the optimal use of sedative and 3 paralytics, the different methods of cooling and need 4 for CNS monitoring, just to name a few, are all areas 5 that will clearly benefit from further experience and 6 evaluation. But despite these unknowns post- 7 resuscitation hypothermia makes a difference. 8 Our hospital has seen noticeable 9 improvements in survival to discharge from out-of- 10 hospital cardiac arrest since starting our program. 11 Other programs also anecdotally report similar 12 results. 13 In both Europe and the United many EMS 14 systems are now seeing striking differences in 15 survival to discharge after initial ROSC when 16 delivering patients to hospitals performing aggressive 17 hypothermia compared to hospitals that do not. 18 There was a frank discussion at a recent 19 EMS Director's meeting specifically talking about 20 whether or not it is unethical to deliver patients 21 with out-of-hospital cardiac arrest to hospitals that 22 do not provide hypothermia and whether or not NEAL R. GROSS COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. (202) 234-4433 WASHINGTON, D.C. 20005-3701 (202) 234-4433 21 1 appropriate patients should be diverted to those 2 hospitals known to provide this therapy. 3 The future focus of survival from cardiac 4 arrest will clearly have post-resuscitation care as a 5 prominent feature. To help spotlight the importance of 6 this currently missing link in the chain of survival, 7 the NRCPR is developing a dataset specifically geared 8 for delivery of care after ROSC and collection of data 9 in this area. Specific attention will be paid to the 10 delivery of mild hypothermia so that many of the 11 current unknowns will be able to be evaluated and 12 tweaked and cared for most carefully. Data on this 13 resuscitation outcomes module will be used by 14 individual hospitals to improve their process of 15 resuscitation as well as by the scientific community 16 as a longitudinal mechanism to track trends in 17 treatment and outcome variables. So a mechanism is 18 already in place for patients who receive hypothermia 19 to be tracked by an independent board of scientists 20 and clinicians. 21 In summary, I have three roles pertinent 22 to the therapy being discussed today. I care for NEAL R. GROSS COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. (202) 234-4433 WASHINGTON, D.C. 20005-3701 (202) 234-4433 22 1 patients who have suffered a cardiac arrest. I teach 2 others to care for patients who have suffered a 3 cardiac arrest. And I do research to find better ways 4 to care for these patients. 5 Everything that I know indicates that this 6 therapy should be applied to certain comatose 7 survivors of sudden death. During the time that we are 8 in this room meeting today over 400 people will die 9 from cardiac arrest and only 20 of them will 10 ultimately survive without improve post-resuscitation 11 therapies such as hypothermia. 12 We are dealing with a disease that carries 13 with it an almost certain death. And although we 14 acknowledge that we do not yet know all the 15 intricacies of how to best deliver this therapy, we 16 do know that despite this hypothermia makes a 17 difference. 18 Please don't sacrifice better for best in 19 considering devices that may help improve the delivery 20 of this therapy. Clinicians need choices and better 21 options to deliver mild hypothermia and patients need 22 a better chance to survive. NEAL R. GROSS COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. (202) 234-4433 WASHINGTON, D.C. 20005-3701 (202) 234-4433 23 1 Thank you. 2 CHAIRMAN MAISEL: Thank you. 3 Is there anyone else who wishes to address 4 the Panel this morning? 5 Is there anyone on the Panel that has a 6 question for either of our speakers? Jeff? 7 DR. BRINKER: I'd just like the last 8 speaker, who is very impassioned, to tell me about 9 whether she uses this device now to do away with all 10 the hassle of leaking ice bags and things? 11 DR. PEBERDY: No. 12 DR. BRINKER: Why? 13 DR. BRINKER: Why? 14 EXECUTIVE SECRETARY WOOD: Please come 15 back to the podium. 16 DR. PEBERDY: The device is currently not 17 FDA approved for this indication and our hospital was 18 quite reluctant to use devices off label. 19 DR. BRINKER: There is no device, 20 including ice bags, approved for this indication. 21 DR. PEBERDY: That is correct. 22 DR. BRINKER: But you use ice bags? NEAL R. GROSS COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. (202) 234-4433 WASHINGTON, D.C. 20005-3701 (202) 234-4433 24 1 DR. PEBERDY: But we don't have to 2 purchase them and they are not regulated. 3 DR. BRINKER: Okay. 4 DR. PEBERDY: This device is approved for 5 hypothermia for other indications. So to our hospital 6 that makes a difference to them. 7 DR. BRINKER: Okay. 8 CHAIRMAN MAISEL: Dr. Vanden Hoek, you can 9 have a seat. No one from the Panel has asked a 10 question to you. 11 DR. VANDEN HOEK: It is possible that, 12 because we do use the catheter in our institution, we 13 also use cooling blankets and ice bags. Our intensive 14 care unit made a decision a year ago to try to 15 implement a cooling pathway as well. And because of 16 the cooling blanket issues with temperature drops, our 17 ICE had decided to implement a cooling catheter and 18 try to control that temperature better. 19 CHAIRMAN MAISEL: Okay. Thank you for 20 your comments. 21 Anyone else on the Panel have a question? 22 John? NEAL R. GROSS COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. (202) 234-4433 WASHINGTON, D.C. 20005-3701 (202) 234-4433 25 1 DR. MARLER: Well, I was just curious if 2 this second speaker could say why in her hospital it 3 wouldn't be possible. I don't know what numbers were 4 involved, but it sounded from the energy of her 5 presentation like there were quite a few patients in 6 the registry. Why would it be so difficult to do a 7 comparison of ice bags to cooling catheters? 8 DR. PEBERDY: I don't think that we have 9 said that there would be a difficulty to do that. 10 There are literally just a handful of hospitals now 11 that are performing this therapy. Many are in the 12 stages of developing protocols to implement 13 hypothermia programs which, in a typical hospital, 14 takes almost a year to work through the entire process 15 and do the education and get the protocol development. 16 So there are not really enough hospitals with patients 17 that we would be able to get a meaning comparison at 18 this particular time, although we are continuing to 19 look at data that gets entered on hypothermia 20 patients. 21 CHAIRMAN MAISEL: Mike? 22 DR. WEISFELDT: To either of the speakers. NEAL R. GROSS COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. (202) 234-4433 WASHINGTON, D.C. 20005-3701 (202) 234-4433 26 1 Were you involved in the recent 2 deliberations of American Heart and ILCOR CBR 3 standards dealing with cooling? And if you were, was 4 there any significant effort to vacate the ILCOR 5 statement that was previously adopted? 6 DR. VANDEN HOEK: In answer to your 7 question, the therapeutic hypothermia worksheets were 8 presented at a plenary session in Dallas at the end of 9 January. And I think that the consensus was that 10 those guidelines will stand. 11 CHAIRMAN MAISEL: Any other speakers that 12 wish to address the Panel this morning? 13 At this point I'd like to close the open 14 public hearing and we will move onto the sponsor's 15 presentation. 16 I'd like to remind the speakers to 17 introduce themselves, to state their conflict of 18 interest as well. Thank you. 19 DR. BLUMENSTEIN: This is Brent 20 Blumenstein. I'm not hearing anything speaking. Is 21 there a reason for that? 22 CHAIRMAN MAISEL: Nor are we. We're just NEAL R. GROSS COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. (202) 234-4433 WASHINGTON, D.C. 20005-3701 (202) 234-4433 27 1 getting started here in a moment. 2 DR. COLLINS: It's the sound of one hand 3 clapping. We will start now. 4 Good morning. Thank you. My name is Dr. 5 Ken Collins. 6 CHAIRMAN MAISEL: Could you speak into the 7 microphone a little more. 8 DR. COLLINS: Is that better? 9 CHAIRMAN MAISEL: Yes. 10 DR. COLLINS: My name is Dr. Ken Collins. 11 Welcome here on St. Patrick's Day. 12 I'm Executive Vice President of Alsius 13 Corporation. Clearly, my conflicts of interests are 14 that I'm a full time employee of Alsius Corporation. 15 Speaking also today will be Dr. Sterz from 16 Vienna. Dr. Sterz is the Associate Professor of 17 Internal Medicine, University of Vienna. 18 And Dr. Risto Roine, he's the Associate 19 Professor of Neurology at the University of Helsinki. 20 Because the order of slides will change if 21 I don't now delete that slide since I've introduced 22 everybody. And now your slide numbers will match. NEAL R. GROSS COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. (202) 234-4433 WASHINGTON, D.C. 20005-3701 (202) 234-4433 28 1 Why we are here. Alsius submitted a 2 510(k) for the CoolGard/Icy catheter system for the 3 induction of hypothermia after cardiac arrest in 4 certain patients. The FDA requested that we conduct a 5 randomized controlled trial for this 510(k). And we 6 appealed this request to the FDA. 7 In response to our appeal, the FDA offered 8 this Panel. Alsius would like to thank the FDA for 9 this flexibility. And for the purposes of this 10 presentation, we will constrict ourselves to the 11 analysis from the 510(k) dataset. 12 This is a 510(k) notification. 13 Next slide. 14 Substantial equivalence to a predicate 15 device is the standard for FDA clearance of a 510(k). 16 The statutory provisions for 510(k)s refers to 17 clinical and scientific data, and there is no specific 18 requirement for an randomized controlled trial. 19 Alsius believes that it has provided the FDA with the 20 data to support substantial equivalence, and therefore 21 clearance of this 510(k). 22 For the purpose of determining substantial NEAL R. GROSS COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. (202) 234-4433 WASHINGTON, D.C. 20005-3701 (202) 234-4433 29 1 equivalence for a device, the 510(k) should include 2 according to the statute as quoted "appropriate 3 clinical or scientific data." And the intent is to 4 show that the device is as safe and effective as a 5 legally marketed device. 6 You previously heard from Dr. Vanden Hoek, 7 who is as you'll see, one of the primary authors on 8 the ILCOR recommendations. ILCOR is the International 9 Liaison Committee on Resuscitation. It is made up of 10 multiple representatives from multiple countries. 11 Typically, for example, in Dr. Vanden Hoek's position 12 in representing the AHA or the European Resuscitation 13 Council, or the Australian Resuscitation Council, the 14 appropriate medical bodies. 15 The recommendations were first reached in 16 October of 2002 and then published as per the 17 reference at the bottom of the slide in 2003. 18 Of note, "unconscious adult patients with 19 spontaneous circulation after out-of-hospital cardiac 20 arrest should be cooled to 32 to 34 degrees for 12 to 21 24 hours with the initial rhythm has been ventricular 22 fibrillation." They also commented that such cooling NEAL R. GROSS COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. (202) 234-4433 WASHINGTON, D.C. 20005-3701 (202) 234-4433 30 1 may be beneficial for other reasons or in-hospital 2 cardiac arrest. 3 It was the statement that was bolded in 4 that slide that became the indication for use for the 5 Alsius 510(k). 6 In terms of predicate devices, the Alsius 7 CoolGard system is cleared for marketing. I will give 8 you a description of the device in following slides. 9 It is cleared for the induction, 10 maintenance and reversal of mild hypothermia in 11 neurosurgery, for rewarming in cardiac surgery and for 12 fever control in the cerebral infarction/intracerebral 13 hemorrhage. The other predicate device was a blanket 14 system, the Thermorite Model HC-83. 15 The device provides controlled 16 hypothermia. This device is already approved and 17 widely used in the European Union and now approved in 18 Canada. 19 In terms of the clinical data that was 20 submitted, and which we will review in subsequent 21 slides, Alsius provided in the 510(k) a review of the 22 literature including summaries of some of the NEAL R. GROSS COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. (202) 234-4433 WASHINGTON, D.C. 20005-3701 (202) 234-4433 31 1 compelling animal models demonstrating the mechanism 2 of the benefits of hypothermia, a meta-analysis, 3 Alsius IDE Feasibility Study and an analysis of 4 cardiac arrest patient registry at the Allegemeines 5 Krankenhaus in Vienna, the university hospital in 6 Vienna. To avoid me stumbling that, I will call it 7 the university hospital in Vienna. 8 Cardiac arrest is one of the most 9 complicated clinical environments. It is an intensive 10 care environment with multiple interventions required 11 simultaneously. Providing hypothermia via a central 12 line is efficient. 13 The existing cooling methods, there are 14 several. Fluids, limited by the amount of volume you 15 can infuse. Ice/lavage, a nurse intensive and the wet 16 surfaces pose risk. Surface cooling limits access to 17 the body and patient and can increase shivering. As 18 you heard today, it's associated with less control of 19 the desired patient temperature. 20 Due to these disadvantages, and as 21 explained by Dr. Peberdy, there is a need for better 22 tool to provide hypothermia. The Alsius' device is a NEAL R. GROSS COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. (202) 234-4433 WASHINGTON, D.C. 20005-3701 (202) 234-4433 32 1 tool that allows controlled convenient hypothermia. 2 The CoolGard 3000 system, it's the picture 3 of the external unit pictured here. It's a heat 4 exchange system. It pumps saline to and from the 5 catheter in a closed loop with temperature control. 6 It cools in a controlled manner at rates between 0.05 7 to 1.5 degree C per hour. 8 On the projection now is a picture of the 9 icy catheter in situ. It's a femoral vein insertion. 10 It's a 8.2 French catheter that ends up with the 11 cooling elements predominately in the inferior vena 12 cava. 13 The close up picture shows the balloons 14 axially mounted on the shaft of the catheter. And I do 15 have and we'll pass it around later, catheters for you 16 to play with, to look at. 17 Cardiac arrest has significant 18 implications for public health. It effects a large 19 number of people with a terrible outcome. Rhea et al 20 reviewed 35 U.S. community hospitals. In terms of the 21 survival for any rhythm it was 8.4 percent overall, 22 and for primary VT/VF it was 17.7 percent. And larger NEAL R. GROSS COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. (202) 234-4433 WASHINGTON, D.C. 20005-3701 (202) 234-4433 33 1 cities, depending upon the emergency care available, 2 the rates varied enormously. Annually in the United 3 States, at least 155,000 people experience EMS-treated 4 cardiac arrest of any rhythm recorded, and 60,000 5 experience EMS-treated ventricular fibrillation-rhythm 6 as a cardiac arrest. It's a significant public health 7 issue. 8 In the 510(k) we presented a meta- 9 analysis. This is subsequently being published as a 10 peer reviewed article in the well respected Critical 11 Care Medicine. I believe you received a copy of that 12 in your Panel pack. 13 Three studies were looked at to establish 14 an expected result. The HACA study, which you've 15 heard about before and which Mr. Sterz and Dr. Roine 16 were both intimately involved, the Bernard study by my 17 countrymen and the Hachimi-Idrissi study. The end 18 result is a clear benefit of hypothermia in the 19 comatose survivors of cardiac arrest. 20 This graph shows survival. It is a meta- 21 analysis presenting the risk difference. You can see 22 the three trials, the HACA, Bernard and Idrissi. And NEAL R. GROSS COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. (202) 234-4433 WASHINGTON, D.C. 20005-3701 (202) 234-4433 34 1 overall -- I'm going to use the lethal-looking laser 2 pointer -- there's a clear benefit in terms of the 3 risk difference and its confidence intervals. 4 Similarly, in terms of survival with good 5 outcome, the three trials are presented. The overall 6 95 percent confidence intervals and the risk 7 difference is significant. 8 Included in our 510(k) were the results of 9 the feasibility IDE. Let me put this in historic 10 context for you. We started with a view to 11 understanding a perspective randomized controlled 12 trial. We experienced very slow enroll despite our 13 best efforts. We started in 2001 in March. 14 In February of 2002 the New England 15 Journal of Medicine articles, the HACA study, the 16 Bernard study were published. ILCOR met in October of 17 2002 and published its recommendations in the mid- 18 2003. 19 At this stage we believed that there was 20 established of hypothermia in cardiac arrest. The 21 feasibility study enrolled 13 patients with inclusion 22 criteria that were tied in line with what we expected NEAL R. GROSS COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. (202) 234-4433 WASHINGTON, D.C. 20005-3701 (202) 234-4433 35 1 would be required in a randomized trial. The 30 day 2 survival was 69 percent and the adverse event profile 3 was consistent with the published studies that I've 4 just mentioned. 5 At the Allegemeines Krankenhaus in Vienna 6 university hospital there is an ongoing data 7 collection activity. They're interested in the use of 8 mild hypothermia and the post-resuscitative care of 9 the comatose survivors in cardiac arrest. It contains 10 data from the randomized controlled trial, patient 11 registry data and includes information on this device 12 and several others. Because of confidentiality, 13 Alsius does not have access to the measurement on 14 other devices. 15 From this dataset selected controls and 16 device data was analyzed and submitted in our original 17 510(k) notification. Over the past year there has been 18 ongoing data collection in the registry. This includes 19 additional patients in both the control and device 20 cohorts. And the analysis that I present today are 21 from the 510(k) dataset. 22 The selection criteria the patients had to NEAL R. GROSS COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. (202) 234-4433 WASHINGTON, D.C. 20005-3701 (202) 234-4433 36 1 be the comatose survivors of cardiac arrest with 2 primary successful cardiac pulmonary resuscitation 3 resulting in return of spontaneous circulation on 4 arrival to the emergency department. This was 5 consecutive series of adults who had survived at least 6 24 hours and who had had non-trivial resuscitation 7 times. 8 This table presents the baseline data. 9 There are differences between the device and control 10 groups, as is made clear in this slide. I would like 11 to point out that the GSC score on admission being 12 equal to three is more common in the device group. And 13 that the average ROSC time is also longer. 14 The imbalance would suggest that the 15 device group where a patient population would grow to 16 risk difference. 17 This is a crude survival analysis. The 18 hypothermia group, 43 of 62 patients survived. And the 19 controlled group 695 out of approximately 1200. 20 The risk difference unadjusted was 11 21 percent with a confidence interval being near 22 significant. NEAL R. GROSS COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. (202) 234-4433 WASHINGTON, D.C. 20005-3701 (202) 234-4433 37 1 Further analyses were done. This is a 30 2 day survival multivariate model with values related to 3 outcome. The univariate analysis that I previously 4 showed you, the survival is on the top line. They 5 present results to both survival and survival with 6 good neurological outcome. 7 If you look at the confidence intervals, 8 you'll see the risk differences at 11 percent for 9 survival unadjusted, 17.7 percent for survival 10 adjusted. Approximately 11 percent for univariate 11 survival with good neurological outcome and 23 percent 12 for adjusted. The confidence intervals are 13 significant. 14 Of clinical relevance, the number needed 15 to treat the patients using hypothermia for the 16 survival is between 6 and 9. And for survival with 17 good neurological outcome is between 4 and 9. 18 It's a remarkable benefit, and it implies 19 that for every six or so patients treated with the 20 Alsius device, a life will be saved. 21 This analysis included propensity scores, 22 and we did do a Hosmer-Lemeshow model of fit for this. NEAL R. GROSS COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. (202) 234-4433 WASHINGTON, D.C. 20005-3701 (202) 234-4433 38 1 In addition, we did other analyses of 2 propensity scores. Propensity scores are a method to 3 attempt to create better match comparisons between 4 cohorts. 5 This slide shows the distribution 6 propensity scores of the device an the control 7 cohorts. The lack of good overlap could suggest the 8 groups are not well matched. However, the model which 9 includes the scores and other based on variable that's 10 displayed in this slide, provides an odds ratio I 11 would suggest significant benefit to the device. 12 On this slide, the dataset, that's the 13 internal code for the CoolGard system. We are looking 14 at all baseline variables. 15 For the code variate set, set number one 16 is the treatment group and the propensity score. Set 17 number two is the treatment group, the propensity 18 score and all other variables used in the propensity 19 score analysis. 20 I draw your attention to the odds ratio. 21 Note the highly significant confidence intervals. 22 In addition, we present logistic NEAL R. GROSS COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. (202) 234-4433 WASHINGTON, D.C. 20005-3701 (202) 234-4433 39 1 regressions of survival with good neurological outcome 2 for both the unadjusted and adjusted and death -- I'm 3 sorry for switching axis for you, less than discharge. 4 And, again, looking at the confidence intervals 5 around the odds ratios, these are significant results. 6 In summary, may I first of all point out 7 that the efficacy outcome is also the primary safety 8 outcome. Efficacy is survival. 9 Vienna registry data shows significant 10 improvement in survival and survival with good 11 neurological outcome with the Alsius CoolGard system. 12 Dr. Roine will later discuss the meaning 13 of the term "good neurological outcome" and the use of 14 the CPC scale. 15 The effect as seen is consistent across 16 all the different analyses with that reported in the 17 New England Journal of Medicine published randomized 18 controlled trial and the meta-analysis based upon 19 them. These data are appropriate and adequate to 20 demonstrate that the device is as safe and effective 21 as the legally marketed predicate. 22 I will now hand you to or hand over the NEAL R. GROSS COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. (202) 234-4433 WASHINGTON, D.C. 20005-3701 (202) 234-4433 40 1 microphone to Dr. Fritz Sterz. 2 DR. STERZ: Good morning, ladies and 3 gentlemen. I hope you will understand my Viennese 4 English. My teacher, whom I want to give credit to, 5 always said it's Vienglish. My teacher was Peter 6 Safar at the University of Pittsburgh. And without 7 him, I wouldn't have been able to stay here and talk 8 to you, which I am very proud about. 9 So Peter Safar 15 years ago in his lab has 10 taught me how to apply hypothermia in animals. 11 For this meeting I am paid Alsius with 12 regards to the travel expenses. And with regards to 13 the soldiers working at home, I get both paid a fellow 14 by Alsius. Unfortunately, that's all what I get by 15 Alsius. I would like much, much more. 16 We opened our department in 1995 at the 17 Vienna General Hospital. And since this time I'm 18 collecting cardiac arrest data according to the 19 recommendations which was initially coming from Peter 20 Safar's PRCP trials and later on from the Utstein 21 styled recommendation. And since this time I have a 22 committee approval HACA registry running at our NEAL R. GROSS COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. (202) 234-4433 WASHINGTON, D.C. 20005-3701 (202) 234-4433 41 1 department. At the moment we are counting 2,500 2 patients in this registry, which have been admitted to 3 our department. 4 We have also initiated together with Dr. 5 Roine of the University of Helsinki, the so called 6 hypothermia cardiac arrest trial, which was a 7 multisample trial in Europe and somehow in New England 8 Journal has been published and proven that hypothermia 9 seems to work. 10 We continued after HACA cooling patients, 11 not only with Alsius, also with other companies which 12 I'm grateful for because they paid the other soldiers 13 which I needed to do this whole work. So I'm paid by 14 several companies, and I might not be biased to what's 15 Alsius in this regard. 16 So we are entering patients in this 17 registry who had cardiac arrest either in the 18 hospital, in other departments, admitted to our 19 department either outside the hospital or even if they 20 had their arrest in the emergency department. The 21 criteria for getting into this registry was they had 22 to be in our department. NEAL R. GROSS COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. (202) 234-4433 WASHINGTON, D.C. 20005-3701 (202) 234-4433 42 1 And finally but not least, we have gotten 2 where we are grateful to the data from Bernard and 3 Hachimi-Idrissi to do a so called meta-analysis 4 together with our HACA data. 5 Next slide. 6 To give you an idea, this is our hospital. 7 It's a 2,500 bed hospital in the middle of Vienna. 8 It's one of the major university hospitals in Austria. 9 And it has a Seattle-type emergency department where 10 I am based. It has nothing to do with emergency 11 medical service, which was created by our Emperor and 12 which was established already 120 years ago. And since 13 then is run by emergency physicians. 14 We have physician staffed ambulances in 15 Vienna. We have also a helicopter. And these 16 ambulances are running 24 hours a day. Beside this we 17 a lot of EMT-staffed ambulances. This is only to give 18 you a picture about our department and about my 19 surrounding. 20 The department is treating about 300 21 patients per day. 22 Next slide. NEAL R. GROSS COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. (202) 234-4433 WASHINGTON, D.C. 20005-3701 (202) 234-4433 43 1 And this is how it looks in our 2 department. Maybe a little bit different than in 3 American states from what I have seen. 4 We have a so called acute care unit within 5 our department where we can treat patients like in an 6 intensive care unit, and we are approved as an 7 intensive care unit. And this is how it looks like if 8 a patient is treated with the Alsius device and what 9 kind of establishment is there, I don't have to 10 describe in detail. 11 What I want to point out in recent times 12 we have added to the Alsius device giving these 13 patients in the beginning when they have been 14 admitted, cold fluids to be faster in initiating the 15 cooling or initiating the lower temperature because it 16 always takes a little bit of time to get the Alsius 17 device established. 18 Next slide. 19 This was the reason for changing to Alsius 20 and the changing to the cold fluids given in the 21 initiation because it took us a very long time in the 22 HACA trial with the cold air blowing on these patients NEAL R. GROSS COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. (202) 234-4433 WASHINGTON, D.C. 20005-3701 (202) 234-4433 44 1 to get the temperature down to our, between Risto and 2 myself and the other partners of our HACA trial 3 decided target temperature which was based mainly on 4 the animal trials which I did with Peter Safar. And I 5 had a continuous conversation with Peter Safar how we 6 should do it, and he was somehow a consultant for this 7 study. 8 And we kept these humans for 24 hours in 9 this kind of range, and then rewarmed them, at this 10 time, not actively unfortunately, which we should have 11 done. 12 Next slide. 13 This is now the same picture with the 14 Alsius device where we are much faster, much better in 15 controlling this temperature and much better in 16 controlling the rewarming. And this has been only on 17 those patients where no cold fluid has been used. And 18 what you can see, why we now switched to cold fluids 19 in the beginning is this increase of temperature in 20 the beginning of the admission time. 21 Next slide. 22 And these patients now and patients from NEAL R. GROSS COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. (202) 234-4433 WASHINGTON, D.C. 20005-3701 (202) 234-4433 45 1 our registry which hadn't been used for testing other 2 devices for cooling the HACA patients, we used to 3 analyze the safety between the device and the 4 controlled group. However, we decided it wouldn't be 5 fair to put all these patients into the analyses, and 6 therefore we selected between both groups a certain 7 group of patients which had ventricular fibrillation 8 on presentation, presumed cardiac cause of cardiac 9 arrest. So we made before we delivered the data to 10 our statistician a selection of our patients to have 11 the group somehow the same in both groups. We, of 12 course, not included in this analyses of patients who 13 had, for example, stroke as their reason for cardiac 14 arrest. 15 In the controlled group you can see the 16 mortality was still very, very high, as we have seen 17 it in the HACA trial. 18 And here you can see the green, the 19 normothermia group where we have selected now 81 20 patients, where the hypothermia group the so called 21 safety data with regards to what is always discussed 22 bleeding, pneumonia, sepsis, pancreatitis, rental NEAL R. GROSS COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. (202) 234-4433 WASHINGTON, D.C. 20005-3701 (202) 234-4433 46 1 failure, bradycardia and all the other arrhythmias 2 which could occur during cooling. What you can see is 3 that we have tiny little bit more renal failures or 4 much more renal failures. This was due to the 5 definition of our renal failure. Our renal failure 6 definition was an increase of the serum creatinine of 7 about 50 percent. However, no one of these patients 8 needed hemodialysis. 9 Bradycardia was expected to be a little 10 bit more in the cooling group because that's due to 11 the cooling. But there was no more bleeding, no more 12 pneumonia and the only thing which is different is the 13 pancreatitis issue. But if you look at the number it's 14 here 4 in the hypothermia and zero in the controlled 15 group. I don't know if we can really count on this, 16 however this pancreatitis was also only defined by the 17 serum amylase level which was increased and resolved 18 within one week. 19 Next slide. 20 So again, we had no major problems with 21 regards to bleeding to hematologic situation. We had 22 no significant differences in lethal arrhythmias. WE NEAL R. GROSS COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. (202) 234-4433 WASHINGTON, D.C. 20005-3701 (202) 234-4433 47 1 had more bradycardias. We had this renal serum 2 creatinine increase but it was solved within 3 rewarming. 4 You can see these data presented in a 5 paper which was just recently published in 6 Resuscitation that it resolves by itself. And we had 7 this observation that the serum amylase increased, 8 however also resolved within 24 hours. 9 We had pneumonia in both groups, but no 10 significant differences. 11 This compares somehow to the HACA trial, 12 but we also prospectively looked at these side effects 13 where we have in the protocol given definitions for 14 all these kinds of side effects or safety issues. 15 However, we haven't been in the presentation of the 16 data of the HACA trial, such rigid on the arrhythmias 17 which could be presented because we have this data 18 available. But comparing this data to our data with 19 the CoolGard device doesn't show a major difference. 20 Okay. You go ahead. 21 Once more, thank you very much. And I hope 22 I clear a little bit of this picture. NEAL R. GROSS COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. (202) 234-4433 WASHINGTON, D.C. 20005-3701 (202) 234-4433 48 1 DR. COLLINS: In summary, these are 2 critically ill comatose patients. This is an 3 intensive care environment with multiple interventions 4 required and there's a high rate of adverse events in 5 both groups. 6 There were no cardiac and hematologic 7 compromise from cooling. And the increased rates of 8 renal insufficiency and chemical pancreatitis resolved 9 with rewarming. 10 The use of the device provides the desired 11 cooling with an acceptable safety profile. 12 I'd now like to ask Dr. Roine, Risto Roine 13 to address the Panel. 14 DR. ROINE: Mr. Chairman, dear Panel 15 members, my name is Risto Roine and I'm a stroke 16 neurologist from Helsinki. I am the Associate 17 Professor of Neurology at the University of Helsinki, 18 Finland and the chief physician of the Acute Stroke 19 Unit which is one of the largest in Europe. 20 I have been involved in resuscitation 21 research since '85. And I was one of the founding 22 members of the HACA trial, as Fritz Sterz told you. NEAL R. GROSS COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. (202) 234-4433 WASHINGTON, D.C. 20005-3701 (202) 234-4433 49 1 And I'm also involved in the European Resuscitation 2 Council HACA registry. 3 And my financial disclosure is that I have 4 no financial interest in Alsius, any of their products 5 or any other product in the market. But Alsius is 6 taking care of my expenses to attend this meeting. 7 I was asked to comment briefly on the 8 outcome scale, cerebral performance categories scale 9 used in the HACA trial. 10 As you know, it reminds very much the 11 other outcome scales used in stroke research like 12 Glasgow Outcome Score and the modified Rankin score. 13 And the main thing is that there is a cut off point 14 between CPC 2 and CPC 3 defining independent or 15 dependent outcome, which was also used as the 16 dichotomous outcome in the HACA trial. 17 Next. 18 The CPC Outcome Scale is currently being 19 recommended by the Utstein style uniform reporting 20 guidelines ever since 1991, and it still is. It's 21 recommended by most, if not all, reviews written on 22 this topic. And it's used in most major resuscitation NEAL R. GROSS COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. (202) 234-4433 WASHINGTON, D.C. 20005-3701 (202) 234-4433 50 1 research trials. I found 52 papers since 1990. 2 It's always used in the conjunction with 3 the OPC scale, the overall performance categories. And 4 it's considered to be a more relevant measurement for 5 cognitive outcome than the Glasgow Outcome Scale or 6 modified Rankin score used in stroke research. But 7 it's easy to derive the Glasgow Outcome Score Scale 8 and the modified Rankin scale from the CPC and OPC 9 scores. 10 And, as I said, the limit between 11 independent and independent categories between CPC 2 12 and CPC 3, this is a very, very clear cut definition. 13 CPC is a valid scale for cardiac arrest outcome 14 studies. 15 Next please. 16 Then I very briefly described the 17 situation in Finland. As you know, Finland is a cold 18 Nordic country with a population of 5 million people. 19 But we quite heavily use therapeutic hypothermia in 20 Finland. It's the hypothermia for cardiac arrest is 21 adopted in all national and local guidelines. It's 22 being routinely used by all five universities NEAL R. GROSS COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. (202) 234-4433 WASHINGTON, D.C. 20005-3701 (202) 234-4433 51 1 hospitals, and all these university hospitals, those 2 have the Alsius product that we are talking about 3 today for endovascular cooling. And three university 4 hospitals do also have devices for external cooling, 5 mainly the Allon 2001 device. 6 My Helsinki University Central Hospital 7 has four units of this Alsius device and two units of 8 the KCI TeraKool device for external cooling. More 9 than 90 percent of our patients receive endovascular 10 cooling instead of the external cooling at this point. 11 We just did a survey in Finland by the 12 Critical Care Society of Finland just a few days ago 13 showing that six of our 15 central hospitals have the 14 Alsius CoolGard device only, and eight of the 15 have 15 the Allon device only. One central hospital did not 16 reply. 17 Next please. 18 So in Helsinki, more than 90 percent of 19 all eligible out-of-hospital VF cardiac arrest 20 patients are routinely cooled, that was 48 patients in 21 2004. And of all patients who were entered into the 22 European Resuscitation Council HACA registry in 2004, NEAL R. GROSS COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. (202) 234-4433 WASHINGTON, D.C. 20005-3701 (202) 234-4433 52 1 72 percent are now alive and at home. This figure is 2 considerably higher than the general outcome of VF 3 cardiac arrest patients at the time when I did thesis 4 about this very topic in 1993. 5 So I finish here. Thank you very much for 6 your attention. Thank you. 7 DR. COLLINS: In conclusion then, this is 8 a 510(k). The product is already clear and on the 9 market for three different temperature management 10 indications. Of course, hypothermia and normothermia 11 applications. 12 There is clear independent evidence of the 13 survival benefits of hypothermia in cardiac arrest 14 patients. The ILCOR recommendations are clear. 15 We have presented data to show that the 16 Alsius CoolGard device achieves the desired result 17 effectively and with a favorable safety profile. 18 CHAIRMAN MAISEL: Thank you very much for 19 a very concise presentation. 20 I'd like to open the discussion up to the 21 Panel to ask any questions of the sponsor, of course 22 reminding the Panel that we'll have several hours to NEAL R. GROSS COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. (202) 234-4433 WASHINGTON, D.C. 20005-3701 (202) 234-4433 53 1 ask questions later. 2 Rick, why don't we start with you? 3 DR. PAGE: Thank you. 4 The feasibility study enrolled only 13 5 patients in 18 months with several centers. Can you 6 explain that to me, because I'm hearing of the zeal 7 for this technology and the need for it, and that 8 enrollment is surprisingly low? 9 DR. COLLINS: I think the comments about 10 the historical context. This technology is evolving 11 very rapidly. At the time we were used an informed 12 consent, which is very difficult to do when someone 13 arrives basically dead. So we were unable to obtain 14 informed consent, is the largest reason for not being 15 able to enroll. 16 And the community resistance in two of the 17 areas when we started to examine community consent 18 around the Duke University at that time, there was 19 considerable community resistance to involvement in 20 clinical trials under community consent. And we did 21 not go down that path. 22 DR. PAGE: Thank you. NEAL R. GROSS COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. (202) 234-4433 WASHINGTON, D.C. 20005-3701 (202) 234-4433 54 1 CHAIRMAN MAISEL: Jeff? 2 DR. BRINKER: Ken, you mentioned the lack 3 of shivering -- or actually you had mentioned the lack 4 of shivering, you said external devices can produce 5 shivering. This device doesn't produce shivering? 6 DR. COLLINS: All devices produce 7 shivering. Shivering is a -- both a spinal mechanism 8 with a central control and the degree to which you see 9 temperature responses to which you see shivering 10 depends upon the patient's level of consciousness, 11 the drugs on board. But the initiation is highest if 12 the areas of skin around the neck, the armpits, the 13 exposed vessels have high numbers of sensors for the 14 response to be simulated. 15 Once you get any patient's temperature 16 down to somewhere 35.5 and 36 you will get shivering 17 in patients. But the skin contact alone can 18 potentiate the degree of shivering experience. 19 DR. BRINKER: There's a trial of a 20 intravascular device for the performance of 21 interventional cardiology. And that produced a huge 22 amount of shivering. Those patients, of course, were NEAL R. GROSS COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. (202) 234-4433 WASHINGTON, D.C. 20005-3701 (202) 234-4433 55 1 more conscious and require drugs to control this. 2 So the question is do patients need to be 3 treated with sedatives and/or blocker? 4 DR. COLLINS: Well, I'll make one comment 5 and then I'll pass this to the clinicians. 6 This is indicated for the comatose 7 survivors. And in the comatose survivors, at least 8 initially, it's not such an issue. But I'll pass on 9 to Dr. Sterz. 10 DR. STERZ: If patients are lucky, they're 11 found by bystanders. Then the ambulance service is 12 called and tries to resuscitate them. Then after 13 establishing restoration of spontaneous circulation, 14 they either receive sedative or analgesic drugs by the 15 ambulance service, depending on the awareness or 16 depending on how they are doing. But most of these 17 patients come unconsciousness without any sedation and 18 drugs to our department. And they're immediately 19 assessed on admission about their Glasgow Coma Score 20 Scale and Pittsburgh Brain Stern Score and so on. 21 For then further treating them we had a 22 standard order of procedure that sedation and NEAL R. GROSS COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. (202) 234-4433 WASHINGTON, D.C. 20005-3701 (202) 234-4433 56 1 analgesia plus paralyzers has to be used in these 2 patients according to a protocol for 24 hours. 3 So the assessment of the patient was 4 either done by the ambulance physicians or mostly by 5 ourself with regards to being comatose for being 6 included in the study and then immediately afterwards 7 we started with sedation, analgesia and paralyzers for 8 the duration of cooling until they reached 36 degrees 9 again. 10 DR. BRINKER: Okay. And the patients in 11 the studies that were normothermic, did they get the 12 same blocking agents and sedatives? 13 DR. STERZ: This is a routine protocol 14 regardless without or with cooling. And the data in 15 the HACA trial have shown that the same drug amounts 16 of paralyzers and sedation and analgesia was used. 17 Right now in this series most of the control patients 18 came out of the HACA trial, therefore the same 19 regiment was used. And in addition this regiment is 20 used anyhow if they get cooled or not. 21 DR. COLLINS: I think you're actually 22 referring to Alsius as normothermia trials were you? NEAL R. GROSS COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. (202) 234-4433 WASHINGTON, D.C. 20005-3701 (202) 234-4433 57 1 DR. BRINKER: Yes. 2 DR. COLLINS: Yes. Many of those patients 3 were ventilated and therefore under some form of 4 agents. In the normothermia patients we tend not to 5 get shivering provided the skin around the groin is 6 protected from the cold of the catheter. 7 DR. BRINKER: So when you give these 8 drugs, do you actually -- in the hypothermia patients, 9 you do not see shivering? Do you see physically 10 shivering? What I'm getting at is could the shivering 11 account for something like the renal problems that 12 I've been seeing, either by myoglobin or something 13 like that? 14 DR. STERZ: Well, for example in the HACA 15 trial we didn't see these renal problems. This with 16 regards to the renal problems, I cannot report about 17 if our patient shiver or not, because they have both 18 groups, control and hypothermia groups, on this 19 sedation and analgesia and paralyzing drugs right from 20 the beginning, before they reach the temperature. 21 We have experienced this in some 22 myocardial infarction patients which have been NEAL R. GROSS COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. (202) 234-4433 WASHINGTON, D.C. 20005-3701 (202) 234-4433 58 1 conscious using this device and trying to cool them. 2 And there we got incredible problems because of 3 shivering and discomfort of our patients. But these 4 were conscious patients and not cardiac arrest 5 survivors. 6 DR. BRINKER: Fine. Thank you. 7 DR. COLLINS: And one final comment. The 8 company, Alsius has done a feasibility trial in acute 9 myocardial infarction and the results are published, 10 and therefore in the public record. 11 In those patients in which adequate 12 paradigm was present, adequate being they were still 13 breathing but were not shivering, there did not seem 14 to be any ECG evidence of myoclonic activity 15 suggesting that there wasn't actually sort of 16 subobvious shivering going on. It can be suppressed. 17 CHAIRMAN MAISEL: Dr. Brott and Dr. 18 Somberg. 19 DR. BROTT: Two, hopefully, brief 20 questions. 21 We were provided the HACA paper, and it 22 states to prevent shivering paralysis was induced by NEAL R. GROSS COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. (202) 234-4433 WASHINGTON, D.C. 20005-3701 (202) 234-4433 59 1 the intravenous administration of pancuronium for two 2 hours. 3 It's a little ambiguous. Was every patient 4 in normothermia paralyzed for 32 hours? 5 DR. STERZ: Yes. Clear, straight answer. 6 Yes. 7 DR. BROTT: Okay. Second question. Thank 8 you very much for coming, Dr. Roine from Finland. And 9 I thought your information was very interesting. 10 I'm wondering if you could give some raw 11 numbers? You know, we had percentages. You know, 12 greater than 90 percent of patients had endovascular 13 cooling. It said four hospitals. It's at your 14 university hospital. But do you have numbers in terms 15 of total admissions of patients with coma after 16 cardiac arrest? How many received cooling of any 17 kind? How many received cooling with this device? 18 How many had this SAE or didn't? You know, some hard 19 numbers. 20 DR. ROINE: Yes. Thank you. 21 In Helsinki all cardiac arrest patients 22 are being treated at one hospital. They have the NEAL R. GROSS COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. (202) 234-4433 WASHINGTON, D.C. 20005-3701 (202) 234-4433 60 1 central hospital. And between 90 and 95 percent of 2 those patients will be treated using hypothermia. Only 3 if it's found out that the resuscitation was not 4 indicated or the patient is in terminal condition, or 5 there is a contraindication for intensive care, then 6 hypothermia was not used. And nine patients out of 7 ten will receive endovascular cooling because we have 8 actually three units available. The fourth unit is in 9 another hospital. 10 DR. BROTT: I understand that. What I was 11 wondering the raw numbers. Not percentages. 12 DR. ROINE: Yes. Okay. 13 DR. BROTT: The absolute raw numbers of 14 patients who are admitted with out-of-hospital cardiac 15 arrest. 16 DR. ROINE: Yes. 17 DR. BROTT: How many with coma, how many 18 were treated. You know, the raw numbers with 19 hypothermia of any kind. 20 DR. ROINE: All right. 2004 and 48 21 patients were treated with endovascular cooling at our 22 hospital. They were all VF cardiac arrest patients. NEAL R. GROSS COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. (202) 234-4433 WASHINGTON, D.C. 20005-3701 (202) 234-4433 61 1 Forty-eight. 2 DR. BROTT: And how many with this device? 3 DR. ROINE: All of them were treated with 4 this device. 5 DR. BROTT: Thank you. 6 CHAIRMAN MAISEL: John? 7 DR. SOMBERG: A couple of quick questions 8 relating to your current presentation. One is I'm 9 most interested in the Austrian registry and what 10 you've presented. Could you tell me the time from 11 event to resuscitation and the time from event to 12 cooling? One of the things that came up in an earlier 13 Panel meeting was the difference between the European 14 experience and the United States experience. 15 DR. STERZ: Due to having this acute care 16 unit in the emergency department, which is an 17 intensive care unit, we have this tool of making this 18 chain of survival very short and not having these 19 problems within the hospital to get patients to the 20 ICUs. And, therefore, our lack or the time which was 21 missing was the time of the ambulance drive to the 22 hospital, which was in an average 20 minutes. NEAL R. GROSS COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. (202) 234-4433 WASHINGTON, D.C. 20005-3701 (202) 234-4433 62 1 So these patients got cool within an 2 average to 33 degrees, as you can see on these 3 temperatures curves which is always counting from 4 restoration of spontaneous circulation until reaching 5 the target temperature, of approximately if I recall 6 it right four to five hours. I don't have it now in my 7 mind, but reaching the target temperature was in the 8 endovascular cooling between four and five hours. And 9 in the HACA trial around eight hours. I don't know 10 how it is -- 11 DR. SOMBERG: But from the time of the 12 event to the time of initiation of this process? 13 DR. STERZ: Initiation? How long it takes 14 from admission to initiate -- 15 DR. SOMBERG: No, no. Let's say someone 16 has an arrest and they are discovered. From the point 17 they're down they receive -- you know, from the time 18 of the arrest to the time they are down, it's all 19 you've had in Europe, the time is 2, 3, 4 minutes up 20 to 6 minutes; it's different than the States. I just 21 wanted what the time was for this subset you have 22 there. NEAL R. GROSS COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. (202) 234-4433 WASHINGTON, D.C. 20005-3701 (202) 234-4433 63 1 Do you have rapid resuscitation in 2 Austria? 3 DR. STERZ: Yes. 4 DR. SOMBERG: Okay. So you do. So you're 5 in these very low numbers. And then from the time that 6 they receive the resuscitation effort to the time they 7 initiate cooling? 8 DR. STERZ: It's approximately 20 to 30 9 minutes. 10 DR. SOMBERG: Twenty to 30 minutes. Okay. 11 Also, can you tell me in this registry I 12 was confused by the material booklet in that many of 13 the patients who received the CoolGard system also 14 received in the subanalyses rapid infusion of cold 15 saline. Was this the case in the material you 16 presented? 17 DR. STERZ: This was the case in the last 18 series of patients, which we did now. Not in the 19 first series of patients where we didn't do ice cold 20 fluid cooling. The percentage of patients, I think 21 the first 50 patients hadn't been cooled with 22 additional ice cold fluids. Then due to this short NEAL R. GROSS COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. (202) 234-4433 WASHINGTON, D.C. 20005-3701 (202) 234-4433 64 1 delay of 50 minutes until getting endovascular cooling 2 started, we decided it have to been earlier and to 3 take out the fluids from the fridge and initiate 4 cooling right when they are coming in the door. 5 DR. SOMBERG: So you would say that the 6 fluid is an integral part of the process of -- 7 DR. STERZ: Right now, yes. 8 DR. SOMBERG: Yes. Okay. And can you 9 also in the registry clarify how the controlled group 10 is constituted? Is this done by a committee that 11 doesn't know the results of the intervention group? 12 You know, is it a blinded selection? Is it 13 prespecified criteria before the controls are 14 selected, etcetera? 15 DR. STERZ: The endovascular cooling or 16 the cooling at all, which device whatever we take, the 17 patient have to have certain inclusion criterias. And 18 unfortunately right now the controlled group shouldn't 19 have these inclusion criterias. So the controlled 20 group are different. 21 And the inclusion criterias I have shown 22 in this one slide are very general right now as NEAL R. GROSS COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. (202) 234-4433 WASHINGTON, D.C. 20005-3701 (202) 234-4433 65 1 compared to the HACA trial where we have been much 2 more strict. I'm hearing now that they're even much, 3 much more generous than we are. We take, for example, 4 no patients which had very short resuscitation times. 5 Whether they're comatose? They have to 6 be, they have to have primary successful restoration 7 of spontaneous circulation, they have to be over 18 8 years and they have to have patients who have at least 9 survived 24 hours, but this was done for the analyzers 10 retrospectively. And for the analyzers 11 retrospectively we took patients only which 12 resuscitation times of more than one minute. 13 DR. SOMBERG: But I thought I understand 14 you is that you an overall control group, which was 15 very broad in general, and then you clarified that 16 down or distilled it down to a smaller group. I just 17 don't understand the process of how that was done. 18 DR. STERZ: The majority of the overall 19 control group was historic group. Was the control 20 group before 2003 when we started with endovascular 21 cooling. The majority of these control group patients 22 is coming from this patient population. And much of NEAL R. GROSS COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. (202) 234-4433 WASHINGTON, D.C. 20005-3701 (202) 234-4433 66 1 them or many of them are coming either from the HACA 2 trial where we did the prospective randomized trial 3 and where we had the controlled group selected. 4 DR. COLLINS: I think to answer your 5 question, because I do know the answer, Alsius 6 approached the Professor for access to his data. 7 There is a statistician on staff, Dr. Marcus Mullner 8 at that time at the university. He wrote a prospective 9 selection criteria, and then that is applied. The set 10 was extracted and the analyses was done. 11 Does that answer your question? 12 DR. SOMBERG: Well, it tries to. 13 And I have one just final question, very 14 quickly. What is the cost of this procedure of 15 cooling? 16 CHAIRMAN MAISEL: We're not here to 17 consider the financial issues. You're welcome to 18 answer the question if you wish, but you're not 19 obligated to. 20 Okay. John? 21 DR. MARLER: Yes. We're looking at a 22 device that, as I understand it, is put in through the NEAL R. GROSS COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. (202) 234-4433 WASHINGTON, D.C. 20005-3701 (202) 234-4433 67 1 groin into a major vein. Left there for a long period 2 of time, many hours and then withdrawn. And yet in 3 all of the complications, I looked through the 4 material and perhaps I missed it, but I don't see any 5 complications like bleeding like hitting an artery or 6 a nerve instead of the vein or injuring them in the 7 process. I don't see any evidence of any pulmonary 8 emboli. I don't see any evidence of having to withdraw 9 the catheter early or to use more than one device to 10 obtain the successful cooling. And that just kind of 11 goes against my common sense that the nature of this 12 kind of device. And I was wondering if there's any 13 such events that happened or have they just not been 14 reported? How is this possible? 15 DR. STERZ: With regards to pulmonary 16 embolism and deep vein thrombosis, all these patients 17 are heparinized. A lot of these patients receive 18 thrombolysis or go to the cath lab because they have 19 been myocardial infarction patients with cardiac 20 arrest. And we haven't seen such kind of emboli or 21 some deep vein thrombosis. We have seen bleeding, but 22 this data have been presented. NEAL R. GROSS COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. (202) 234-4433 WASHINGTON, D.C. 20005-3701 (202) 234-4433 68 1 We haven't any major problems as usually 2 what you have with puncturing a vein. If you are in 3 the artery, you withdraw and then you try to hit the 4 vein beside it. But that's routine clinically doing 5 if you use hemodialysis or if you cannot a vein in the 6 subclavian vein, then no major problems with regards 7 to puncture or no major problems with regards to 8 placing the catheter. I don't know if Risto has the 9 same experience. 10 DR. ROINE: Yes. I have nothing to add to 11 this. 12 DR. MARLER: Is anticoagulation a routine 13 a routine part of external cooling? 14 DR. STERZ: Not of external cooling, but 15 of these patients. All these patients are intensive 16 care unit patients and they receive somehow 17 anticoagulants. 18 DR. COLLINS: The company has also 19 submitted to the FDA in a previous application the 20 randomized control trial of normothermia patients. 21 And as a central line, the catheter performs as a 22 central line with the usual complications of a central NEAL R. GROSS COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. (202) 234-4433 WASHINGTON, D.C. 20005-3701 (202) 234-4433 69 1 line. 2 CHAIRMAN MAISEL: Henry? 3 DR. HALPERIN: A few questions. 4 There was a substantial difference in the 5 statistical significance between the analyses that 6 were done unadjusted and adjusted. Could you comment 7 on the particular variables that made the biggest 8 difference in the adjustment? 9 DR. COLLINS: I'm going to ask Joel to 10 come and help me with this one. 11 DR. VERTER: Good morning. My name is 12 Joel Verter. I'm a statistician with Statistics 13 Collaborative. And I helped the company with some of 14 its analysis. I did not do the original analysis, as 15 Dr. Collins noted. That was done by Dr. Mullner in 16 Vienna. 17 The variables that we used were pretty 18 much -- there were many models, first let me say. But 19 the variables that we used were the baseline variables 20 that were available to us. And I believe what you're 21 asking did we do some kind of stepwise analysis -- 22 DR. HALPERIN: Well, what particular NEAL R. GROSS COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. (202) 234-4433 WASHINGTON, D.C. 20005-3701 (202) 234-4433 70 1 variables made the biggest difference is really what 2 I'd like to know. 3 DR. VERTER: Right. Yes. And I believe 4 that the only answer to that would be if we did some 5 sort of stepwise, and we did not do that. We did the 6 univariate models, we did bivariate, we did group in 7 each individual variable and then we did the complete 8 set. 9 DR. HALPERIN: So how many variables were 10 used in the adjustment? Was all those, there were 11 like variables or something like that? 12 DR. VERTER: That's about correct, yes. 13 DR. HALPERIN: Because you have like 60 14 patients or something like that? 15 DR. VERTER: There was 62 coolings. 16 DR. HALPERIN: And did you do an analysis 17 to see if you could use that many variables to adjust? 18 DR. VERTER: The issue for us was that, as 19 Dr. Collins noted, we were limited by the 510(k) 20 application. And that model which was done in Vienna 21 used all those variables. I would agree that ten, but 22 62 may be pushing the limits. NEAL R. GROSS COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. (202) 234-4433 WASHINGTON, D.C. 20005-3701 (202) 234-4433 71 1 DR. HALPERIN: So you didn't really look 2 for one particular thing like time to resuscitation or 3 age or anything like that that was actually a 4 particularly significant variable? 5 DR. VERTER: The only analysis I could 6 speak to you about that is the bivariate ones which we 7 did here which included group and each one of those 8 individually. And I'd have to go check my notes, but 9 on an individual basis none of them seemed to have a 10 major impact. When you put them altogether, they had 11 the biggest impact. 12 DR. HALPERIN: Okay. In the Helsinki data 13 you mentioned there were 40 patients or so that met 14 your inclusion criteria over some period of time. 15 Could you comment on many total cardiac arrests there 16 were in Helsinki? 17 DR. ROINE: I didn't bring the actual 18 numbers with me. And, unfortunately, to match 19 everything else the cardiac arrest cases are VF in 20 Helsinki. And of those patients with restore 21 spontaneous circulation and admission to hospital, 22 almost all will receive hypothermia at our NEAL R. GROSS COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. (202) 234-4433 WASHINGTON, D.C. 20005-3701 (202) 234-4433 72 1 institution. 2 DR. HALPERIN: But these 40 patients, what 3 percentage -- 4 DR. ROINE: Forty-eight. 5 DR. HALPERIN: Forty-eight. What 6 percentage of the total cardiac arrest population does 7 that represent? 8 DR. ROINE: It's more than 100 in 9 Helsinki, in the city of Helsinki. 10 DR. HALPERIN: So there's a 100 cardiac 11 arrests in Helsinki over that period of time? 12 DR. ROINE: Sorry not to bring the actual 13 numbers with me. I just don't have the actual numbers. 14 DR. HALPERIN: Okay. And from 15 historically do you know what the survival was in 16 those patients before they got cooling? 17 DR. ROINE: Yes. The secondary survival 18 rate in the patient material in my thesis was around 19 40. 20 DR. HALPERIN: Forty. So you went from 40 21 to 70 in that limited population. 22 DR. ROINE: Yes. NEAL R. GROSS COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. (202) 234-4433 WASHINGTON, D.C. 20005-3701 (202) 234-4433 73 1 DR. HALPERIN: Okay. And then one other 2 thing is there was an issue of informed consent. You 3 said that that limited the number of patients enrolled 4 early. And this would be consent in patients who were 5 successfully resuscitated and then were in the 6 hospital. So the pressure of time probably really 7 wasn't really there like what it would be during 8 trying to do a new CPR intervention during actual 9 resuscitation. 10 So what were the issues in obtaining 11 informed consent? 12 DR. COLLINS: From memory the way it was 13 structured, at last the patients who were comatose, 14 you had to get family member consent. And that was the 15 time -- 16 DR. HALPERIN: And then what's changed in 17 allowing this to become generally used? Because the 18 same issues would be there? 19 DR. COLLINS: I'm sorry, I don't 20 understand the question. The device is released for 21 this indication in the United States. 22 DR. HALPERIN: So you're talking about NEAL R. GROSS COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. (202) 234-4433 WASHINGTON, D.C. 20005-3701 (202) 234-4433 74 1 this would be just in the U.S., not in Europe? 2 DR. COLLINS: Yes. 3 DR. HALPERIN: Okay. 4 CHAIRMAN MAISEL: I wondered if you could 5 address an issue of surface cooling versus 6 endovascular cooling? The only randomized data you're 7 presenting today is on surface cooling. We've heard 8 from a number of speakers this morning about how the 9 time course for the endovascular cooling is different 10 from surface cooling. We heard from a public speaker 11 about overshooting or not reaching the temperatures 12 fast enough. We heard from Dr. Sterz about how the 13 endovascular catheter cools much more rapidly. So I 14 have several questions related to that. 15 Number one, do we have any data that 16 cooling faster is better? 17 Number two, with regard to the registry, 18 maybe you could just be a little more explicit and 19 explain why some patients were cooled and some were 20 not, because that seems that the issue of interpreting 21 the data you've presented. 22 And I also wonder if you could comment on NEAL R. GROSS COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. (202) 234-4433 WASHINGTON, D.C. 20005-3701 (202) 234-4433 75 1 why some patients were endovascularly cooled in the 2 registry and some apparently were surface cooled or 3 cooled by other means? 4 DR. STERZ: So when we finished HACA, we 5 were approached by Alsius and they were asking us to 6 use the Alsius device. So in the first period, I 7 don't know when we started exactly, we used the Alsius 8 device only. Then later on Allon came with this 9 surface cooling device. And a little bit later on 10 Medivance came with their surface cooling device. And 11 just recently we have been approached by KCI to use 12 their new surface cooling device, which we have 13 formally used in the HACA trial. 14 Data of all these surface cooling devices 15 are available, but I have undersigned with the 16 companies that are not allowed to present them. 17 Therefore, I cannot present them. Maybe, I don't know 18 -- but I have them. I have them on my laptop. If 19 it's really needed and if it's permitted. 20 With regards to which patient is getting 21 what when, we have a list in our department where 22 boxes are empty below the certain surface cooling or NEAL R. GROSS COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. (202) 234-4433 WASHINGTON, D.C. 20005-3701 (202) 234-4433 76 1 endovascular cooling methods. And to be fair to every 2 method, this list has always to be in a straight line 3 that all these kind of devices are used in the same 4 amount of numbers than the others. However, due to be 5 Alsius first with us, they had an advantage of being 6 used in one year only their device. And therefore, in 7 the beginning mostly the Alsius device used. Just 8 recently we used all of the other devices. 9 With regards to the inclusion and 10 exclusion -- 11 CHAIRMAN MAISEL: Can I interrupt for one 12 second. Have you compared the endovascular cooling to 13 the surface cooling in your registry data base? 14 DR. STERZ: Yes, we have, for us. 15 CHAIRMAN MAISEL: Without violating any of 16 your confidentiality agreements about specific 17 companies, can you tell us whether they are 18 comparable? 19 DR. STERZ: They are comparable. 20 CHAIRMAN MAISEL: So with regard to a 21 mortality and safety issues -- 22 DR. STERZ: With regard to the efficacy. NEAL R. GROSS COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. (202) 234-4433 WASHINGTON, D.C. 20005-3701 (202) 234-4433 77 1 With regard to the outcome, I have too less data in 2 these patients with surface cooling yet. 3 CHAIRMAN MAISEL: So there is no 4 statistically significant difference in survival or 5 survival with good neurologic outcome between 6 endovascular cooling and surface cooling in your 7 database? 8 DR. STERZ: At the moment it doesn't look 9 like this, no. 10 CHAIRMAN MAISEL: Okay. 11 DR. STERZ: Of course we don't have the 12 data. 13 CHAIRMAN MAISEL: Right. I understand. 14 DR. STERZ: With regard to the inclusion 15 and exclusion, I want to point one thing out. When we 16 stopped HACA we were so convinced that cooling helps 17 these patients, that at the beginning we stated this 18 SOPs with the inclusion very general. However, to get 19 a team like our team moving in this direction, in the 20 beginning of such a new treatment you lose a lot of 21 patients which are not cooled at the end, because in 22 the night shift there's a fellow who maybe doesn't NEAL R. GROSS COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. (202) 234-4433 WASHINGTON, D.C. 20005-3701 (202) 234-4433 78 1 like it. 2 So in the beginning we had maybe lost a 3 lot of patients which should have been cooled. Right 4 now we don't lose any patient anymore because the 5 people are used to it now and we have the experience 6 of 120 endovascular cooling patients now. And I think 7 that's quite a lot. And this proves that it's in 8 general use. 9 CHAIRMAN MAISEL: Okay. I'm a little 10 troubled that there is data that would potentially be 11 very useful for this Panel to review with regard to 12 the surface cooling and your database that we aren't 13 allowed to look at. 14 Mike? 15 DR. WEISFELDT: Yes. I want to pursue the 16 subject of the acute renal failures statistically 17 significant difference in part as an extension of Dr. 18 Marler's comments about the potential complications of 19 putting a catheter in through the vasculature. And I 20 want to confirm what I think I've heard, I guess 21 first, which is that although the word acute renal 22 failure is the descriptor, the definition that was NEAL R. GROSS COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. (202) 234-4433 WASHINGTON, D.C. 20005-3701 (202) 234-4433 79 1 used is a 0.5 milligram percent increase in 2 creatinine. Is that -- 3 DR. STERZ: Yes. This was taken from the 4 literature. 5 DR. WEISFELDT: Okay. 6 DR. STERZ: I think this is a very tough 7 definition. This definition is not acute renal 8 failure which needed hemodialysis in these patients, 9 or which needed some type of specific treatment. And 10 if you look at our recent publication about the renal 11 problem in cooling such patients published by Andrea 12 Zeiner in Resuscitation it resolves within seven days. 13 You don't see it anymore. You don't have to do 14 anything except that you have to do the fluid 15 management according to -- but that's what you have to 16 do anyhow in such patients. 17 DR. WEISFELDT: I missed your last 18 statement, but I want to go on with my line of 19 questioning. You've answered the first question. 20 The second question is I want to confirm 21 again that this is not seen with surface cooling as in 22 the HACA trial? So this is -- the increase in NEAL R. GROSS COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. (202) 234-4433 WASHINGTON, D.C. 20005-3701 (202) 234-4433 80 1 creatinine to that level which is statistical 2 significant was seen in the database study and it was 3 not seen with surface cooling as in the HACA trial. 4 DR. STERZ: That's right. 5 DR. WEISFELDT: Okay. And can you give me 6 the mean or the variance or do you have a plot of the 7 actual highest creatinine in the patients who have had 8 acute renal failure by that definition? 9 DR. STERZ: I have it in this paper. There 10 is a very graph where you have the mean value over the 11 time. 12 DR. WEISFELDT: In these patients? 13 DR. STERZ: In these patients, yes. 14 DR. WEISFELDT: Okay. And where is that? 15 DR. STERZ: It's in Resuscitation just 16 2004, Zeiner was the first author. Andrea Zeiner. 17 DR. WEISFELDT: Do you remember how many 18 had a creatinine over two or three? 19 DR. STERZ: Very few. 20 DR. COLLINS: I just please respond to Dr. 21 Maisel. The company cannot coerce other companies to 22 submit their data. And although I understand your NEAL R. GROSS COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. (202) 234-4433 WASHINGTON, D.C. 20005-3701 (202) 234-4433 81 1 discouragement, we cannot as a company nor can the 2 Panel force a company to participate who is not a 3 Panel presenter. 4 CHAIRMAN MAISEL: I understand. And I did 5 not mean to imply that the company in anyway was 6 withholding data. I guess I should have better 7 underscored that. We're talking now about registry 8 data where we don't actually have full access to the 9 data. 10 Anyone else on the Panel have questions 11 for the sponsor? 12 Norm? 13 DR. KATO: Do you have any other 14 information about the performance of this catheter in 15 other clinical situations? And one of the questions 16 we're asked is to measure this device against itself. 17 And while apparently it is indicated for use in cardio 18 thoracic surgery, as a practicing heart surgeon I 19 haven't seen this device ever used. So I'm kind of 20 curious to see what other -- in order to make this 21 leap for your 510(k) submission, we have to have 22 enough data in order to have some basis for that next NEAL R. GROSS COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. (202) 234-4433 WASHINGTON, D.C. 20005-3701 (202) 234-4433 82 1 step. So do you have anything to present along those 2 lines? 3 DR. COLLINS: The company has three 4 indications in the United States, all three of which 5 will be, I guess, normothermia in cerebrovascular 6 hemorrhage. A 300 patient randomized controlled trial 7 was done and the data was submitted. 8 The company is involved in Europe in 9 cardiothoracic surgery indications and has just 10 published, and I will try to obtain for you if I can-- 11 I didn't bring them with me -- information related to 12 the use of the product in the post-surgical recovery 13 of patients. The catheter's purpose there is simply 14 to prevent the after drop decrease in core temperature 15 delays extubation in patients after cardiothoracic 16 surgery. 17 Our company is involved in the HACA-ERC 18 registry. The registry is a several hundred patient 19 now study in Europe that looks at cardiac arrest. I 20 may not under European law share that information with 21 the Panel until such time as it has been made public. 22 That's their privacy directive. I can't change that. NEAL R. GROSS COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. (202) 234-4433 WASHINGTON, D.C. 20005-3701 (202) 234-4433 83 1 But we have a large ongoing post-market surveillance 2 for that in Europe. 3 In terms of the normothermia application 4 post-market, we have an ongoing post-market 5 surveillance of the normothermia population for which 6 I think you received a copy of our latest report. 7 And the report of the 300 patient 8 randomized controlled trial was available to you by 9 the 510(k) submission if you wish to see it. 10 DR. KATO: But, I mean, you don't have any 11 data or slides -- 12 DR. COLLINS: I didn't come prepared with 13 other than this Panel presentation. 14 DR. KATO: Okay. Thank you. 15 CHAIRMAN MAISEL: Mike? 16 DR. WEISFELDT: In those patient groups 17 how long is the catheter in place, and this is not the 18 cardiac arrest patients for whom the device is 19 approved, how long is the device used in neurosurgery 20 or other, obviously in comparison to the 24 hours 21 here? 22 DR. COLLINS: The period post-surgery is NEAL R. GROSS COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. (202) 234-4433 WASHINGTON, D.C. 20005-3701 (202) 234-4433 84 1 typically the 24 hour recovery period. In the 2 normothermia condition it's up to seven days. The 3 catheter in this case is labeled not to be used for 4 more than four days. 5 CHAIRMAN MAISEL: We'll have additional 6 time later today to ask questions. 7 Why don't we take a 15 break at this point 8 and reconvene at 10:00 a.m. for the FDA presentation. 9 (Whereupon, at 9:42 a.m. off the record 10 until 10:02 a.m.) 11 MR. FELTEN: I'm Richard Felten. I was the 12 team leader reviewer for the Alsius 510(k). The other 13 members of the review team and who will be presenting 14 are here: Dr. Swain, who will be doing the clinical 15 review; Dr. Zhao who is our statistician giving the 16 statistical review, and; Dr. Lazar will give you a 17 short presentation on neurological endpoints as we've 18 used those to interpret this data here. 19 As Dr. Collins has already mentioned to 20 you the Alsius CoolGard 3000 is already a legally 21 marketed product through the pre-market identification 22 process. And the device that is the subject of this NEAL R. GROSS COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. (202) 234-4433 WASHINGTON, D.C. 20005-3701 (202) 234-4433 85 1 discussion is identical to the device that has already 2 been cleared through pre-market identification for 3 three specific indications for use. 4 The first indication for use, as you 5 notice, is for fever reduction as adjunct to 6 antipyretic therapy in patients with cerebral infarcts 7 and intracerebral hemorrhage who require access to 8 central venous catheter circulation and who are 9 intubated and sedated. 10 Next slide. 11 This indication was actually based on a 12 clinical trial data from Alsius. And one of the 13 things our division routinely does when we have a very 14 new use or a very new indication for use in the pre- 15 market notification is ask the companies to include 16 some of their clinical trial data. Alsius has done 17 this, as you notice with this warning, because in 18 their actual clinical trial they actually looked at 19 four different groups of patients. Our plan was 20 limited to only two of those because there is some 21 suggestion in this data that there is absolute change 22 in mortality, although those were not significantly NEAL R. GROSS COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. (202) 234-4433 WASHINGTON, D.C. 20005-3701 (202) 234-4433 86 1 different. 2 The package that you received does contain 3 the most recent summary of the post-market 4 surveillance data that they are now conducting in this 5 area of fever reduction. 6 Next slide. 7 The second indication for use they have is 8 for use in cardiac surgery patients to achieve and/or 9 maintain normothermia during surgery and 10 recover/intensive care. And as Dr. Collins also 11 indicated, this means that the device actually was 12 used probably up to 24 hours after the completion of 13 surgery. And the intent was, as he mentioned, to 14 stabilize the rewarming process as a way to avoid the 15 downside. 16 Next slide, please. 17 And the third indication is to induce, 18 maintain and reverse mild hypothermia in neurosurgery 19 patients in surgery and recovery/intensive care. 20 You should also be aware that all three of 21 these indications for use were granted to Alsius and 22 several other companies based on clinical trial data. NEAL R. GROSS COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. (202) 234-4433 WASHINGTON, D.C. 20005-3701 (202) 234-4433 87 1 So that all of these studies do have clinical data to 2 support indication use they have. And the indications 3 for use are very specific because the clinical trial 4 data is very specific for that use. 5 Next slide. 6 As you also are aware now, Alsius is now 7 requesting a new indication for use. And this 8 indication for use, again, is very specific and it's 9 based on the ILCOR recommendation. And that is for use 10 in the induction, maintenance and reversal of mild 11 hypothermia in the treatment of unconscious adult 12 patients with spontaneous circulation after out-of- 13 hospital cardiac arrest when the initial rhythms was 14 ventricular fibrillation. 15 And to support this request -- next slide 16 -- what Alsius has presented to us is the meta- 17 analysis with the three surface cooling studies, a 13- 18 patient prospective uncontrolled U.S. feasibility 19 study which was done under an approved IDE. And then 20 the prospective, non-randomized single-site 21 observational registry with the matched controls from 22 AKH Registry Data. And this clinical trial data will NEAL R. GROSS COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. (202) 234-4433 WASHINGTON, D.C. 20005-3701 (202) 234-4433 88 1 be discussed by Dr. Swain. 2 Thank you. 3 DR. SWAIN: Let's see if I can find the 4 presentation here. Okay. 5 Hello. I'm Julie Swain, cardiovascular 6 surgeon advisor to the FDA. And prior to being in my 7 present position, I was Chief of Cardiac Surgery at 8 three institutions, Professor of Surgery and a senior 9 investigator at NIH. 10 My career has really been spent in 11 studying hypothermia especially relating to 12 ventricular fibrillation thresholds and brain 13 function. 14 So with that introduction we'll go over 15 the data. 16 As Richard just said, we're looking at the 17 data presented by the sponsor. And it's been a 18 pleasure to work with the sponsor. They've been very 19 responsive in sending us information. 20 We have clinical issues, though, with 21 several of the pieces of data that have been 22 submitted. The meta-analysis, specific data from NEAL R. GROSS COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. (202) 234-4433 WASHINGTON, D.C. 20005-3701 (202) 234-4433 89 1 Alsius, some safety data and a question about the 2 clinical issue of applicability of the general date to 3 the Alsius device. 4 The three studies, as you know, included 5 the Bernard Austrian study. We have the public no 6 patient-level data, HACA patient-level data, and the 7 Belgium study no patient-level data. And the AKH 8 Registry. I just wanted to go over a few minutes the 9 comparisons between these. 10 Bernard study, Australia, HACA, Europe and 11 the Brussels study. And I think there's always 12 questions about applicability of out of U.S. data to 13 U.S. data. And I think I learned from the Princess 14 Diana story about the differences in delivery of 15 health care. And I think that's one of the questions 16 that the Panel just asked. So we need to know about 17 the specifics of that. 18 Bernard study, they're all relatively 19 small studies. Forty-three hypothermia patients out 20 of 77 total. 137 in the HACA study of hypothermia. 21 And 16 in the Belgium study. And the AKH Registry 22 which contains a lot of patients with various NEAL R. GROSS COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. (202) 234-4433 WASHINGTON, D.C. 20005-3701 (202) 234-4433 90 1 protocols and various types of patients. 2 Inclusion criteria are somewhat different 3 between all of these studies. Bernard was VF, not VT, 4 VF. Men over 18 but women over 50. They're excluded 5 if there are no ICU bed, cardiac arrest coma. 6 HACA study has the inclusion criteria 7 listed here. And they actually looked at the 8 denominator, which I think Dr. Somberg was asking 9 about, and found that 8 percent of the patients 10 screened without a -- cardiac arrest were eligible for 11 these study with these inclusion criteria. 12 The Belgium study had the inclusion 13 criteria as listed, hemodynamically stable, things of 14 that sort. 15 AKH, because it's a registry and from '91 16 to 2003 we received one protocol from 1995 which was 17 the HACA protocol which clearly was not used with this 18 device, and a lot of the others in the external 19 cooling devices I think that were mentioned. And 20 before '95 wasn't used for the data from '91 to '95. 21 So we're not sure of the inclusion criteria in the 22 registry other than cardiac arrest patients. NEAL R. GROSS COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. (202) 234-4433 WASHINGTON, D.C. 20005-3701 (202) 234-4433 91 1 And most importantly, this included in- 2 house or out-of-hospital cardiac arrest patients. And 3 the question is that in-hospital may in fact reduce 4 time to resuscitation, although that's a very 5 different patient group than out-of-hospital cardiac 6 arrest. 7 The duration of cooling, 12 hours in one 8 study, 24 hours, less than 4 hours in another. We 9 don't know in the AKH Registry because there are 10 various protocols used the exact conditions. How they 11 were cooled, very much different between the three 12 different studies that were published. Everything from 13 a helmet to cool ice packs and all that. 14 They were started in the field in 15 Australia. The cooling was started in the field in the 16 ambulance. They're started in the hospital in HACA. 17 In the hospital in the Belgium study. And I would 18 assume in the hospital in the AKH Registry, although 19 that is not clear to me. 20 Also rewarming, there was active rewarming 21 in the Australian study, passive rewarming in the 22 other two. I'm not sure about the rewarming methods in NEAL R. GROSS COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. (202) 234-4433 WASHINGTON, D.C. 20005-3701 (202) 234-4433 92 1 all of the patients in the AKH Registry. It's not 2 data that we received. 3 Prespecified study endpoints. Survival to 4 hospital discharge with neuro function allowing home 5 or rehab for Australia. That's different from a CPC 6 good or moderate at six months for the HACA study. 7 There were really no prespecified endpoints for the 8 Belgium Idrissi feasibility study. And since the AKH 9 Registry was really a chart review from '91 to '94, 10 apparently, and then a registry after that time, there 11 are really no prespecified endpoints. 12 What's very interesting is something that 13 actually I read the Bernard paper probably ten times 14 over two years before I finally saw that it in small 15 print in the statistical analysis section, it was a 16 planned sample size of 62 and they completed the 17 study. At the end of the study the primary endpoint 18 was nonsignificant. A failed study. So they added 19 more patients. And they added 12 hypothermia and three 20 controlled. They didn't say they were added 21 randomized, and I just had Dr. Irony, our statistician 22 do a quick calculation. And I believe there's NEAL R. GROSS COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. (202) 234-4433 WASHINGTON, D.C. 20005-3701 (202) 234-4433 93 1 something like a 1.4 percent chance that this was a 2 random occurrence. So I don't know how the 12 and 3 3 were added. And the paper then gives a p-value of 4 .046 without talking about this interim analysis or 5 adding patients, or anything of that sort. So we have 6 a very difficult time interpreting that p-value. It 7 could be interpreted that this really a hypothesis 8 generating study. It was a negative study that's 9 hypothesis generating. But there may be some question 10 about that. 11 The HACA study we don't know how many 12 patients were planned prospectively in this study. 13 All it says it that the study was stopped prematurely 14 because of low enrollment and the end of funding. And 15 we don't know if an analysis was done then or what, 16 when and how more patients or less patients got added 17 or what. So it's very difficult to interpret how this 18 was done. And there was sort of marginal 19 significance. The data is not strongly positive. So 20 that is, I think, a question that we have. 21 The Idrissi study, the Belgium study was 22 an observational feasibility study that ended four NEAL R. GROSS COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. (202) 234-4433 WASHINGTON, D.C. 20005-3701 (202) 234-4433 94 1 hours. The official study ended four hours after the 2 patient's admission. 3 AKH, again, we don't -- it's not a 4 prospective study, so we really don't have for this 5 '91 to 2003 an endpoint that was specified at that 6 time. 7 Well, what about the results of these 8 studies? So we have three different success 9 endpoints. And when you look at the Bernard study, we 10 don't know how to interpret that p-value because of 11 the problems I've mentioned. 12 The HACA study if you look is a confidence 13 interval of 1.08 to 1.81. So barely significant at 14 that view. 15 The Idrissi study, since there were no 16 endpoints, we don't know success. 17 When we look at mortality, and that's been 18 mentioned here, we have in the Bernard study a 19 nonsignificant p-value for mortality. 20 The HACA study it was a confidence limit 21 to up to .95. Again, close. So there's a marginal 22 benefit of mortality there. NEAL R. GROSS COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. (202) 234-4433 WASHINGTON, D.C. 20005-3701 (202) 234-4433 95 1 The Idrissi study had an 87 percent 2 mortality in-hospital mortality with both groups. 3 The issues we have with the registry is 4 that it's kind of retrospective prospective. I believe 5 medical students abstracted the data in parts of it. 6 Observational. It's a chart review versus a protocol, 7 versus other protocols that we don't know about. And 8 then the possibility of patient selection or treatment 9 bias. And I think Dr. Sterz mentioned that as well. 10 It's an institution with Dr. Sterz who is 11 a ardent proponent of hypothermia. And the standard 12 of care at the institution was hypothermia, but some 13 patients didn't get hypothermia. And we don't know 14 why they didn't. We know a certain group didn't. It 15 was a group that needed cardiac or neurological 16 imagining, and that's a very different patient 17 population from people who come with cardiac arrest 18 who don't need cardiac or neuroimaging. And one 19 propensity analysis item that I wanted was who the 20 attending physician was, but we don't have that data 21 collected. And as Dr. Sterz was saying, that maybe 22 the fellow that was working at night and may be a far NEAL R. GROSS COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. (202) 234-4433 WASHINGTON, D.C. 20005-3701 (202) 234-4433 96 1 different experience and abilities than Dr. Sterz, 2 didn't do hypothermia. Therefore, that's a control. 3 So there's a lot of question about how 4 comparable the control groups are. Dr. Zhao will be 5 talking about that. 6 We also have historical patients early 7 1990s didn't get hypothermia at all, and they're 8 included. 9 So we have unknown covariates, known 10 covariates and unknown covariates that we cannot 11 compare. 12 One of the very most important issues is 13 that patients who died within 24 hours were excluded. 14 And having done work in looking at ventricular 15 fibrillation from a threshold and hypothermia, that's 16 a group I would be very interested in seeing. But all 17 of those patients were excluded from the registry. 18 For safety, they compared the AKH Registry 19 device with core cooling treatment group versus those 20 that didn't get hypothermia. Again, a comparison that 21 may be problematic. And compared the AKH Registry 22 core cooling with the HACA trial surface cooling from NEAL R. GROSS COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. (202) 234-4433 WASHINGTON, D.C. 20005-3701 (202) 234-4433 97 1 data at one institution. 2 It's important to mention that none of 3 these trials were powered to -- and many of the meta- 4 analysis trials were powered to detect differences in 5 individual adverse events. So therefore saying 6 something is not significant is that we don't have the 7 power to really determine that. 8 And there were no prespecified safety 9 endpoints in any of these studies. 10 The HACA study looked at complications 11 only during the first seven days. And I think that 12 goes to Dr. Marler's comment about pulmonary embolism 13 and DVT and things of that sort. 14 So there were no prespecified endpoints. 15 The end total was 137 for hypothermia and 138 in the 16 control. And you can see that there is some 17 difference, again not significant, in each of these 18 complications; bleeding, pneumonia, sepsis, pulmonary 19 edema and arrythmia. Again, in the first seven days. 20 Three patients had hypothermia stopped 21 because of arrhythmias or hemodynamic instability. 22 The Bernard study looked at only at NEAL R. GROSS COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. (202) 234-4433 WASHINGTON, D.C. 20005-3701 (202) 234-4433 98 1 complications at hospital discharge, and 77 total. 2 There were no specified endpoints. There's a 3 statement no significant hemorrhagic complications, 4 but there's no other mention of safety events. But 5 there was -- excuse me. The wrong slides. 6 There wasn't an 87 percent mortality. I 7 believe there was like 30 percent mortality in that 8 group. Sorry. 9 The next in the Hachimi-Idrissi study from 10 Belgium. That one had an 87 percent mortality. 11 Again, no prespecified safety endpoints. 12 They mentioned that they monitored the 13 various complications, and then they say no other 14 significant complications occurred in any patients. 15 But 87 percent died in the hospital. And I think they 16 must have meant in the four hours that the study was 17 being conducted. 18 So these studies are not helpful for us in 19 determining the safety of hypothermia. 20 AKH Registry, arrhythmias and bleeding 21 only had a follow up up to 32 hours. Pneumonia, 22 sepsis, renal failure, pancreatitis up to seven days. NEAL R. GROSS COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. (202) 234-4433 WASHINGTON, D.C. 20005-3701 (202) 234-4433 99 1 So we really don't have long term data. And again 2 when you're putting a device in thermal vein or 3 instrumenting any parts of the vascular system, I'm 4 unfamiliar with studies that have no complications, 5 although we have no complications in this registry 6 listed after the seven days or studied after the 7 seven days. 8 And then when you look at the AKH Registry 9 of noncardiac adverse events given, I think, the slide 10 that the sponsor just showed from the first 11 submission, we see differences but again nothing is 12 powered as an individual safety endpoint for any of 13 these complications. And the question is the 14 definitions of renal failure and things of that sort. 15 So it's difficult to understand these complications or 16 to be reassured by a lack of complications. 17 Well, what else do we have? We've got a 18 couple of studies, two other studies I'll mention 19 today that are actually well conducted prospective 20 randomized controlled study looking at cooling. And 21 one I think Dr. Becker just mentioned, data presented 22 by Bill O'Neill at TCT in 2003 looking at left NEAL R. GROSS COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. (202) 234-4433 WASHINGTON, D.C. 20005-3701 (202) 234-4433 100 1 ventricular infarct size and the effect of po st-event 2 cooling on that. And that was a negative study with no 3 difference between the LB infarct size endpoints. So 4 a hypothesis generating study. 5 And when you look at the safety results, 6 again, it was not powered to look at individual safety 7 complications. But you can see that there are 8 differences in the safety profiles of the two ways. 9 Again, no significant difference. It wasn't powered to 10 detect a significance difference. 11 We look at Guy Clifton's study of 12 traumatic brain injury published in the New England 13 Journal in 2001. And their endpoint was percent of 14 patients with poor outcome by their definition. Very 15 sophisticated neurological tests for these patients 16 again found no difference in the primary endpoint and 17 negative study. 18 What was interesting even though the study 19 was not powered to detect differences in individual 20 events, we did find in this study a significant 21 difference in the amount of hypotension, bradycardia 22 with hypotension. And hypotension is significant NEAL R. GROSS COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. (202) 234-4433 WASHINGTON, D.C. 20005-3701 (202) 234-4433 101 1 hypotension with end organ dysfunction. Bradycardia 2 with hypotension and percent of hospital days with 3 complications were all significant. 4 So what we have is a body of data 5 submitted to us that shows us that there is actually 6 burden of proof on the sponsor to show us that the 7 method of cooling and all of these do not effect 8 outcomes either by efficacy or safety. 9 And in summary, we have questions 10 remaining regarding the safety and effectiveness of 11 surface cooling for the proposed indication. It's 12 unclear whether data on surface cooling can be used to 13 support the safety and effectiveness of endovascular 14 cooling for the proposed indication. We think there 15 are limitations in the AKH Registry data. And the risk 16 benefit profile of the Alsius device for the proposed 17 indication is unclear. 18 Thank you. 19 DR. ZHAO: My name is Yihua Zhao. I was 20 the statistical reviewer for this submission. 21 I will present our statistical review for 22 this submission now. NEAL R. GROSS COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. (202) 234-4433 WASHINGTON, D.C. 20005-3701 (202) 234-4433 102 1 During my presentation I will first give 2 an overview of the examination. I will talk about the 3 two study objectives and the data sources, as well as 4 sponsor's statistical analyses used in this 5 submission. 6 Following that I will review the sponsor's 7 meta-analysis and a propensity score analysis And 8 after that I will give a brief comments on the safety 9 analysis. And will conclude my presentation with our 10 statistical summary. 11 There are two study objectives. The first 12 one is to assess the effectiveness of mild therapeutic 13 hypothermia delivered via any methods in improving 14 survival and a neurological recovery in primary 15 survivors of cardiac arrest. 16 The second objective is to assess the 17 effectiveness and safety of mild endovascular 18 hypothermia delivered by Alsius CoolGard system in 19 improving survival and a neurological recovery in 20 primary survivors of cardiac arrest. 21 The main datasets used in the submission 22 is the AKH Cardiac Arrest Registry. This was an NEAL R. GROSS COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. (202) 234-4433 WASHINGTON, D.C. 20005-3701 (202) 234-4433 103 1 observational study conducted in the emergency 2 department in Vienna General Hospital in Austria. The 3 data used in their analysis was collected between 1991 4 and 2003. There were 67 patients receiving 5 hypothermia via CoolGard system. One patient died 6 within 24 hours and four patients had missing 7 covariates. 8 There were 1536 normothermia patients, 9 among them 205 patients died within 24 hours and 140 10 patients had missing covariates. 11 In the sponsor's analysis patients who 12 died within 24 hours were excluded and patients who 13 had missing covariates were also excluded. 14 Additional data sources used in the 15 submission come from three published studies. The 16 first one is the HACA study conducted between 1996 and 17 2001. It was a randomized controlled trial contained 18 in nine centers in five European countries. There 19 were 137 hypothermia patients received hypothermia 20 through cool air and there were 138 normothermia 21 patients in this study. 22 The second study is the Bernard study NEAL R. GROSS COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. (202) 234-4433 WASHINGTON, D.C. 20005-3701 (202) 234-4433 104 1 conducted between 1996 to 1999. It was also a 2 randomized controlled trial conducted in four centers 3 in Melbourne, Australia. There were 43 hypothermia 4 patients and 34 normothermia patients in this study. 5 The third study is the Idrissi study 6 conducted over six months in 2000 and 2001. It was 7 randomized controlled feasibility study conducted in a 8 single center in Belgium. There were 15 hypothermia 9 patients and fourteen normothermia patients. 10 Two assess of effectiveness of mild 11 therapeutic hypothermia in improving survival and 12 neurological recovery the sponsor performed a meta- 13 analysis using aggregated data from HACA Bernard and 14 Idrissi studies. And they used the fixed effects model 15 to combine point estimates from the three randomized 16 controlled trials. 17 To assess the safety and effectiveness of 18 mild endovascular therapeutic hypothermia applied via 19 the CoolGard system in improving survival and 20 neurological recovery, the sponsor used the AKH 21 Cardiac Arrest Registry study. Because data from this 22 registry did not come from a randomized controlled NEAL R. GROSS COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. (202) 234-4433 WASHINGTON, D.C. 20005-3701 (202) 234-4433 105 1 study, the sponsor conducted a propensity score 2 analysis to reduce spires due to imbalance in observed 3 baseline characteristics. 4 Now I will review sponsor's meta- 5 analysis. 6 The three studies used meta-analysis have 7 different survival and neurological endpoint. 8 In HACA study, as pointed out by Dr. 9 Swain, in HACA study the survival endpoint was the 10 overall mortality at six months and the good 11 neurological recovery was defined using Pittsburgh 12 Cerebral-Performance Category of 1 or 2. 13 In the Bernard study the survival endpoint 14 was survival to hospital discharge. And the good 15 neurological recovery was defined as having 16 sufficiently good neurological function to be sent 17 home or to a rehabilitation facility. 18 In the Idrissi study the survival endpoint 19 was survival to the end of study, which is four hours 20 after applying hypothermia. And the good neurological 21 recovery was not explicitly described in the Idrissi 22 study. NEAL R. GROSS COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. (202) 234-4433 WASHINGTON, D.C. 20005-3701 (202) 234-4433 106 1 The three studies also have different 2 patient cohorts because they use different 3 inclusion/exclusion criteria and they were conducted 4 at different locations. 5 The three studies also used different 6 surface cooling methods. In HACA study patients who 7 are assigned to the hypothermia group were put in a 8 mattress with a cover that delivers cold air over the 9 entire body. If the target temperature was not 10 reached, patients will be applied ice pack around 11 their head and heck. 12 In the Bernard study patients receive ice 13 packs around head, neck, pulse and limbs. 14 In Idrissi study hypothermia patients 15 receiving cooling helmet around their head and neck. 16 Those three studies used different target 17 temperatures. In HACA study cooling was initiated in 18 the hospital and the target temperature was 32 to 34 19 degrees celsius. And the cooling was sustained for 24 20 hours followed by passive rewarming. 21 In the Bernard study cooling was initiated 22 in ambulance and the target temperature was 33 celsius NEAL R. GROSS COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. (202) 234-4433 WASHINGTON, D.C. 20005-3701 (202) 234-4433 107 1 for 12 hours followed by active rewarming. 2 And in Idrissi study cooling was initiated 3 in hospital. The target temperature was 34 celsius for 4 four hours followed by passive rewarming. 5 The issues with the sponsor's meta- 6 analysis include the following: 7 Combining the three randomized controlled 8 trials is questionable due to: 9 Different inclusion/exclusion criteria; 10 Different times, places for initiating 11 cooling; 12 Different target cooling temperatures; 13 Different cooling methods, and different 14 cooling durations; 15 Different rewarming techniques, and; 16 Different neurological endpoints employed 17 in these three studies. 18 There were no CoolGard or endovascular 19 cooling patients in any of the three studies. 20 Recently the sponsor proposed 21 retrospective Bayesian meta-analysis in which a 22 sequential updating approach was used. This approach NEAL R. GROSS COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. (202) 234-4433 WASHINGTON, D.C. 20005-3701 (202) 234-4433 108 1 is equivalent to pulling old data from the three 2 randomized controlled approach. The proposed approach 3 can only be used when patients in the three studies 4 are exchangeable; in other words when the patients in 5 the three studies can be clinically considered as 6 coming from the same population. And, again, 7 exchangeability remains questionable due to the 8 differences among the three studies. 9 Even if the three studies were similar, 10 the agency would recommend the following steps 11 whenever a Bayesian analysis is performed. 12 The first use of prior information should 13 be agreed upon in advance by sponsor and FDA. 14 Second, comparability among studies should 15 be agreed upon in advance by clinicians. 16 And third, to guard against unforeseen 17 differences among studies, Bayesian hierarchical 18 models are recommended. 19 And lastly, simulations are strongly 20 recommended in advance to assess operational 21 characteristics of study design and to control Type 1 22 error. NEAL R. GROSS COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. (202) 234-4433 WASHINGTON, D.C. 20005-3701 (202) 234-4433 109 1 Now I will review the statistical 2 inference derived from AKH Registry study. 3 In the effective analysis, the sponsor 4 considered the following true endpoints. The first 5 one is survival to 30 days or discharge. 6 The second one is survival to 30 days or 7 discharge and good neurological recovery, which was 8 defined as CPC equals 1 or 2. 9 In the effective analysis the sponsor did 10 not explicitly explain how to use these two 11 effectiveness endpoints to define study success. And 12 also patients who died with 24 hours and patients 13 having missing covariates were excluded from the 14 effectiveness analysis. 15 So there was CoolGard patients and 1191 16 normothermia patients in their analysis. 17 In the safety analysis the sponsor 18 measured arrhythmias and the bleeding up to 32 hours 19 and also measured the pancreatitis, pneumonia, sepsis 20 and rental failure up to seven days. 21 Because the AKH Registry study was not a 22 randomized controlled trial, the baseline NEAL R. GROSS COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. (202) 234-4433 WASHINGTON, D.C. 20005-3701 (202) 234-4433 110 1 characteristics between CoolGard and the normothermia 2 groups are very different. 3 The following two slides will show the 4 baseline covariates that are significantly different 5 between the CoolGard and normothermia groups. From 6 this slide we can see that CoolGard patients were 7 younger and had a longer duration of cardiac arrest 8 than the normothermia patients. 9 And this slide shows that CoolGard had 10 less often history of diabetes. Milder NYHA Score on 11 admission. Had more comatose patients on admission. 12 Were more often out-of-hospital cardiac arrest of 13 presumed cardiac cause and had more often VT or VF and 14 received more often basic life support than the 15 normothermia patients. 16 This bar plot shows the patient frequency 17 by year in the AKH Registry between 1991 and 2003. 18 And we can see that CoolGard patients were only 19 present in the year 2002 and 2003. 20 So CoolGard and the normothermia groups 21 are different and may not be comparable at baseline 22 because there are CoolGard patients only in 2002 and NEAL R. GROSS COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. (202) 234-4433 WASHINGTON, D.C. 20005-3701 (202) 234-4433 111 1 2003. And there is imbalance in several observed 2 baseline covariates between the two groups. As a 3 result, any direct treatment comparisons on 4 effectiveness endpoint are inappropriate. 5 We may not know the extent of imbalance 6 between the two groups regarding variables that were 7 not measured and may be important in predicting 8 treatment allocation and outcomes. Such variables may 9 include cardiac neuro/imagining, attending physicians, 10 etcetera. 11 And the treatment comparison may be 12 improved via propensity score analysis. 13 Now I will briefly talk about -- introduce 14 the propensity score analysis. 15 Propensity score analysis provides 16 approximate balance in observed baseline covariates. 17 And all important covariates should be considered in 18 the propensity score model. 19 Propensity score analysis cannot adjust 20 for unobserved covariates which could be important in 21 predicting treatment assignment and outcomes. If 22 there are important baseline covariates which NEAL R. GROSS COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. (202) 234-4433 WASHINGTON, D.C. 20005-3701 (202) 234-4433 112 1 influence the treatment assignment but were not 2 collected, propensity score analysis can be seriously 3 degraded. 4 Due to limitations of observational 5 studies, randomized controlled trials are strongly 6 encourage when they are possible, because randomized 7 controlled trials can balance both observed and 8 unobserved imbalance between the two treatment groups. 9 When propensity scores are balanced across 10 the CoolGard and the normothermia groups the 11 distributions of all observed covariates which are 12 included in the propensity score model are balanced in 13 expectation across the two groups. As a result 14 propensity scores can be used as a diagnostic tool to 15 measure comparability between the CoolGard and the 16 normothermia groups. 17 If the two treatment groups overlap well 18 enough in terms of the propensity scores, we can 19 compare them adjusting for propensity scores. 20 In the sponsor's propensity score analysis 21 they include the following covariates in the 22 propensity score model, and this is also what is NEAL R. GROSS COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. (202) 234-4433 WASHINGTON, D.C. 20005-3701 (202) 234-4433 113 1 included in their propensity score model. And this 2 slide shows the covariates that were collected but 3 were not included in their propensity score model. 4 Note that the following covariates were 5 not collected and, therefore, were not included in the 6 propensity score model used by the sponsor: Cardiac 7 neuro/imaging, treating team physician and the reason 8 for not receiving hypothermia in the hospital where 9 hypothermia was standard of care. And there's no way 10 to know if there is still imbalance between the two 11 groups regarding these covariates. 12 The following table shows the distribution 13 of patients in propensity score strata. Patients in 14 the same stratum have similar propensity scores and we 15 can see that in the first stratum there are 251 16 normothermia patients. But there are no CoolGard 17 patients have similar propensity score in this strata. 18 So after we got the propensity scores, how 19 could we use them in our analysis? We can match the 20 control patients to the CoolGard patients using the 21 propensity score. We can also perform stratification 22 analysis using the propensity score strata. And we NEAL R. GROSS COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. (202) 234-4433 WASHINGTON, D.C. 20005-3701 (202) 234-4433 114 1 can also use regression adjustment by including 2 propensity score as the continuous covariates in the 3 regression model. 4 The sponsor used matching and their method 5 is not clear to us. 6 What we used is first excluded patients in 7 the first propensity score strata and then we 8 performed the stratification analysis by doing 9 separate analysis within each strata and then 10 combining the results across the strata. 11 And we also did a logistic regression 12 adjustment by including propensity score as the 13 continuous covariates in the logistic regression 14 model. 15 Also included in this logistic regression 16 model are all covariates which were used in the 17 propensity score model. 18 Here is our result from the stratification 19 analysis. I used odds ratio in our analysis. If odds 20 ratio is greater than one, then CoolGard system is 21 better than normothermia regarding the specific 22 effectiveness endpoint. Because the sponsor did not NEAL R. GROSS COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. (202) 234-4433 WASHINGTON, D.C. 20005-3701 (202) 234-4433 115 1 explicitly specify the success criteria, we used 2 Bonferroni correction and we reported 97.5 confidence 3 interval here. If the lower limit of the 97.5 4 confidence interval of the odds ratio is greater than 5 one, then CoolGard system is statistically 6 significantly better than normothermia regarding the 7 specific effectiveness endpoint. And if the 97.5 8 percent confidence interval including one, then 9 CoolGard patients is not statistically different 10 between normothermia patient. 11 And for survival to 30 days or discharge, 12 the odds ratio between CoolGard and the normothermia 13 is 1.69. And the 97.5 percent confidence interval is 14 .85 to 3.49. And the lower limits, this confidence 15 interval include one. So CoolGard is not significantly 16 different between normothermia regarding survival. 17 For survival and a good neurological 18 recovery, the odds ratio is 2.56. And again, the 19 corresponding 97.5 confidence interval does not 20 include one, so the CoolGard is significantly better 21 than normothermia in survival and the good 22 neurological recovery. NEAL R. GROSS COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. (202) 234-4433 WASHINGTON, D.C. 20005-3701 (202) 234-4433 116 1 And this is our result from regression 2 adjustment. And regarding survival endpoint, the odds 3 ratio is 1.73 and again, the 07.5 confidence interval 4 does include one. So the CoolGard is not significantly 5 different between the normothermia. 6 And the for the survival and a good 7 neurological recovery endpoint, the odds ratio is 8 3.02. And there 97.5 percent confidence interval does 9 not include one, so CoolGard is significantly better 10 than normothermia regarding survival and good 11 neurological recovery. 12 So because date of cardiac arrest may be 13 an important variable that is not included in the 14 propensity score analysis, and there were only 15 CoolGard patients in 2002 and 2002, we performed an 16 analysis considering only patients treated in 2002 and 17 2003. And here is the distribution of patients in the 18 propensity score strata if we only using patients 19 enrolled in 2002 and 2003. And here in the first two 20 strata there were no CoolGard patients having similar 21 propensity scores as the normothermia patients in the 22 same strata. And I want to point out in that in the NEAL R. GROSS COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. (202) 234-4433 WASHINGTON, D.C. 20005-3701 (202) 234-4433 117 1 last strata there were more CoolGard patients than the 2 normothermia patients have similar propensity scores. 3 So what we did is we also excluded the 4 patients in the first and second strata and we 5 performed the stratification analysis and the logistic 6 regression adjustment. And this is our result from 7 stratification analysis. 8 For survival to 30 days and a discharge, 9 the odds ratio is 1.14. And the 97.5 percent 10 confidence interval does include one, which suggests 11 that CoolGard is not significantly better than 12 normothermia. 13 For survival and a good neurological 14 recovery the odds ratio is 2.91. And the 97.5 15 confidence interval also include one, so the CoolGard 16 patient is not significantly different than the 17 normothermia patient. 18 And this is our result from the regression 19 adjustment. For the survival endpoint the odds ratio 20 is .89 and the 97.5 percent confidence interval does 21 include does include one. So the CoolGard is not 22 significantly different than normothermia. NEAL R. GROSS COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. (202) 234-4433 WASHINGTON, D.C. 20005-3701 (202) 234-4433 118 1 And for survival and a good neurological 2 recovery the odds ratio is 3.98. And this time the 3 97.5 confidence interval is barely above one. So we 4 can see the CoolGard device is marginally 5 significantly different -- better than the 6 normothermia patients. 7 In the first safety analysis the sponsor 8 used 66 patients in the AKH Registry study. And they 9 selected 81 normothermia patients from the AKH 10 Registry to match the inclusion/exclusion criteria. 11 I want to point out that in this safety 12 analysis normothermia patients were selected 13 differently from the propensity score analysis. They 14 were not selected based on the propensity score, but 15 they were selected to match the inclusion and 16 exclusion criteria. 17 And in the second safety analysis the 18 sponsor used the 66 CoolGard patients in the AKH 19 Registry and they used 134 hypothermia patients 20 treated with cool air in the HACA study. 21 And also I want to point out that patients 22 in these groups may not be comparable at baseline. NEAL R. GROSS COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. (202) 234-4433 WASHINGTON, D.C. 20005-3701 (202) 234-4433 119 1 So in summary, combing HACA, Bernard and 2 Idrissi studies in the meta-analysis may be 3 questionable due to the several differences among the 4 three studies. 5 Not all important covariates were included 6 in the propensity score analysis. And the propensity 7 score analysis is just an effort to reduce bias due to 8 non-randomization, but it cannot balance two treatment 9 groups on uncollected covariates. 10 Using the current propensity score model, 11 only survival to 30 days and a good neurological 12 recovery is marginally significantly different between 13 the CoolGard and normothermia groups. And normothermia 14 patients in the safety analysis are selected 15 differently from those in the propensity score 16 analysis. 17 Thank you. 18 DR. LAZAR: My name is Ronald Lazar. I'm 19 a Professor of Clinical Neuropsychology in Department 20 of Neurology and Neurological Surgery at Columbia 21 University College of Physicians and Surgeons, and the 22 Director of Levine Cerebral Localization Laboratory. NEAL R. GROSS COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. (202) 234-4433 WASHINGTON, D.C. 20005-3701 (202) 234-4433 120 1 I've been working in clinical trials for 2 almost 20 years involving physical neurological and 3 neurocognitive outcomes. And most recently involved 4 in mechanical circulatory devices for end stage heart 5 failure. And I served on this Panel a couple of years 6 ago. 7 What I'm going to address this morning 8 really comes to the notion of what constitutes a good 9 neurological outcome. And some of the material I'm 10 going to talk about this morning was presented to the 11 Panel back in September, and I'm also going to give 12 some additional considerations. 13 As most know, the effects of postanoxic 14 encephalopathy following cardiac arrest follow a 15 continuum that ranges anywhere from mild to severe. 16 So that at the lighter end of the spectrum patients 17 who have brief periods of anoxic from arrest can have 18 inattentiveness, weakening of judgment and motor 19 incoordination. Sometimes the mild deficits are 20 transient, and sometimes they're permanent. 21 At a great degree of severity you have 22 memory impairment, apathy, disinhibition and poor NEAL R. GROSS COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. (202) 234-4433 WASHINGTON, D.C. 20005-3701 (202) 234-4433 121 1 judgment. 2 And at the most severe levels of 3 encephalopathy short of coma, at the physical level 4 there's spasticity, paresis, ataxia, pseudobulbar 5 palsy. And from a mental status point of view there's 6 language disorders, disorders of orientation in space, 7 purposeful movement of motor function, memory 8 disorders and so forth. 9 As was pointed out earlier, probably the 10 most commonly use outcome instruments to take a look 11 at the brain integrity following cardiac arrest is the 12 Cerebral Performance Categories, which actually got 13 its origin from Jennett and Bond's work in head injury 14 in Scotland back in 1975, then was used in cardiac 15 arrest beginning in the 1980s. And as outlined 16 earlier, there are five levels of function. 17 There's good cerebral performance where 18 the patient is essentially conscious with mild 19 deficits and presumably can lead a normal life. They 20 might have some minor neurological problems. 21 At a more severe level there's moderate 22 cerebral performance where the patient is also NEAL R. GROSS COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. (202) 234-4433 WASHINGTON, D.C. 20005-3701 (202) 234-4433 122 1 conscious but presumed capable of part time work in a 2 sheltered environment or independent activities of 3 daily living and may have neurological impairment 4 including hemiplegia, dystaxia, dysphagia, dysarthria, 5 seizures or permanent memory impairment. And I'll 6 come back to that a little later on. 7 And then there is severe cerebral 8 performance where patients are conscious but 9 presumably are dependent on others for daily support 10 because of impaired brain function. 11 Then there's coma and finally death. 12 So let's take a look at out-of-hospital 13 cardiac arrest. And these are the studies that have 14 been cited this morning as support for the sponsor for 15 this device. And we're going to use these three 16 studies as a frame of reference, especially the 17 Bernard study and the Holzer meta-analysis, because 18 for them a good neurological recovery is defined as a 19 CPC score of 1, good cerebral performance and a CPC 20 score of 2, which is moderate cerebral performance. 21 And I'll come back to these in just a minute. 22 Now I think one of the best studies ever NEAL R. GROSS COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. (202) 234-4433 WASHINGTON, D.C. 20005-3701 (202) 234-4433 123 1 published in the field about neurocognitive outcomes 2 following cardiac arrest is Dr. Roine's study from 3 1993 that appeared in JAMA. And what they did was 4 they did an analysis in a placebo controlled study of 5 nimodipine versus placebo for cardiac arrest. And so 6 out of 677 possible patients that could have been 7 studied, they were able to follow 68. And what they 8 did as major outcome measures, they looked at 9 neurocognitive scores at 3 and at 12 months. 10 And what they found was that at 12 months 11 48 percent of the patients of the 68 had moderate to 12 serious deficits in the areas of delayed recall, 13 manual dexterity, calculations, skilled motor 14 movement, planning, attention and motivation. And I 15 think equally significantly about half the patients 16 had significant depression. And I think this goes to 17 one of the points that was stressed in the sponsor's 18 material submitted for our review this morning, and 19 that is it was felt that these patients are glad 20 merely to be alive. And, in fact, these data indicate 21 that half of the patients don't necessarily agree with 22 that point. NEAL R. GROSS COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. (202) 234-4433 WASHINGTON, D.C. 20005-3701 (202) 234-4433 124 1 So let's take a look at good cerebral 2 performance. Again, this is the conscious patients 3 which are presumed able to have the best kind of life 4 afterwards. And what's important to point out, Dr. 5 Roine mentioned that there were 52 studies in the 6 literature in which a CPC was used, but in fact I 7 could only find one study that was a validation study 8 about the CPC. And that was Hsu published in the 9 Annals of Emergency Medicine in 1996. 10 And what they noted was that in their view 11 the CPC was subjective and categories poorly defined, 12 and frequently used only at hospital discharge. 13 Although we know since 1996 it's been used for 30 day 14 and 60 day and longer term outcomes. But most 15 importantly, it had never been validated or compared 16 with any other measures in the past, which is not true 17 in the case of the scales used in stroke, such as the 18 modified Rankin scale where there's a lot of validity 19 data. And so that's what Dr. Hsu did. 20 And what she found was in essence that if 21 you compare the outcome just for CPC scores of 1, the 22 best presumed neurological recovery, in fact there was NEAL R. GROSS COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. (202) 234-4433 WASHINGTON, D.C. 20005-3701 (202) 234-4433 125 1 very little specificity of the CPC compared to the 2 Functional Status Questionnaire which is a commonly 3 used standardized instrument of function in a variety 4 of emergency medical situations. And in fact, the 5 correlation of CPC at discharge and at follow-up, was 6 only 3.2 which is not significant. So other than Hsu's 7 data, which was essentially a negative study, there 8 are no validation studies for the CPC, even at the 9 best level of function. 10 But what about a poorer level of function? 11 Let's take a look at the moderate cerebral 12 performance. And here patients are presumed to be 13 capable of part time work and sheltered environment or 14 independent activities of daily living. 15 And if you look at Holzer's paper he 16 stated favorable long term neurological outcome was 17 defined as good neurologic recovery and being alive at 18 six months ...sufficient cerebral function for 19 activities of daily living would include dressing, 20 travel by public transportation, food preparation and 21 so forth. 22 And if you just take a look at really the NEAL R. GROSS COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. (202) 234-4433 WASHINGTON, D.C. 20005-3701 (202) 234-4433 126 1 physical specification of a moderate cerebral outcome, 2 patients who are hemiplegic, that is they do not have 3 use of one side of their body, cannot dress 4 themselves. They cannot take public transportation. 5 And they cannot prepare their own food. 6 Well, what about at a cognitive level of 7 function? Well, if you look at Dr. Roine's data, 48 8 percent of his patients at 12 months who had moderate 9 to severe impairment would be eligible for Social 10 Security disability in the United States with a CPC 11 score of 2. 12 Well, the argument is well the sponsor 13 said well these patients are older anyway. You know, 14 they're not going to go back to work because these are 15 presumed patients who are beyond that point. But, in 16 fact, if you look at the Public Access Defibrillator 17 Trial which was published in the New England Journal 18 last year, one-third of those treated by EMS were in 19 fact lower than 65 years of age. And in the CoolGard 20 presentation today their average age is 51. So these 21 people are capable of work and would be disabled with 22 a CPC score of 2. NEAL R. GROSS COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. (202) 234-4433 WASHINGTON, D.C. 20005-3701 (202) 234-4433 127 1 So, is a more standardized evaluation 2 available? Can we actually do something that is a 3 little bit more extensive with regard to neurological 4 function. 5 Well, let's take a look at this from a 6 number of different dimensions. First, from the 7 viewpoint of the disease, that is out-of-hospital 8 cardiac arrest we can point to Lim's work published 9 last year in the Journal of Neurology. From the 10 viewpoint of treatment, hypothermia for brain injury, 11 which Dr. Swain talked about before, there was the 12 Clifton study published a few years ago in the New 13 England Journal. 14 And if you look at the patients of 15 comparable age and symptom severity, we could take a 16 look at the patients with end stage heart failure who 17 have to go on permanent circulatory device support, 18 and we could take a look at the HeartMate trial, the 19 MicroMed trials currently underway. And what all these 20 trials have in common, all these studies is that they 21 all evaluated memory, mental speed, decision making, 22 language perception and motor function. NEAL R. GROSS COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. (202) 234-4433 WASHINGTON, D.C. 20005-3701 (202) 234-4433 128 1 So it is possible to do something more 2 standardized. And I'm not necessarily advocating that 3 we do all these tests, but there are tests available 4 and they can be done. And, in fact, if in the Roine 5 study if they had correlated the outcome on CPC with 6 his outcomes, we would have had validation of that 7 measure. But, unfortunately to my knowledge, those 8 data don't exist. 9 So based on the existing evidence that we 10 have, the physiologic impact of cerebral anoxia 11 following cardiac arrest is well documented with 12 effects that can be transient or permanent, mild to 13 severe. And that the field is already moving toward 14 objective validated measure of brain functions that 15 include physical and cognitive outcomes. 16 The measurement of brain function in a 17 clinical trial should be performed by clinical 18 neuroscience specialists who are blinded to treatment 19 or at least not involved in the treatment to minimize 20 potential bias. 21 And finally, the neural endpoints need to 22 be obtained in the acute period, at discharge and at NEAL R. GROSS COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. (202) 234-4433 WASHINGTON, D.C. 20005-3701 (202) 234-4433 129 1 longer term follow-up in order to assure patient 2 meaningful outcomes. 3 Thank you. 4 CHAIRMAN MAISEL: Thank you. 5 Do any members of the Panel any questions 6 they'd like to address to the FDA? Dr. Brott? 7 DR. BROTT: Thank you, Dr. Lazar 8 Could you put Slide 7 up? 9 I was interpreting (2) as independent 10 activities of daily life. And I noticed that it's not 11 uncommon for neurologists, even, to sometimes be loose 12 with the term "hemiplegia." Is that parenthetical 13 statement in all forms of this examination? Because 14 hemiplegic contradicts independent activities of daily 15 life. Somebody who is hemiplegic cannot do that. And 16 so there's an internal contradiction. And I'm 17 wondering if it's a semitic problem? 18 DR. LAZAR: Well, I can't answer that 19 since these are the published criteria for the CPC. 20 DR. BROTT: So that parenthesis is always 21 there in a written form? 22 DR. LAZAR: That is correct. NEAL R. GROSS COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. (202) 234-4433 WASHINGTON, D.C. 20005-3701 (202) 234-4433 130 1 DR. BROTT: Okay. Okay. 2 DR. LAZAR: These are the quotations from 3 that literature. 4 DR. BROTT: That answers that question. 5 I guess I'd ask Dr. Sterz -- 6 CHAIRMAN MAISEL: Why don't we -- okay. Is 7 that all right? 8 DR. BROTT: It has to do with this. 9 Were patients in category 2 both 10 hemiplegic and judged to be independent in activities 11 of daily living in the trial that you were in, the 12 HACA trial? 13 DR. STERZ: Straight answer, yes. This 14 was -- the criteria for being 2 or 1. However, I have 15 learned the Ulstein style by heart since he is now. I 16 don't remember that his practice are there. What is 17 written in the practice I don't remember that it is 18 written there. It's a very clear stated in the 19 Ulstein style that they have to be independent 20 activities of daily life. I don't recall this. I have 21 to throw the Ulstein style again. Sorry. 22 CHAIRMAN MAISEL: Any additional questions NEAL R. GROSS COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. (202) 234-4433 WASHINGTON, D.C. 20005-3701 (202) 234-4433 131 1 for the FDA? Yes, Jeff? 2 DR. BRINKER: Julie, your discussion puts 3 us in a little bit of a quandary because we have to 4 make two decisions. One decision I thought up front 5 would be easy. There are published guidelines 6 suggesting that hypothermia in fact should be and 7 actually in publication is the standard of care for 8 treating patients with cardiac arrest caused by 9 ventricular fibrillation. And you're suggesting that 10 perhaps this is wishful thinking based on a few less 11 than optimal studies. 12 So could you be perhaps more specific in 13 saying that you reject the recommendations by AHA in 14 this regard? 15 DR. SWAIN: Well, talking from the FDA 16 standpoint today, you know we evaluate data. Not what 17 someone thinks about data. And you and I, and most of 18 the members here, have been in society guidelines 19 creating and government guidelines creating jobs. 20 I've done that for the unstable angina guidelines for 21 health care, and various other society guidelines. 22 And there are various considerations taken in NEAL R. GROSS COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. (202) 234-4433 WASHINGTON, D.C. 20005-3701 (202) 234-4433 132 1 guidelines. I've been an associate editor of several 2 journals and on the editorial board of a whole lot. 3 And there's publications. We make mistakes sometimes. 4 And there are other reasons we may publish something. 5 You know, we're just looking at the data 6 here. And when I look at the data, and I must say 7 after the last Panel meeting two Panel members came up 8 to me and said, gee, I didn't see that stuff about the 9 Australian trial being a failed trial and then adding 10 more patients. I didn't see it until I was on the 11 airplane last time. I had read that thing for two 12 years. 13 So when I look at the level of evidence 14 that we normally require, especially in the 15 cardiovascular division, those studies don't match the 16 level of evidence both the first, which was a true 17 failed trial until patients were added and then we 18 don't know why it was stopped. And the second one 19 that didn't meet the enrollment endpoint and we don't 20 know why. There's also publication bias, things of 21 that. 22 So simply looking at the data there is NEAL R. GROSS COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. (202) 234-4433 WASHINGTON, D.C. 20005-3701 (202) 234-4433 133 1 not, I would say, two good randomized trials showing 2 the efficacy of post-event hypothermia. My personal 3 opinion. 4 DR. BRINKER: That's why you, therefore, 5 personally think there would be no ethical qualms 6 about doing a randomized controlled trial against 7 normothermia? 8 DR. SWAIN: No. 9 CHAIRMAN MAISEL: John? 10 DR. SOMBERG: I'm not a statistician, 11 which everyone probably realizes. I was very much 12 helped by your analysis. And I just wanted to go 13 through my understanding, if it's correct, that the 14 reason you required a higher level of confidence, 92. 15 something percent, which is very high; that was 16 necessitated by using the Bonferroni. And that was 17 necessitated by the lack of comparability of the 18 different groups? Am I correct in that? 19 DR. ZHAO: Using a wider confidence 20 interval will be more conservative because the sponsor 21 used the two effective endpoints and we don't know how 22 they defined the study success if, like, both should NEAL R. GROSS COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. (202) 234-4433 WASHINGTON, D.C. 20005-3701 (202) 234-4433 134 1 be like significant or either one should be 2 significant if it can be defined as success. And so 3 we choose the more conservative way and we reported a 4 wider confidence interval. 5 DR. SOMBERG: Okay. So you say you choose 6 the more conservative way, but for I guess a 7 layperson, which I am here, is what does that mean 8 less conservative, more conservative? I think if 9 we're talking about probabilities of success, can you 10 put that into some sort of number of knowing what 11 you're doing? 12 DR. ZHAO: More conservative means that 13 if, like if we use the 95 percent confidency interval 14 and it's marginally significant and now we're using a 15 wider confidency interval and it's no longer 16 significant. So we will just -- by using conservative 17 means that we won't approve a device that is falsely 18 significantly better than the normothermia patients. 19 DR. SOMBERG: What I'm trying to get at it 20 is we usually take a nominal p-value of, you know, 21 we're willing to take a 1 in 20 mistake or something. 22 Why are you changing the levels of acceptance of NEAL R. GROSS COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. (202) 234-4433 WASHINGTON, D.C. 20005-3701 (202) 234-4433 135 1 mistakes? 2 DR. ZHAO: The p-value is another side of 3 the story, which if you go to the 95 percent 4 confidence interval, which does not include one, then 5 the p-value is less than one. Then the p-value less 6 than .05. And here just simply reporting p-value it 7 doesn't mean anything. Because, like, you have the 8 point estimate and you have the p-value. And you 9 don't know what's the range of these estimate, like 10 how precisely estimate. 11 So I think by providing confidence 12 interval you will have more information with the 13 possible range of estimate and with the precision of 14 this estimate. And which we choose cost precision 15 because we don't know the study success criteria. 16 MS. IRONY: Hi. I'm Telba Irony. I'm the 17 Branch Chief of General and Surgical Devices Branch, 18 Division of Biostatistics. 19 I just wanted to add another bit of 20 information of why we did that correction. 21 You wanted to connect that with the 22 possibility of making a mistake and controlling to NEAL R. GROSS COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. (202) 234-4433 WASHINGTON, D.C. 20005-3701 (202) 234-4433 136 1 make it up to five percent. 2 When we received the submission, we didn't 3 know what the endpoint was. If it was only survival 4 or survival plus neurological recovery. And that might 5 be if you get involved in points, median points, some 6 will be significant by chance. So because we had these 7 two and we didn't know if the success of the trial 8 will be both are successful, either one are successful 9 or maybe a third one that was not successful and was 10 not even presented there. In order to control the Type 11 1 error and make an overall type error at maximal at 12 five percent we had to make this correction. 13 I don't know if that -- it has nothing to 14 do with the variables. 15 Does it help? 16 DR. SWAIN: Yes. And if you look at the 17 ultimate, as mentioned, safety as mortality, then 18 there really are two endpoints. And so one does a 19 correction normally for multiple endpoints. 20 CHAIRMAN MAISEL: Henry? 21 DR. HALPERIN: Julie, it's a very nice 22 presentation. NEAL R. GROSS COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. (202) 234-4433 WASHINGTON, D.C. 20005-3701 (202) 234-4433 137 1 I had a question about the Clifton study 2 because I didn't see it in the packet, and maybe you 3 could clarify. 4 What was the patient population there? 5 Were they patients with strokes or -- 6 DR. SWAIN: No. It was traumatic brain 7 injury, as I put on a slide. It's a TBI study that 8 was, I believe, multiple institutional. 9 DR. HALPERIN: But they were never 10 hypotensive. 11 DR. SWAIN: Hypotensive? I don't know, 12 you know. As I said, it has different amounts of 13 cooling, different types of cooling. It's just yet 14 another post-event cooling study actually well done 15 with the endpoints that Ron Lazar -- 16 DR. HALPERIN: But in that particular 17 brain injury is there adequate cerebral profusion, 18 typically? 19 DR. SWAIN: You could probably answer 20 that. 21 DR. LAZAR: I can't remember the details 22 of the study per se, typically there is. And we're NEAL R. GROSS COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. (202) 234-4433 WASHINGTON, D.C. 20005-3701 (202) 234-4433 138 1 really talking about a brain concussive event that 2 puts people into the hospital and need to be treated. 3 And they try to use hypothermia in these cases to 4 reduce the amount of swelling and so forth in the 5 brain. So it's not a profusion area defect, it's 6 rather more of a global, you know, a trauma to the 7 brain as a whole. 8 But if there was a cardiac problem, then I 9 don't know the answer to that associated with the head 10 trauma, per se. 11 DR. MARLER: The whole field of head 12 injury, many of the treatments are focused on the fact 13 that a lot of the injury is due to alternation and 14 profusion of the injured portion of the brain. And a 15 lot of the treatment is directed toward a -- a lot of 16 the neuroprotective treatment is the same as that, 17 say, for stroke where there is decreased profusion. 18 DR. LAZAR: But it's profusion within the 19 brain itself as opposed to a source, let's say, from 20 the heart. 21 DR. MARLER: Right. But in either case, 22 the target we're talking about is the brain function, NEAL R. GROSS COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. (202) 234-4433 WASHINGTON, D.C. 20005-3701 (202) 234-4433 139 1 correct? 2 DR. LAZAR: Yes. 3 DR. HALPERIN: Because, I mean the issue 4 would be how applicable is that to a post-cardiac 5 arrest situation where theoretically, at least -- I 6 mean I don't know about this delayed reprofusion 7 issues, but at least the artery should be open and 8 there should be the possibility of having adequate 9 profusion. Where if there were some situation where 10 you were comparing whether there was actual ischemia 11 ongoing, brain ischemia, then that actually might not 12 be a comparable kind of a situation to extrapolate the 13 data to. 14 DR. SWAIN: Yes. Same problem of, you 15 know, heterogeneity of patient population like an in- 16 and-out hospital. Cardiac arrest patients are also 17 heterogeneous. 18 DR. SOMBERG: Can I ask a follow-up on 19 that? 20 CHAIRMAN MAISEL: Sure. 21 DR. SOMBERG: Just be specific, so a 22 concussed injury and on injury do to hypoperfusion are NEAL R. GROSS COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. (202) 234-4433 WASHINGTON, D.C. 20005-3701 (202) 234-4433 140 1 we saying that is a different pathophysiology or a 2 similar in terms of -- and you can sort of say that an 3 intervention would be similarly effecting that and 4 maybe it's the variance of the populations, or is it 5 totally different or we don't know? 6 DR. LAZAR: That's a complicated question. 7 And there's probably some overlap, but fundamentally 8 they're different pathophysiologies there. 9 CHAIRMAN MAISEL: Dr. Brott, did you want 10 to comment? 11 DR. BROTT: I think that both basic and 12 clinical neurologists and neurosurgeons would agree 13 that this is apples and oranges. 14 CHAIRMAN MAISEL: Rick? 15 DR. PAGE: Dr. Zhao, thank you for your 16 explanation. I just want to make sure I got something 17 right in terms of slide 34 where you commented there 18 was marginally significant improvement in survival to 19 30 days or discharge and good neurological recovery 20 every using a confidence interval of 97.5 percent, 21 it's marginally significant as I interpret it and part 22 related to relatively low numbers. But the actual NEAL R. GROSS COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. (202) 234-4433 WASHINGTON, D.C. 20005-3701 (202) 234-4433 141 1 effect, there is a fourfold increase? 2 DR. ZHAO: Yes. 3 DR. PAGE: And the result that we would be 4 hoping for, which is indeed both discharge and what's 5 considered good neurologic activity, is that correct? 6 DR. ZHAO: The point estimate, the odds 7 ratio is four -- almost four. 8 DR. PAGE: So the thing that's marginal is 9 the statistical test, but it did meet your level of 10 statistical significance. But the effect is actually a 11 fourfold increase in survival with what's considered 12 good neurologic function? 13 DR. ZHAO: Yes. Yes. 14 DR. MARLER: What would the absolute 15 numbers be on that? 16 DR. ZHAO: What do you mean absolute 17 numbers? 18 DR. MARLER: You gave us a ratio of 2 19 percentages, but are they low percentages? 20 DR. ZHAO: I cannot say from the top of my 21 head. Sorry. 22 DR. MARLER: Okay. NEAL R. GROSS COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. (202) 234-4433 WASHINGTON, D.C. 20005-3701 (202) 234-4433 142 1 DR. ZHAO: But I think the odds ratio, 2 it's more informative here. 3 DR. MARLER: But not if it's one patient 4 in one group and four in the other? 5 DR. ZHAO: I cannot say. Sorry. 6 DR. SWAIN: The question is the groups. 7 And, again, the questions we have about comparability 8 of patients who got hypothermia in a hospital were 9 normally -- that's the treatment of care and who 10 didn't get it. So it's not just a statistical point 11 that Mary made. It's also is the control group 12 comparable for the reasons she listed. 13 CHAIRMAN MAISEL: Any other questions for 14 the FDA? 15 Okay. I'd like to thank the FDA for their 16 presentation. 17 And at this point I would like to open the 18 discussion. 19 I think at this point since we have 20 already covered a lot of the topics, why don't we move 21 on to our primary reviews. And I'll start with Dr. 22 Somberg, if you would please do your -- NEAL R. GROSS COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. (202) 234-4433 WASHINGTON, D.C. 20005-3701 (202) 234-4433 143 1 DR. SOMBERG: Well, thank you, Mr. 2 Chairman. 3 I was asked to review this material and 4 submit, which I will for the record, a written review. 5 I will read parts of my written review of the 6 material. I might also say that I reviewed the first 7 material approximately two weeks ago. And 8 approximately six days ago received the supplemental 9 packet and reviewed that as well. So there are two 10 basic material packets that are in review here. 11 As background, I would like to say that a 12 Circulatory System Device Panel meeting was held on 13 September 21, 2004 to discuss trial design issues for 14 cardiac arrest studies as well as the role of 15 hypothermia as a treatment for post-arrest. Dr. Swann 16 presented a good review of the studies today. The MI 17 study found no difference in outcome with or without 18 cooling and was a perspective randomized controlled 19 study comparing cooling and normothermia, but in an MI 20 situation. 21 Clifton, et.al. performed a prospective 22 randomized controlled trial of normothermia to NEAL R. GROSS COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. (202) 234-4433 WASHINGTON, D.C. 20005-3701 (202) 234-4433 144 1 hypothermia in patients following brain injury and 2 also found no benefit. 3 Dr. Swann pointed out two studies of 4 hypothermia following cardiac arrest, Bernard which 5 is the Australian study and an European study. Both 6 studies were performed outside the U.S. Their 7 response times are average or two or three minutes 8 different from the U.S. system. 9 The summary of the problems with the two 10 studies is to be found in the submission pack tab 2. 11 The Panel on September 21, 2004 discussed 12 the topic extensively and concluded that the data are 13 interesting and promising, but would not support an 14 application for a particular device or a therapeutic 15 approach. The Panel did not feel that the standard of 16 care was hypothermia in the U.S. and that the studies 17 were small, different from the types of patients seen 18 in the U.S. and used different types of cooling 19 approaches. 20 "The Panel went on to discuss if surface- 21 induced hypothermia is the same as core-induced 22 hypothermia. The Panel felt that endovascular NEAL R. GROSS COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. (202) 234-4433 WASHINGTON, D.C. 20005-3701 (202) 234-4433 145 1 technique raised a different set of safety issues from 2 surface-induced hypothermia." And I'm quoting this 3 from the Panel summary. 4 Many felt that a randomized controlled 5 trial would be needed to evaluate an intervention. 6 The proposal that the sponsor's requesting 7 approval for the endovascular cooling system based on 8 the similarity of device to a predicate device and the 9 assertion on page 11 of the sponsor's material in the 10 briefing package of the benefits of hypothermia in 11 treatment of comatose survivors of sudden cardiac 12 arrest due to ventricular fibrillation have been 13 established in randomized controlled trials. 14 My review. One. I do not believe that a 15 predicate device exists. The initial device was a 16 heat exchange blanket. A catheter was not been used 17 for the indication requested, and does not serve as a 18 predicate. A thermal blanket has not been approved 19 for post-arrest ventricular fibrillation patients. 20 Two. As reported in the September '04 21 Panel meeting a consensus did not exist for the 22 acceptance of hypothermia as the treatment of choice NEAL R. GROSS COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. (202) 234-4433 WASHINGTON, D.C. 20005-3701 (202) 234-4433 146 1 for post-VF arrest patients. The data was felt very 2 promising, but insufficient to establish hypothermia 3 as the standard of care in the U.S. or determine that 4 endovascular catheter is the appropriate way to 5 establish hypothermia. In fact, reviewing all 6 hypothermia studies, one finds that the Cool MI study 7 which was controlled and randomized found a higher 8 mortality hypothermia group. The Clifton study found 9 no improvement with hypothermia. An additionally, in 10 the Hackett study, the Bernard study and the 11 Australian study, none of the patients were treated 12 with the CoolGard system, the system we're reviewing 13 today. 14 Three. Even without the lack of predicate 15 device and hypothermia controversy, an evaluation of 16 potential toxicity endovascular cooling needs to be 17 done in terms of hypercoagulability, live toxicity 18 effects on creatinine levels, and incident of 19 infection. All of these areas are suggested as 20 problematic from studies and none have been 21 systematically evaluated with the CoolGard system. 22 Additional information on how to deal with NEAL R. GROSS COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. (202) 234-4433 WASHINGTON, D.C. 20005-3701 (202) 234-4433 147 1 shivering neurovascular blocking drugs and the optimum 2 protocol need to be established and placed in the 3 guidelines for use of this device. 4 Four. A key study is the Alsius study. 5 That was an observational study with a retrospective 6 control group that was treated differently than a more 7 recent treatment group. The study used various methods 8 to obtain hypothermia. The sponsor also provided a 9 reanalysis of data comparing the AKH Cardiac Arrest 10 Registry to the results of the CoolGard 3000 system. 11 One disturbing part of the analysis is 12 that patients who died within 24 hours of treatment 13 were excluded, which could bias the study. I would 14 have liked to have seen an analysis with these 15 patients included. 16 Additionally, the monitoring was 17 inadequate since the records were in German. And it 18 was disturbing to note that the person who did monitor 19 the study, as noted in the materials provided, did not 20 read German. 21 The comparability of the groups being 22 compared cannot be evaluated from the data available, NEAL R. GROSS COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. (202) 234-4433 WASHINGTON, D.C. 20005-3701 (202) 234-4433 148 1 and thus it's impossible to reach a conclusion on the 2 validity of the data presented. 3 The supplemental materials provided 4 additional data from a meta-analysis of three studies 5 in 96 patients with selected and matched controls. 6 The data is put together on a retrospective data and 7 no basis for matching the patients controlled versus 8 intervention is reported, and no justification for the 9 selection of the patients over groups is made. 10 In fact, all newly added patients seem 11 also to have concomitant cold fluids administered, 12 making this group noncomparable to a controlled group 13 which do not receive fluids. And the fluids would 14 have to be of a normal temperature. 15 An attached study by Kliegel from 16 Resuscitation highlights the potential problem of two 17 liters of iced fluids causing cooling induction. 18 Additionally, selection of 26 out of the 19 167 patients of the study, basis not explained, a time 20 of 38 minutes from return of circulation to 21 administration of fluids an 53 minutes from start of 22 resuscitation to cold fluid administration are times NEAL R. GROSS COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. (202) 234-4433 WASHINGTON, D.C. 20005-3701 (202) 234-4433 149 1 not comparable to the U.S. population. 2 All these differences highlight the 3 significant difficulties of making comparison. 4 Descriptions, possibly identifying the differences in 5 the 96 are not available from the sponsor's report. 6 But are probably no less than those seen in the 26 7 patient subset in the Kliegel study. 8 In terms of efficacy, the additional 9 information on these patients is not helpful due to 10 possible selection bias and potential noncomparability 11 of the control group. 12 Also, the toxicity noted on table 2 13 presented by the sponsor in the supplemental 14 information is disturbing, given the high incidence of 15 toxicity and the inability to exclude a selection bias 16 in the choice of controls in table 3 of the 17 supplemental information provided. The comparison to 18 controls is supposed to place in perspective the 19 toxicity associated with cooling. However, the 20 selection of controls retrospectively fails to do this 21 since the method of selection of the controls remains 22 unknown and questionable. NEAL R. GROSS COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. (202) 234-4433 WASHINGTON, D.C. 20005-3701 (202) 234-4433 150 1 That concludes my advance review. 2 CHAIRMAN MAISEL: Do you have any 3 questions for the sponsor before we move on or the 4 FDA? 5 DR. SOMBERG: Not at this time. 6 CHAIRMAN MAISEL: Okay. Dr. Yustein, 7 maybe I could ask you to comment regarding the Panel 8 involvement's in the determination of whether a 9 predicate device exists, which is what Dr. Somberg 10 brought up. My understanding would be that that is 11 the purview of the FDA and not this Panel? 12 DR. SOMBERG: I just wanted to interject 13 that I did not suggest that I'm making the decision. 14 I'm just suggesting that if I in my review thinking, 15 which I wanted present was that if a predicate device 16 existed, it would be a different set of risk benefit 17 analyses. And if one does not feel that there was 18 approval of a device for resuscitation, one would ask 19 for a different risk benefit assessment of the device. 20 And that's all I was suggesting in my review. But 21 I'm certainly on the legal person to decide that. 22 DR. YUSTEIN: We certainly appreciate Dr. NEAL R. GROSS COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. (202) 234-4433 WASHINGTON, D.C. 20005-3701 (202) 234-4433 151 1 Somberg's comments, but what you said, Dr. Maisel, is 2 correct. 3 CHAIRMAN MAISEL: So why don't we move on 4 to our second review, which is Dr. Brott. 5 DR. BROTT: Thank you. 6 I'm a neurologist who hangs out in 7 intensive care units. I'm a hospitalist/neurologist. 8 Was the principal designer of the NIH Stroke Scale and 9 had the original IND for tPA for stroke. And also 10 have an interest in brain hemorrhage. So brain injury 11 and urgent intervention and trying to measure effects 12 of interventions are things I've been working on for a 13 while. 14 And I had the opportunity to review this 15 material in February. At the time I reviewed it with 16 regard to the draft questions that were provided, and 17 that's how I'll respond today. 18 I submitted a written report. But I must 19 say I keep learning about this topic as well every day 20 and with each presentation, as Dr. Swain pointed out. 21 First of all, the importance of cardiac 22 arrest coma and of its treatment is very well NEAL R. GROSS COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. (202) 234-4433 WASHINGTON, D.C. 20005-3701 (202) 234-4433 152 1 described and justified within the materials. I'm not 2 certain, though that the physiology is well understood 3 either experimentally or in humans. The basic 4 references provided relate to therapeutic hypothermia. 5 Information regarding depth of hypothermia and 6 duration and therapeutic hypothermia or the 7 complications of experimental hypothermia are provided 8 in the submission, but there was not a great deal of 9 depth. 10 We've heard about the clinical data, and 11 I'll try not to repeat what we've heard today. But 12 first with the Bernard study. 13 I noted that randomization imbalance. 14 And, actually, it was 31/31 at the end of the trial 15 and then ended up 43/34. But what hasn't been brought 16 up today is that good outcome was being discharged 17 home or to a rehab facility. And it was based on the 18 evaluation of a specialist in rehabilitation medicine. 19 But there were no objective criteria provided as to 20 how this rating was to be done. And this rating was 21 the only determinate of whether the patient fulfilled 22 the primary outcome. NEAL R. GROSS COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. (202) 234-4433 WASHINGTON, D.C. 20005-3701 (202) 234-4433 153 1 The authors actually conclude at the end 2 of their New England Journal article, the last two 3 sentences are "However, treatment assignment was not 4 blinded and there is the possibility that some aspects 5 of care differed between groups. Therefore, further 6 studies are required to confirm these findings and 7 determine the optimal duration of hypothermia." 8 The second study, of course, is larger. I 9 think it was carried out in more rigorous fashion than 10 the first. I did have some concerns. There was a 11 difference in the two groups which was impressive to 12 me, but the therapy was delivered on the average about 13 eight hours after circulation had ceased. And as a 14 neurologist who deals with focal brian injury, this 15 raised questions with me. And then today I did learn, 16 and this was very troubling, that category 2 and 17 category 3 which I missed, one could be hemiplegic and 18 independent in all activities of daily living or be 19 hemiplegic and be dependent in all activities of daily 20 living. And that disturbs me in terms of the cut point 21 used in this trial. 22 I do recognize that the assessment was NEAL R. GROSS COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. (202) 234-4433 WASHINGTON, D.C. 20005-3701 (202) 234-4433 154 1 blinded at six months. And, hopefully, that decreased 2 the likelihood for investigator bias given the 3 weakness that we learned about today specifically with 4 the scale. 5 The third study, a randomized trial, was 6 small as you know and did not explicitly describe good 7 neurological recovery. 8 So these are the randomized trials upon 9 which some of us might address predicate device or 10 not. And these studies and the advisory statements of 11 the Advanced Life Support Task Force of the 12 International Liaison Committee on Resuscitation 13 published in the July 8, 2003 issue of Circulation, 14 they certainly posed a dilemma. 15 Alsius states in their submission that 16 mild hypothermia is standard of care. My colleagues 17 at the Mayo Clinic informed me that this treatment is 18 almost never used in our intensive care units. A 19 cardiology colleague who is chair of our Internal 20 Medicine Department at Mayo is not aware of any 21 general usage. 22 A cardiology college at Cincinnati whose NEAL R. GROSS COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. (202) 234-4433 WASHINGTON, D.C. 20005-3701 (202) 234-4433 155 1 group covers every hospital on the Ohio side of the 2 Cincinnati, northern Kentucky metropolitan area states 3 that this treatment is not used at any of those 4 hospitals treating over one million people. 5 I spoke with the Director of Intensive 6 Care Units for Kaiser in San Diego. To the best of 7 his knowledge hypothermia is not used within the 8 Kaiser system for post-arrest coma. 9 Therefore, one must question why this data 10 has apparently not resulted in a change in care in 11 these examples of standard of care within the United 12 States. 13 With regard to safety and effectiveness of 14 the CoolGard system itself, the randomized control 15 data referred to support the safety and effectiveness 16 of surface cooling with a temperature drop of 17 approximately .9 degrees per hour maintained for 12 to 18 24 hours, these data were also reviewed as we all 19 heard at the advisory Panel September 21st. At that 20 time the Panel concurred that the randomized trials 21 were interesting, but as was just stated, would not be 22 sufficient support for an application for a particular NEAL R. GROSS COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. (202) 234-4433 WASHINGTON, D.C. 20005-3701 (202) 234-4433 156 1 device. 2 Quote from that hearing. "One cannot say 3 that any cooling apparatus capable of dropping body 4 temperature to a certain point should be labeled as 5 indicated for cardiac arrest." The Panel quote 6 concurred that endovascular techniques raise a 7 different set of safety issues from surface induced 8 hypothermia. And they went on to discuss that which I 9 will not repeat. 10 We were given evidence from the 13 patient 11 feasibility trial. We also requested and I was 12 provided, as all Panel members were, additional 13 surveillance data on 20 patients who were treated. And 14 we also received some additional information with 15 regard to patients with intracerebral hemorrhage and 16 cerebral infarction. 17 And first the AKH, we've heard about that 18 study. And I would just conclude that I tend to agree 19 with the specific limitations that we heard about in 20 that trial. And just summarize by saying, you know 21 the medical students did review the data without 22 written procedures. I was under the impression the NEAL R. GROSS COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. (202) 234-4433 WASHINGTON, D.C. 20005-3701 (202) 234-4433 157 1 records were primarily in English. I agree, the 2 auditor didn't speak German. But what troubled me most 3 were that table 3 shows significant differences at 4 baseline with regard to the history of diabetes, the 5 New York Heart Association Heart Failure Score, the 6 frequency of out-of-hospital cardiac arrest, evidence 7 for a presumed cardiac cause, ventricular tachycardia 8 or V-fib on the first EKG, whether nor not basic life 9 support measures were being given, Glasgow Outcome 10 Scale on admission and patient age. And with 11 statistically significant differences on those 12 variables, I really was unable to make a confident 13 inference from this dataset myself. 14 With regard to the feasibility study of 13 15 patients, which were studied over a prolonged period 16 of time, as we've heard, four of these patients died. 17 All were classified as non-device related. One 18 patient died of a cardiac cause and three died after 19 withdrawal of the life support. Of the remaining 20 nine, two were in a persistent vegetative state, two 21 were severely disabled, five had a good neurological 22 recovery with a Glasgow Outcome Scale of 1 to 2. NEAL R. GROSS COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. (202) 234-4433 WASHINGTON, D.C. 20005-3701 (202) 234-4433 158 1 Alsius, this submission actually states, 2 "this was a feasibility IDE of limited scope. It 3 demonstrated that the Icy catheter system was able to 4 provide reliable and controllable thermal 5 manipulation." No statements were made with regard to 6 safety and efficacy. 7 So that's the dataset that we were given. 8 And then we were given the additional information, as 9 I mentioned. And we had a table with regard to 10 complaints. And it had to do with technical failures 11 of the device. And I'm co-PI for the CREST trial, 12 which is a trial comparing carotid stenting to carotid 13 endarterectomy. And in the course of that trial with 14 over a 1,000 patients we have had two technical 15 complications, which of course were immediately 16 reported to FDA. But we have a much greater 17 responsibility than to just look at technical 18 complications amongst the patients that we study. And 19 this was referred to by Mr. Marler and also several of 20 the Panel members with regard to other aspects of 21 safety that might relate to endovascular manipulation. 22 And this was not really provided to us. NEAL R. GROSS COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. (202) 234-4433 WASHINGTON, D.C. 20005-3701 (202) 234-4433 159 1 I will not summarize my conclusions with 2 regard to the first four questions, but just head on 3 to the fifth question, and one related to appropriate 4 endpoints. 5 Up until today I thought the CPC was 6 perhaps an acceptable scale. Dr. Roine pointed it has 7 many similarities to scales that we use, the modified 8 Rankin scale, the Glasgow Outcome Scale. And I think 9 that if that ambiguity or inconsistency where you can 10 have a patient with complete hemiplegia who is deemed 11 independent in activities of daily living, and Dr. 12 Sterz stated there were such patients put into 13 category 2, if I understood your answer -- no? 14 DR. ROINE: No. 15 DR. BROTT: So there were no hemiplegic 16 patients in category 2? 17 DR. ROINE: Not a single one. 18 DR. BROTT: Not a single one. Well, 19 that's encouraging. Because I do feel that a 20 categorical scale like the CPC is appropriate. But I 21 think it can be improved if you do a detailed 22 inventory of activities of daily living first. This NEAL R. GROSS COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. (202) 234-4433 WASHINGTON, D.C. 20005-3701 (202) 234-4433 160 1 is what we did in the NINDS IPA Stroke trial, as Dr. 2 Roine knows. The Barthel Index is one such inventory 3 where one has to ask questions with regard can you use 4 -- can you get dressed, can you walk a certain 5 distance, can you go up and down steps, can you 6 completely independently use the toilet. It goes 7 through these basics. And it takes a little while. 8 But then when you have that score, which itself may 9 not be that particularly useful, you have gone through 10 and been forced to inventory what activities the 11 patient can and cannot do. Then performing a more 12 limited categorical scale has more objectivity and is 13 less open to investigator bias. 14 And as a primary endpoint, such an ordinal 15 scale with a few categories I think is still 16 appropriate. 17 I learned again today from the 18 presentation of Dr. Lazar that, certainly, I think it 19 would be worth our while to add some simple, easily 20 tolerated measures of cognitive function. And 21 certainly we do have several of those that could be 22 carried out within 2 or 3 minutes. He and I discussed NEAL R. GROSS COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. (202) 234-4433 WASHINGTON, D.C. 20005-3701 (202) 234-4433 161 1 the Folstein, which is not the best scale by any 2 means, but given that this treatment has not been 3 accepted nationally and if it is an appropriate 4 treatment, clearly we need to persuade our physician 5 colleagues around the United States the Folstein or 6 some very widely recognized scale that can relate to 7 all neurologist, all cardiologist, I think would be an 8 appropriate secondary endpoint. 9 And other brief tests that we discussed -- 10 where is Dr. Lazar? 11 Trials A and B, I think those three could 12 be done very easily, would be well tolerated and I 13 think could enhance such a trial. 14 The second part of question 5 mentioned 15 randomized controlled trial. My primary concern with 16 this specific device is whether or not it is 17 substantially equivalent in safety and efficacy to the 18 cooling methods used in the randomized controlled 19 trials that we've discussed today. The new questions 20 of safety have been mentioned by the other Panel 21 members. Such a trial could have two arms comparing 22 surface cooling to endovascular cooling. NEAL R. GROSS COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. (202) 234-4433 WASHINGTON, D.C. 20005-3701 (202) 234-4433 162 1 I personally think that the data that we 2 have had reviewed for us today with regard to 3 hypothermia is not so strong as to make a third arm of 4 the trial, a normothermia group, unethical in the 5 United States. 6 And at that point, I'd close. 7 CHAIRMAN MAISEL: Thank you, Dr. Brott, 8 for your comments. And at this point why don't we 9 start having the Panel members make their additional 10 comments. 11 We'll start with Dr. Brinker. 12 DR. BRINKER: Can I ask a couple of 13 questions or is that -- 14 CHAIRMAN MAISEL: No. You can make 15 comments or ask the FDA or the sponsor questions. 16 DR. MARLER: Ken, maybe you can delegate 17 who should answer this question. But it seems to me 18 when you have a patient who suffered a cardiac arrest 19 and is in coma, they very often have a lot of other 20 things done to them during the hospitalization. And 21 sometimes, not unoften, not infrequently, they have a 22 great impact themselves on what happens to the NEAL R. GROSS COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. (202) 234-4433 WASHINGTON, D.C. 20005-3701 (202) 234-4433 163 1 patient. 2 So what percentage of patients are we 3 looking at that have actually had cath intervention, 4 bypass therapy, etcetera? And were they in some way 5 censored if they had an adverse event consequent to 6 one of those procedures? 7 DR. COLLINS: I think this is a question 8 to hand to Fritz Sterz. 9 Just to make sure I understand, you're 10 asking about the control group that was presented, 11 were they -- 12 DR. BRINKER: Well, I'd like to know if 13 either group and whether in fact that would influence 14 their placement in the control group or the active 15 group, or whether they were censored. For instance, 16 if they had another cardiac arrest during their stay 17 in the hospital during one of these procedures, 18 etcetera? 19 DR. STERZ: With regards to HACA, we have 20 been asked all these questions and we have resubmitted 21 these data in our revisions. 22 There have been no differences in using NEAL R. GROSS COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. (202) 234-4433 WASHINGTON, D.C. 20005-3701 (202) 234-4433 164 1 thrombolysis in either groups. No differences in 2 using cath lab procedures. And no difference in using 3 either other procedures like you said like you said 4 before. 5 And we have also submitted regarding HACA 6 that we were shooting for 500 patients. We did no 7 interim analysis. I don't think that this is written 8 in the paper, but this data would be unavailable. 9 With regard to the CoolGard data, this 10 data would be available. WE didn't present them today 11 because in the prospective trial they didn't have any 12 influence on the outcome. 13 DR. BRINKER: So the other half of my 14 question was no patient was censored for any reason 15 once they were admitted to the trial as far as outcome 16 goes? 17 DR. STERZ: With regards to you mean 18 censored -- 19 DR. BRINKER: Well, "censored" meaning 20 excluded for analysis because they had an arrest or 21 died during a CABG operation or an angioplasty or 22 something like that. NEAL R. GROSS COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. (202) 234-4433 WASHINGTON, D.C. 20005-3701 (202) 234-4433 165 1 DR. STERZ: Then he would fall in the 2 mortality group. 3 DR. BRINKER: So he wasn't censored then? 4 Okay. That's the question. Thank you. 5 My general comments are that I tend to 6 agree with the two reviewers, that I came here 7 actually willing to accept a benefit for hypothermia 8 in patients suffering VT cardiac arrest. I think, 9 however, that the information upon which this 10 recommendation has been based, that is the efficacy of 11 hypothermia, is on less firm grounds than I would like 12 to have it seen. And then once we say that, once we 13 say that there is some equipoise about whether 14 hypothermia is the standard of care, a lot of other 15 things then fall out of that. 16 So my feeling is that I would have loved 17 to have seen a truly randomized trial comparing this 18 device with normothermia care of these patients. 19 CHAIRMAN MAISEL: Thank you, Jeff. 20 Rick? 21 DR. PAGE: I'm a cardiac physiologist and 22 have cared for patients post-cardiac arrest for 15 NEAL R. GROSS COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. (202) 234-4433 WASHINGTON, D.C. 20005-3701 (202) 234-4433 166 1 years or more now. And I must say that as I was 2 thinking of the patients I've cared for, and some of 3 the most tragic are the ones who actually have 4 survived with significant impairment, the 5 nonindependent livers, and hemiplegia is not something 6 I typically see. So that seemed to be from my 7 standpoint not a major issue, although we've made 8 something of it. And I think it's interesting to hear 9 that among your class 2s there weren't patient that 10 you're recalling that were truly hemiplegic, and that 11 would certainly be consistent with my clinical 12 experience. 13 I, too, came here with probably more zeal 14 for hypothermia and its potential and for patients 15 post-arrest. I'm a little bit less reluctant to give 16 up some remaining enthusiasm for this. 17 I'm impressed by the fact that the 18 international bodies got together and examined these 19 data and as a group recommended that this be standard 20 of care. Now the question is why isn't it standard of 21 care. And I think the obvious answer is that there 22 are no tools. Hefty bags full of ice is not a way to NEAL R. GROSS COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. (202) 234-4433 WASHINGTON, D.C. 20005-3701 (202) 234-4433 167 1 make a major change in how you're dealing with post- 2 arrest patients. And so I think that accounts for what 3 might appear to be skepticism, and I think has in 4 part, just an issue that there is no tool to 5 administer this practically. 6 In terms of the safety issues we're 7 talking about, I'm concerned that I don't have as much 8 data in terms of safety as I wish. On the other hand, 9 as I think about who are these patients we're dealing 10 with, we're dealing with patients who most of the time 11 expire and are left when they don't expire with 12 persistent profound neurologic disability that leave 13 them dependent for the rest of their lives. 14 And when I'm looking at data that suggests 15 a four time increase in survival to functional 16 neurologic status, I find that compelling even with 17 the problems that I wholeheartedly agree we can find 18 in each individual trial. 19 So I suppose I am warmer to this still; no 20 pun intended. But if this group were to recommend and 21 if the FDA were to approve this, I think I'd really 22 want to see the data and have collection of data to NEAL R. GROSS COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. (202) 234-4433 WASHINGTON, D.C. 20005-3701 (202) 234-4433 168 1 know whether the right decision had been made. 2 CHAIRMAN MAISEL: Thank you, Rick. 3 Henry? 4 DR. HALPERIN: I'm a Professor of 5 Medicine, Radiology and Biomedical Engineering at 6 Hopkins. I've been doing CPR research for more than 20 7 years. I'm very familiar with this area. I've done a 8 little bit of hypothermia work myself. And I have 9 been a past Chairman of the American Heart 10 Association's Advanced Cardiovascular Life Support 11 Subcommittee wherein some of that time we did deal 12 with this issue. So I'm actually very familiar with a 13 lot of the aspects of this issue. 14 Our own hospital has implemented 15 hypothermia in our coronary care unit ever since Dr. 16 Sterz and others, and Dr. Bernard's studies were 17 published. And, actually, you know ancedotally since 18 some anecdotes were already presented by Panel 19 members, our own anecdotal experience has actually 20 been very positive with hypothermia. There were some 21 patients that we thought would never survive that 22 actually did. This experience has been duplicated at NEAL R. GROSS COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. (202) 234-4433 WASHINGTON, D.C. 20005-3701 (202) 234-4433 169 1 a couple of other universities that I'm aware of that 2 I actually won't mentioned, because I actually haven't 3 asked for their permission to do that. With similar 4 very positive anecdotes. I don't think any of those 5 places actually used this particular device, though. 6 So then I think there's a couple of major 7 issues here, one of which is it hypothermia per se 8 that causes the benefit or is the way you achieve 9 hypothermia that causes the benefit? Personally I 10 think it's the hypothermia itself rather than the way 11 it's achieved. Because I think the major downside 12 potentially of the device under question is in fact 13 the complication profile. And since this device is 14 approved for a couple of other indications and the 15 adverse events probably have been pretty well 16 documented, the issue is just cardiac arrest per se, 17 add a new covariable that would make the adverse event 18 profile different in a post-cardiac arrest situation 19 versus post-surgery or whatever else it's being used 20 for. And I don't have an answer for that, although 21 I'd be surprised if that was an issue. 22 So I think then at looking at the data, I NEAL R. GROSS COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. (202) 234-4433 WASHINGTON, D.C. 20005-3701 (202) 234-4433 170 1 mean certainly the data has been very rigorously 2 looked at in many different ways. And to me the bottom 3 line is that even under the most rigorous scrutiny of 4 this data, there's still seems to be a benefit, 5 although marginally statistically significant when 6 viewed at least by the FDA's point of view. I would 7 be interested in to how often 97.5 percent confidence 8 intervals versus 95 confidence intervals are actually 9 used. But that's probably less of an issue. Because 10 in fact there's been no intervention other than 11 hypothermia that when started after a cardiac arrest 12 occurred that showed any amount of benefit at all. 13 And I think that, you know, we can argue 14 and will over how good an intervention hypothermia 15 probably is, but nothing else has even shown any 16 glimmer of hope. So I'm a bit more hopeful I think 17 about the use of hypothermia in cardiac arrest still. 18 CHAIRMAN MAISEL: Thank you. 19 Dr. Blumenstein, are you still there? 20 DR. BLUMENSTEIN: Yes, I'm here. I have 21 some brief comments. Is it appropriate to give them 22 now? NEAL R. GROSS COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. (202) 234-4433 WASHINGTON, D.C. 20005-3701 (202) 234-4433 171 1 CHAIRMAN MAISEL: Yes. That would be 2 perfect. 3 DR. BLUMENSTEIN: Sorry, I didn't hear the 4 response. 5 CHAIRMAN MAISEL: Yes. Please give your 6 comments now. 7 DR. BLUMENSTEIN: All right. Well, the 8 sponsor has used four techniques in trying to 9 resuscitate the data. They've used Bayesian analysis, 10 propensity score, meta-analysis. These are all 11 techniques that if you add a poor quality randomized 12 clinical trial, that you could call these things 13 Hamburger Helper. 14 In this case where you have a mishmash of 15 convenience data, I think that you could say that 16 these things would be called "dog food helper." 17 A randomized clinical trial is essential 18 in this situation. And I don't know how one could 19 come to a conclusion that there has been a 20 demonstration that efficacy or safety without a 21 randomized clinical trial. 22 There was one question that was asked NEAL R. GROSS COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. (202) 234-4433 WASHINGTON, D.C. 20005-3701 (202) 234-4433 172 1 about if there is a requirement for randomized 2 clinical trial what sort of endpoint serves. And my 3 suggestion would be something like a bad thing-free 4 survival where bad thing is determined when a patient 5 enters a state for which there's no substantial chance 6 of improvement, such as a neurological deficit or 7 something along those lines. And I'm suggesting doing 8 a survival analysis here because I think that you'll 9 get some greater sensitivity and a greater 10 understanding of what's going on if one designs the 11 trial for an assessment of a endpoint, a failure time 12 endpoint. 13 That's all I have to say. 14 CHAIRMAN MAISEL: Thank you for your 15 comments. 16 And we'll move on to Norm. 17 DR. KATO: My comments are really directed 18 at two separate issues. The first being on the issue 19 of hypothermia for cardiac arrest. Looking at the 20 experience of cardiothoracic surgery, we have for a 21 long time believed that hypothermia was necessary for 22 the performance of -- and even mild hypothermia was NEAL R. GROSS COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. (202) 234-4433 WASHINGTON, D.C. 20005-3701 (202) 234-4433 173 1 necessary for the performance of cardiovascular 2 surgery. However, in looking over the historical 3 information that actually came about because we never, 4 I don't believe there was ever any randomized study 5 that looked at hypothermia per se. But it actually 6 was because of the fear of actually keeping the 7 patient on the cardiopulmonary bypass machine for a 8 long period of time. Hypothermia was thought to be 9 neuroprotective, thought to be myocardial protective. 10 But the reality is in the 1990s when we began doing 11 warm cardiac surgery and keeping the patient basically 12 warm and doing warm continuous mycardiopreservation 13 techniques, we basically realized that hypothermia 14 wasn't necessary at all. 15 As a matter of fact, we learned that our 16 biggest problem in the operating room was keeping the 17 patient warm. It is actually very common that 18 hypothermia below 34 degree centigrade occurs very, 19 very quickly in the operating room setting without any 20 need for ice or any other intervention, but just being 21 naked in a air condition room suffices quite well. 22 I've heard today that there have been a NEAL R. GROSS COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. (202) 234-4433 WASHINGTON, D.C. 20005-3701 (202) 234-4433 174 1 lot of anecdotal reports about hypothermia in cardiac 2 arrest from many distinguished universities and 3 distinguished colleagues here. And I think that 4 before a panel such as this or any other group 5 basically rules on or establishes a standard of 6 hypothermia as a standard of care in cardiac arrest, 7 that the randomized prospective study does need to be 8 done as suggested by many of the Panel members before 9 me. 10 That being said, that hypothermia is at 11 least -- we do not have sufficient data to claim that 12 hypothermia is a standard of care or is the standard 13 of care in this situation, I'm a little big 14 disappointed with the sponsor for not taking the -- or 15 not assessing the scientific field correctly by not 16 performing that randomized study with the device. 17 I am somewhat fearful that on occasion the 18 510(k) predicate device pathway sometimes allows 19 sponsors to avoid the -- or attempts to avoid the 20 issue of performing that necessary clinical trial 21 which will prove that efficacy issue once and for all. 22 So I would challenge the sponsor that NEAL R. GROSS COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. (202) 234-4433 WASHINGTON, D.C. 20005-3701 (202) 234-4433 175 1 while this device looks like it may have a role in 2 this area, to proceed with that clinical trial. Seek 3 the advice of experts such as Dr. Brott and others in 4 the neurological field for their knowledge about 5 outcome data. And seek out other experts in terms of 6 clinical trials who have much more experience than I 7 do. And do that study and show once and for all 8 whether this device does work, and really take the 9 high road. Because I think the other thing that's 10 becoming clear also with the increased scrutiny of 11 both devices as well as drug products is we definitely 12 need to have more and more data available to us. 13 CHAIRMAN MAISEL: Thanks, Norm. 14 I would just simply comment that the 15 510(k) process does not exclude the possibility of a 16 randomized trial being required. That's not -- doesn't 17 necessarily make it a PMA. 18 DR. KATO: Yes. And I didn't want to say 19 that this was not an issue -- that the 510(k) process 20 did not require that trial. But I was just saying that 21 I think that the -- I wanted to challenge the sponsor 22 to take the high road and do the trial. NEAL R. GROSS COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. (202) 234-4433 WASHINGTON, D.C. 20005-3701 (202) 234-4433 176 1 CHAIRMAN MAISEL: Okay. Thanks, Norm. 2 Mike? 3 DR. WEISFELDT: As will relate to some of 4 my answer, let me just -- with regard to the overall 5 proposition of the benefit or lack of benefit of 6 hypothermia, I have I think a special relationship to 7 the issue which I'll comment on. 8 Again, I'm a cardiologist by background. 9 I'm in an administrative position now at Hopkins. But 10 about nine months ago I became the study chair for 11 what is called the Resuscitation Outcomes Consortium 12 which is a five year NIH Department of Defense and 13 Canadian similar group sponsored study of 14 resuscitation from cardiac arrest and from traumatic 15 injury. The network is to do definitive clinical 16 trials in those two disorders in eight U.S. cities or 17 communities and three Canadian with the potential, at 18 least, based upon numbers of patients of entering, 19 3,000 patients per year in studies of trauma and 20 10,000 patients per year in studies of cardiac 21 resuscitation. So if you will, the potential for 22 doing a study actually exists. NEAL R. GROSS COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. (202) 234-4433 WASHINGTON, D.C. 20005-3701 (202) 234-4433 177 1 So let me make my focus comments and then 2 with that as a background orientation statement. 3 The comment on the -- I'm going to make a 4 brief comment on the second of the two issues, which 5 is this device relative to other devices. And my 6 opinion is that the device needs a prospective 7 randomized trial for safety relative to surface 8 cooling performed in some way. 9 So finished with that comment, let me now 10 go to the really to me extremely difficult situation 11 of having the data we have presented and discussed 12 about the core issue of the value of hypothermia in 13 this subset of patients versus no hypothermia. 14 Resuscitation from cardiac arrest there is 15 no drug, there is no procedure, there is no device 16 other than the defibrillator that's ever been shown in 17 a randomized study to provide benefit, no matter what 18 the drug, device is. The only device is the automatic 19 implantable defibrillator, where I was to some degree 20 involved in the study that was published in the New 21 England Journal of Medicine, which as in passing, a 22 rather difficult study that is not beyond criticism NEAL R. GROSS COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. (202) 234-4433 WASHINGTON, D.C. 20005-3701 (202) 234-4433 178 1 itself. 2 In this arena of cardiac arrest and the 3 performance of research without informed consent or 4 with the proper term is an exemption from the informed 5 consent, we have no national body that has any 6 official capacity relative to what it has equipoise 7 and appropriateness for clinical research. We rely, in 8 fact, upon local IRBs to provide such guidance, such 9 decision making. And I believe that even with the 10 critiques of the studies in place and analyzed, that 11 the degree of difficulty of performing a study such as 12 we've been talking about would indeed, be 13 extraordinarily difficult in any setting because of 14 the lack of -- your opinions may be that it's 15 equipoised. And the FDA's opinions may be that it's 16 equipoised. But nobody really has the singular 17 ability to define. They have no official stance on 18 where there is equipoise. And still you have -- and 19 what you are telling a local IRB is there are national 20 and international standards that this works, but we 21 don't accept the data and therefore we think you as an 22 individual IRB with, if you will, 20 IRBs per study NEAL R. GROSS COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. (202) 234-4433 WASHINGTON, D.C. 20005-3701 (202) 234-4433 179 1 site, you make the decision to do this study. 2 The data and the critiques, one wonders 3 whether further inquiry upon by the FDA or the 4 statisticians into the HACA study and the Bernard 5 study would not allow better analysis of groups from 6 that study that might in fact become more convincing 7 or settle some disputes. 8 The HACA study critique, I would just read 9 back, the study stopped prematurely because of low 10 enrollment and ending of funding. Plan study number 11 not known. Unknown whether interim analysis was 12 performed. Well, those are a set of factual 13 information that could be obtained. 14 The Bernard study some further questioning 15 might clarify a part of that study that would be 16 includable in a meta-analysis between those two 17 studies. The third study seems to me to be trivial to 18 the question. 19 Since there are animal studies that seem 20 to show a benefit done by Dr. Safar and his group, and 21 if we could get more confidence about these studies 22 from delving into them further, we might be able to NEAL R. GROSS COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. (202) 234-4433 WASHINGTON, D.C. 20005-3701 (202) 234-4433 180 1 draw a better conclusion about the indication and the 2 recommendations which are now in place about the use 3 of this treatment. 4 There was one other point I was going to 5 make, but I forgot it, so I'll close. 6 CHAIRMAN MAISEL: Thank you. 7 I'd just like to make a couple of comments 8 with my background as a clinical cardiac 9 electrophysiologist who sees cardiac arrest survivors. 10 I think the ILCOR recommendations are 11 noteworthy. I think a number of smart people 12 reviewed the data and I think their recommendation, 13 while based on the data that we've seen that is 14 somewhat flawed, I think were thoughtful certainly in 15 their review. 16 I do not think it is the standard of care, 17 at least in this country, for people to receive 18 hypothermia following cardiac arrest. That being 19 said, it certainly is a reasonable treatment option 20 for these patients, at least the surface cooling. And 21 the reasons why it is not the standard of care are a 22 little unclear to me, although I suspect as mentioned NEAL R. GROSS COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. (202) 234-4433 WASHINGTON, D.C. 20005-3701 (202) 234-4433 181 1 earlier, I think it's more the reality of trying to 2 actually do surface cooling on a patient. It's 3 extremely difficult and challenging, even if you 4 decide that it's something that you want to do. 5 And so I do see the potential for the 6 device that we are reviewing today to be very useful, 7 meaning that it's a lot "cleaner," maybe easier to 8 actually implement in an emergency situation and not 9 interfere quite as much with patient care. 10 That being said, I have a little trouble 11 making the leap from surface cooling to endovascular 12 cooling for a number of reasons, including most of 13 which have been addressed already this morning 14 including the safety profile. I'm not comfortable 15 that we have enough clarification of the safety issues 16 with the endovascular cooling. 17 The design of a randomized trial I think 18 is a challenge. I do think surface cooling versus 19 endovascular cooling would be an ethical study to 20 conduct. I think the problem that could arise is that 21 the endovascular cooling may have a higher 22 complication rate. And without a normothermia control NEAL R. GROSS COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. (202) 234-4433 WASHINGTON, D.C. 20005-3701 (202) 234-4433 182 1 group we may have difficulty assessing the benefit of 2 endovascular cooling. And if we look at the data of 3 surface cooling versus endovascular cooling, we may 4 decide that the complication rate is higher and is 5 therefore, not a reasonable option. But if surface 6 cooling is not being performed because it's efficient 7 and can't be performed, then a higher complication 8 rate may be acceptable. 9 One question I had as far as clarification 10 regarding the registry, I'm a little bit confused as 11 to why patients were excluded if they died within 24 12 hours. I mean, that seems -- you know, if I'm sitting 13 here in front of a patient that's 38 minutes into 14 their return of spontaneous circulation and I need to 15 make a decision about whether or not to cool them, 16 that decision, I can't wait 24 hours to make that 17 decision. 18 The comparison, to my knowledge, that 19 exclusion was not applied to the published New England 20 Journal papers. And so the comparison we're making of 21 numbers of survival and good neurologic recovery seem 22 a little bit apples and oranges to me. And maybe the NEAL R. GROSS COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. (202) 234-4433 WASHINGTON, D.C. 20005-3701 (202) 234-4433 183 1 sponsor can just address that 24 hour cut off for me. 2 DR. STERZ: They've excluded from analysis 3 but not from treatment. 4 CHAIRMAN MAISEL: Were they enrolled in 5 the registry? 6 DR. STERZ: Yes, of course. But they were 7 then, when we took the data out of the registry, 8 excluded for the analysis. 9 CHAIRMAN MAISEL: Right. And I'm asking 10 why you choose to do that. To me the analysis would 11 have been treatment versus -- you know, normothermia 12 versus endovascular cooling. 13 DR. STERZ: We thought if we do these for 14 both -- you can have it with them. It doesn't make a 15 difference. We looked at it. If we include it's the 16 same results show up. But this is not in information. 17 But we thought being fair to this treatment or being 18 fair to these patients, or whatever, we wanted to say 19 we want to have them at least surviving the certain 20 period of time because they died of cardiac shock or 21 whatever -- of the severity of the cardiac arrest 22 itself. And our -- can answer you the question if the NEAL R. GROSS COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. (202) 234-4433 WASHINGTON, D.C. 20005-3701 (202) 234-4433 184 1 period of no flow gets a certain period of time, you 2 have an estimate, yes. But the real estimate how long 3 this no flow or damage to the heart was if you cannot 4 stabilize them. 5 CHAIRMAN MAISEL: So do you have a -- 6 DR. STERZ: If you look at our data in the 7 CoolGard group, there was only one excluded and then 8 the controlled group, there were 250 excluded. So -- 9 CHAIRMAN MAISEL: Can you put those 10 numbers back? It's sort of like intent-to-treat an 11 on-treatment analysis given your explanation of why 12 you took them out. Can you put that data back in and 13 give us the complication and the mortality rates and 14 neurologic benefits. 15 DR. STERZ: Sure. Of course. 16 CHAIRMAN MAISEL: And then I believe you 17 said there's no difference, but it would be nice for 18 us to be able -- 19 DR. STERZ: Of course. 20 CHAIRMAN MAISEL: Because it would be an 21 important analysis point. 22 DR. STERZ: Sure. NEAL R. GROSS COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. (202) 234-4433 WASHINGTON, D.C. 20005-3701 (202) 234-4433 185 1 CHAIRMAN MAISEL: And maybe after lunch we 2 could see that data? 3 DR. STERZ: Yes, and maybe I will leave. 4 DR. HALPERIN: It's in your computer, 5 right? 6 DR. STERZ: But I think I have them ready, 7 but I have to look it up. I can do over lunch. 8 CHAIRMAN MAISEL: Okay. We'll ask you 9 again after lunch for that information. 10 The final comment I would like to make is 11 simply that where you have presented a number of 12 analysis, and I realize the data is limited, we've 13 essentially looked at the same data in four different 14 ways or three different ways. I mean, we saw the New 15 England Journal studies, and then they were 16 represented. At least some of the data was 17 represented in a meta-analysis and some of the data is 18 represented in the registry. So, you know, these are 19 not independent datasets that we're looking at from 20 three different sources. There is certainly an overlap 21 there, and that also I think limits the 22 interpretability of these studies. NEAL R. GROSS COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. (202) 234-4433 WASHINGTON, D.C. 20005-3701 (202) 234-4433 186 1 So at I think at this point -- oh, yes. 2 Henry? 3 DR. HALPERIN: I'm sorry. One last 4 comment. Because this notion of the standard of care 5 has been thrown around a lot, and I just wanted to 6 address that very briefly. Because the ILCOR 7 statement on hypothermia has been shown. And, in fact, 8 I don't think as august a body as ILCOR is, I don't 9 think most U.S. or cardiac arrest treatment and 10 training facilities would actually take that as the 11 standard of care. Because they actually look to the 12 American Heart Association, which is kind of the self- 13 proclaimed keeper of the guidelines, if you will. 14 Guidelines are published every five to seven years 15 which basically present the current state-of-the-art 16 of what cardiac arrest is. And although the Heart 17 Association is very clear to say it's not the standard 18 of clear, in truth it becomes these standard of care. 19 At least it's what most people wind up doing. 20 And the Heart Association itself has not 21 published a statement definitively on this subject 22 yet. It will come out, though, at the end of this year NEAL R. GROSS COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. (202) 234-4433 WASHINGTON, D.C. 20005-3701 (202) 234-4433 187 1 in the 2005 guidelines that have just been developed 2 are in the process of being developed. The conference 3 was at the end of January, just this past January. 4 And so the various committees are now kind of deciding 5 what level of recommendation to give different things. 6 And one of the those different things is going to be 7 hypothermia. 8 The previous guidelines were in the year 9 2000. And I think these studies did come out after 10 that. So then the Heart Association really has not 11 had an opportunity to really publish formal guidelines 12 on this particular subject. So I think that is one 13 particular reason why this may not have been adopted 14 more than it has been. 15 CHAIRMAN MAISEL: Thanks, Henry. 16 I think at that point we will break for 17 lunch. And let's convene at 1:15, please. 18 (Whereupon, the meeting at 12:08 was 19 adjourned, to reconvene this same day at 1:20 p.m.) 20 21 22 NEAL R. GROSS COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. (202) 234-4433 WASHINGTON, D.C. 20005-3701 (202) 234-4433 188 1 A-F-T-E-R-N-O-O-N S-E-S-S-I-O-N 2 1:20 p.m. 3 CHAIRMAN MAISEL: Good afternoon. 4 Why don't we begin the afternoon session? 5 We're somewhat ahead of schedule and had the Panel 6 members, we've done the lead reviews and have each of 7 the Panel members question the sponsor and the FDA and 8 make their comments. 9 I was asked by the sponsor if they could 10 address some of the Panel questions from this morning, 11 specifically issues related to the exclusion of 12 patients who died with 24 hours and some corrections 13 to some statements that were made this morning. So 14 you may address the Panel at this time, if you wish. 15 EXECUTIVE SECRETARY WOOD: I would ask the 16 sponsor not to sit at the table, but rather whoever is 17 addressing the issues stand at the podium. We like to 18 leave it free so that the Panel can ask questions of 19 either the FDA or the sponsor. 20 DR. COLLINS: There were questions asked 21 this morning, in particular for the patients that did 22 not live 24 hours. The starting number of patients NEAL R. GROSS COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. (202) 234-4433 WASHINGTON, D.C. 20005-3701 (202) 234-4433 189 1 for this analysis was 1882, that's including all 2 CoolGard and control patients. 3 Now the control patients, of course, were 4 control patients. They weren't cooled by any 5 mechanism. 6 They were recruited, treated and went to 7 other centers were 82. So they didn't complete their 8 treatment at AKH. 9 Other methods of cooling were 92. 10 And then within the first 24 hours there 11 were 206 deaths, one CoolGard and 205 normothermia. 12 The odds ratio with the deaths under 24 13 hours excluded, we reported to you, as 1.61. If we 14 add in all the patients who died under 24 hours, the 15 odds ratio is 2.17. 16 With the deaths less than 24 hours 17 removed, the simple survival outcomes are as posted; 18 43 of 62, 695 of 1,191. And with deaths left in for 19 CoolGard, 34 out of 63 and for the normothermia 695 20 out of 1,396. It was conservative for us to produce 21 data with the deaths under 24 hours removed. It made 22 the picture less appealing for the device. Putting it NEAL R. GROSS COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. (202) 234-4433 WASHINGTON, D.C. 20005-3701 (202) 234-4433 190 1 back in again, as you can see, significantly improves 2 the odds ratio. 3 The question was asked about the 2002 to 4 2003 datasets, what the actual numbers were. The 30 5 day survival normothermia versus device, 56 and 119 6 for 47 percent, the device 43 per 63, 68 percent 7 survival with an unadjusted odds ratio of 2.43. 8 Just one comment about ILCOR 9 recommendations and also about HACA. The advisory 10 statement was endorsed by the AHA. It was an interim 11 advisory statement in July 2003 published in 12 Circulation. 13 I believe in the public session this 14 afternoon Dr. Vanden Hoek will be available to talk 15 to that. I think there have been a lot of statements 16 made about AHA has or has not said. That was an AHA 17 advisory statement. And the rather exhaustive 18 mechanism for assessing the data, which I'm told was 19 both bloody and prolonged, was the standard AHA 20 mechanism for doing so. 21 Fritz, did you want to address the HACA? 22 DR. STERZ: Well, with regards to HACA NEAL R. GROSS COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. (202) 234-4433 WASHINGTON, D.C. 20005-3701 (202) 234-4433 191 1 study, again, the sample size we were shooting for was 2 500. And there was no interim analysis done. It was 3 really only given up because we were running out of 4 money after four years. It was a real four year 5 undertaking that we could do it. 6 Regarding the HACA, the safety data have 7 been prospectively defined and prospectively 8 collected. There was no retrospective chart review. 9 It was all prospective in the HACA trial. 10 With regard to the registry, the data on 11 outcome, the data on the baselines have been 12 prospectively input in a database by myself -- 13 controlling all the charts which have been filled out 14 according to a specific defined protocol by our team. 15 It was a team of ten, sometimes 15, physicians who 16 were trained by myself how to do it, how to make the 17 interviews, how to get this paperwork filled out. Then 18 I got the paperwork, if I haven't done it myself, on 19 my desk. Reviewed all charts myself. All the data 20 which are in the database, 2,500 times 500 I put 21 myself into the database and quality controlled them. 22 In addition, I had a physician after NEAL R. GROSS COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. (202) 234-4433 WASHINGTON, D.C. 20005-3701 (202) 234-4433 192 1 myself controlling me if I did the right job and 2 controlling again, if the data were put in an 3 appropriate manner into this database. 4 I would be glad or whatever I can tell you 5 if you want this data and use them for your analysis, 6 I would provide them to you immediately. I'm not a 7 statistician, I'm giving you what I have recorded. 8 And this is the same thing with the meta- 9 analysis. For the meta-analysis we have received all 10 the data from the participating centers, which was the 11 Bernard study and which was the Idrissi study. We 12 have it raw in our hand, and I'm sure they will give 13 me the permission to hand it over to you to reanalyze 14 this meta-analysis because in this database for the 15 meta-analysis we have the follow-ups, and this was 16 published now in Critical Care Medicine, until 17 discharge. Not only for survival, but also but for 18 neurologic outcomes. I would be happy to pass them 19 over to you if you want to reanalyze this. 20 In the HACA trial we had certain time 21 points of follow-ups after cardiac arrest. One day, 22 two day, one week, one month, discharge and six NEAL R. GROSS COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. (202) 234-4433 WASHINGTON, D.C. 20005-3701 (202) 234-4433 193 1 months. And we interviewed the patients by phone, and 2 not only this we called them in to come back to our 3 department and to check them up by blinded 4 investigators. 5 DR. COLLINS: The chart review was our 6 monitoring of their charts, not -- 7 DR. STERZ: The chart review -- 8 DR. COLLINS: And, yes, I used a 9 translator from the German to help me to do that. 10 DR. STERZ: The chart review was done only 11 in the historic control patients used for the safety 12 issues. Not for the HACA. In the '90/'91 patients we 13 didn't look at the safety points because there was no 14 reason to look at it. So in these control patients I 15 was forced to do a retrospective chart review for the 16 safety data only. These were about, I think, 20 to 30 17 percent of the data which were done by chart review 18 and only regarding the safety data. 19 All the other data were done 20 prospectively. 21 CHAIRMAN MAISEL: Okay. I appreciate that 22 clarification. I can't speak for everyone on the NEAL R. GROSS COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. (202) 234-4433 WASHINGTON, D.C. 20005-3701 (202) 234-4433 194 1 Panel, but I don't have any issues with regard to the 2 quality of the data that was presented or the 3 diligence with which you submitted your data. 4 John? 5 DR. SOMBERG: I still need clarification 6 to understand that if I'm correct, that there is a 7 subset of patients from your registry or your data 8 collection -- I won't even use the word "registry" -- 9 from your data collection that have received the 10 device under or have received a therapy with the 11 device under consideration today. And this was a 12 subset analysis called the AKH Cardiac Arrest 13 Registry. Am I correct in stating that? 14 And you're saying that the controls in 15 this group compared to those who got the drug were all 16 done at the same time and they are not retrospective 17 controls versus perspective collection of data? So 18 just take me through. Because I'm not interested in 19 proving a lot of different points. But I'm interested 20 in your device, and I'm interested in is there a 21 comparative group that's done contemporaneous with the 22 same intake criteria and not that they couldn't get NEAL R. GROSS COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. (202) 234-4433 WASHINGTON, D.C. 20005-3701 (202) 234-4433 195 1 the therapy and this group could get the therapy. 2 DR. COLLINS: I think in terms of the 3 HACA, while the HACA study was running -- correct me 4 if I'm wrong, Fritz -- the patients that were 5 recruited into the HACA trial were recruited into the 6 HACA trial. But hypothermia was not the standard of 7 care in your institution, is that correct? It's not 8 correct? Would you please talk to that? 9 DR. STERZ: The HACA trial was running 10 until 2002 or 2001, I don't recall it now anymore. But 11 the HACA trial was -- I didn't interfere with anything 12 else in the HACA trial. The HACA trial was on its own 13 from 1999 until 2002 or 2003. It was on its own. 14 Afterwards, we immediately switched over 15 to Alsius CoolGard device because we wanted to test it 16 and we wanted to see. And this started 2002 where you 17 have here the concurrent analyzed controlled data by 18 the FDA. 19 DR. SOMBERG: And how is the groups go 20 from device to normothermia? What determines that 21 selection process? It's not a randomized controlled 22 study. So how do you -- NEAL R. GROSS COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. (202) 234-4433 WASHINGTON, D.C. 20005-3701 (202) 234-4433 196 1 DR. STERZ: This selection process was 2 done on the standard order, which I have given my 3 fellows. I told my fellows this and this, and this 4 inclusion criteria you have to meet, then you put the 5 patients into cooling procedures. 6 DR. SOMBERG: And if they didn't meet 7 that, they went into the controlled group? 8 DR. STERZ: Therefore, the propensity 9 score scores are so different between these two 10 groups. 11 DR. SOMBERG: Okay. 12 DR. STERZ: Sorry, but that's how it is. 13 Otherwise I wouldn't have given this standard order 14 for procedures in the beginning. 15 DR. COLLINS: There was also a question 16 asked about the relationship to neuropsychological 17 data on neuropsychological testing on the CPC. Dr. 18 Roine has that data. 19 CHAIRMAN MAISEL: So maybe I can invite 20 the sponsor to have a seat. We'll open up the 21 discussion to the Panel and they can ask whoever they 22 would like to ask. NEAL R. GROSS COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. (202) 234-4433 WASHINGTON, D.C. 20005-3701 (202) 234-4433 197 1 So why don't I start with Dr. Marler and 2 see if you have any comments since you didn't get an 3 opportunity to speak this morning? 4 DR. MARLER: Well, I just wanted to say 5 that what I've heard from the applicants and the 6 public speakers is that there's really been a 7 remarkably good and sincere effort to look at the data 8 that's available and trying to make a conclusion about 9 what is effective and safe to use. 10 Instead of the randomized clinical trial, 11 though, the applicants are presenting kind of a series 12 of logical inferences. And each little step in the 13 logic to me introduces a degree of uncertainty which 14 at the end of reading through this and at the end of, 15 at least where I am right now, it leaves me unsure 16 whether patients will truly benefit from the procedure 17 that we're talking about or really unsure that we can 18 be confident that they're likely to benefit. And I 19 just can remember quite a few times when professional 20 judgment and professional standards are developed 21 pretty much through the same pattern of thinking 22 looking at observational studies or just clinical NEAL R. GROSS COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. (202) 234-4433 WASHINGTON, D.C. 20005-3701 (202) 234-4433 198 1 experience to develop standards based on professional 2 judgment and consensus that have been eventually 3 proven quite wrong when actually tested in a objective 4 clinical trial. And I feel that there's the situation 5 that we're there, could possibly be there in this 6 question. 7 CHAIRMAN MAISEL: Thank you. 8 And at this point I would like to ask the 9 Panel if they have any more comments or questions for 10 either the FDA or the sponsor before we move onto the 11 FDA questions. 12 Henry? 13 DR. HALPERIN: I just wanted to clarify 14 one issue about AHA endorsement. I know ILCOR gave it 15 a Class I recommendation is my understanding, which 16 would make it the standard of care. And the AHA, ACLS 17 committee at least that I was on at the time did not 18 sustain that Class I recommendation. 19 I don't know if it's appropriate to maybe 20 call on Terry, if you could clarify that? Because 21 weren't you involved in that AHA process? 22 DR. VANDEN HOEK: Yes, I was. And I've NEAL R. GROSS COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. (202) 234-4433 WASHINGTON, D.C. 20005-3701 (202) 234-4433 199 1 been on the ACLS Subcommittee for I guess almost ten 2 years now. But the ILCOR group, the Europeans put 3 together, have wanted to give it a Class I. I think 4 that there's going to be some finalized discussion by 5 American Heart. But I think that their overall very 6 favorable. I can't say whether it would be a I or a 7 IIa, but I think that there would be some sense that 8 this would be a reasonable thing to in a number of 9 circumstances. 10 DR. HALPERIN: But there's not currently a 11 class recommendation by AHA? 12 DR. VANDEN HOEK: That's correct. 13 DR. HALPERIN: Yes. 14 CHAIRMAN MAISEL: Any other Panel 15 comments? 16 Why don't we move on to the questions. 17 And if I can ask Geretta to read the first question. 18 EXECUTIVE SECRETARY WOOD: Alsius is 19 requesting to add the following new indication for use 20 to the CoolGard 3000 system: 21 "For use in the induction, maintenance and 22 reversal of mild hypothermia in the treatment of NEAL R. GROSS COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. (202) 234-4433 WASHINGTON, D.C. 20005-3701 (202) 234-4433 200 1 unconscious adult patients with spontaneous 2 circulation after out-of-hospital cardiac arrest when 3 the initial rhythm was ventricular fibrillation." 4 In support of this request the sponsor has 5 submitted a meta-analysis of several surface cooling 6 studies and clinical data with their specific device 7 from two different sources: 8 A 13 patient prospective uncontrolled U.S. 9 feasibility study, and; 10 A prospective nonrandomized, single-site 11 observational registry with "matched" controls. The 12 AKH Registry Data. 13 Question number one: Please discuss 14 whether you believe the data provides reasonable 15 assurance of safety for the proper indication. In 16 your discussion, please specifically address whether: 17 (a) The manner in which the data was collected 18 (prospective registry) provides adequate 19 assurance that the rates of adverse events 20 noted in the submission are representative 21 of what might be expected in actual 22 clinical practice. NEAL R. GROSS COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. (202) 234-4433 WASHINGTON, D.C. 20005-3701 (202) 234-4433 201 1 (b) The data adequately addresses the risks 2 and potential concerns of intravascular 3 cooling mentioned at the September 2004 4 Panel meeting, including bleeding, 5 clotting, DIC and ventricular 6 fibrillation. 7 (c) The increased rates of early pancreatic 8 and renal injury raise any new or specific 9 concerns. 10 CHAIRMAN MAISEL: So we had quite a bit of 11 discussion about some of these issues this morning. 12 And, Mike, you asked a few questions on this topic. Do 13 you want to summarize your thoughts regarding the 14 safety issues? 15 DR. WEISFELDT: I think the safety issue 16 remains unclear. You have some information to suggest 17 renal and perhaps pancreatic complications of long 18 term catheter residence in the inferior vena cava with 19 cooling of that catheter to, obviously, a temperature 20 that may or may not have an effect on the blood that 21 goes by. And it certainly does concern me as to 22 whether there is any database for a duration of NEAL R. GROSS COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. (202) 234-4433 WASHINGTON, D.C. 20005-3701 (202) 234-4433 202 1 cooling that mirrors the duration that is recommended 2 currently for cooling with the catheter system, even 3 in the approved indications, that is the ILCOR 4 statement at least is 12 to 24 hours of cooling. And 5 at least so far I haven't heard anything to the notion 6 of safety of this catheter in cooling in any human 7 being for that period of time in the approved 8 indications. And, therefore, we have to look at only 9 the data that's available in the cardiac arrest 10 situation. And there are, certainly, some evidence of 11 renal and pancreatic problems that may not be present 12 with other forms of cooling. So I remain concerned 13 about safety and believe that a randomized trial with 14 safety endpoints for surface cooling versus 15 endovascular cooling would be a highly desirable piece 16 of data. 17 DR. BLUMENSTEIN: Yes. Brent Blumenstein. 18 I'm not hearing. 19 CHAIRMAN MAISEL: We'll try to fix that. 20 Did you have some comments or you just 21 couldn't hear well? 22 DR. BLUMENSTEIN: I was not hearing. The NEAL R. GROSS COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. (202) 234-4433 WASHINGTON, D.C. 20005-3701 (202) 234-4433 203 1 previous speaker just faded away. 2 CHAIRMAN MAISEL: Okay. Anyone else on 3 the Panel have safety comments? John? 4 DR. SOMBERG: Well, the more I think of 5 this, the more it becomes a conundrum because I 6 sympathize with the sponsor here because they're 7 bearing, as the first one, is bring this cooling to 8 the regulatory for it, they're carrying the burden of 9 trying to prove the issue of hypothermia and also 10 prove the issue of safety. And it may have been much 11 better to have initially focused in what we heard 12 today is reanalysis of the AKH Registry. 13 We had two groups receiving different 14 therapy, cooling/noncooling , but contemporaneous 15 at a same time and there is a suggestion, as there is 16 all through the database, that there's a benefit here. 17 The trouble is are the two groups comparable and have 18 they been looked at to be comparable enough. And I'm 19 getting a little bit more comfortable that they may 20 be. But it was not clear from the data packet or any 21 information. 22 So I'm not sure are we suffering from NEAL R. GROSS COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. (202) 234-4433 WASHINGTON, D.C. 20005-3701 (202) 234-4433 204 1 multiple misdata inputs, if you will, or are we just 2 having inadequate information. And with that said, I 3 still do not, as I hear others in the Panel as well 4 who are more experience in the resuscitation area than 5 I am, say they're not comfortable with the safety. 6 But I think the cup is half filled or even more so, 7 and I do not think it's a binary decision yes or 8 forever no in this area. 9 So I think it would be useful just from my 10 advantage point to: (1) have comparable groups 11 exposed or not exposed to the intervention. And one 12 has to be clear what the intervention is. Because 13 it's more than just the catheter, it's also the 14 medications and it's also, I believe in the latter 15 group, this ice saline rapid induction technique as 16 well. So when you put it all together that's what 17 you're going to be looking at as a safety issue. And 18 then to expose it to that. That could still be done. 19 Now the second issue I have is does 20 cooling really work, and there are some questions 21 about that. And I would like to see some data. I 22 believe it does in the European experience. I believe NEAL R. GROSS COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. (202) 234-4433 WASHINGTON, D.C. 20005-3701 (202) 234-4433 205 1 it would be useful to have some data with, 2 unfortunately like the city of Chicago where it takes 3 an hour to get anyplace you know the marked delays and 4 that sort of thing, does it really have a benefit in 5 there. And I'm not sure if the sponsor can answer 6 that issue. And it may be something that, you know 7 even before I even heard about this NIH consortium, 8 it's something that the NIH could need to help as a 9 public health issue. But now there is a consortium 10 and it may be able to answer that sort of thing. 11 So I think the committee's asked for 12 opinions in a lot of areas that are very hard. And I 13 can't speak for the committee, but my opinion is that 14 I'm leaning towards feeling that there is a signal 15 here both in terms of hypothermia efficacy and in 16 efficacy and safety of this device. But it's kind of 17 murky and someone has to, not in this forum, but has 18 to be able to go through in much greater care and 19 probably get some additional information. 20 CHAIRMAN MAISEL: Are there any Panel 21 members who feel we have adequate data in front of us 22 to say that the device is safe? NEAL R. GROSS COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. (202) 234-4433 WASHINGTON, D.C. 20005-3701 (202) 234-4433 206 1 DR. PAGE: I'll address that. And I would 2 first off say that we don't have enough data to say 3 for sure it's safe, hypothermia therapy that is. And, 4 indeed, there have been practice patterns that have 5 gone on for years that have come around by consensus. 6 I gave a lot of Lidocaine to acute 7 infarcts a while back before we figured out that it 8 wasn't really a good thing to do. 9 On the other hand, I don't know if we're 10 going to get any better data than what we have here. 11 And I'm seeing a strong enough signal in terms of 12 safety and efficacy of this of the concept of the 13 hypothermia that I lean in the direction toward 14 getting all the information we can from the data that 15 have been collected. Maybe I'm a pessimist, but I 16 don't believe we'll have the randomized trial that we 17 all wished we had before us right now. And that being 18 lacking, I can give an endorsement to the concept of 19 hypothermia. 20 CHAIRMAN MAISEL: For those members who do 21 not feel that safety has been adequately expressed, 22 what specific endpoints do you feel need to be NEAL R. GROSS COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. (202) 234-4433 WASHINGTON, D.C. 20005-3701 (202) 234-4433 207 1 obtained, and are there any study designs short of a 2 randomized trial that can specifically address this 3 safety issue. Not necessarily effectiveness, but the 4 safety issue. For example, would a prospective 5 registry of another 50 patients or a 100 patients 6 supply you with what you need? 7 John? 8 DR. SOMBERG: And I want to repeat. I'll 9 just be very brief. Is that randomized trial is 10 preferable. But if one for reasons cannot do that, 11 then the reanalysis of the AKH Registry raises the 12 issue are the two groups comparable? Because why 13 didn't one group in an institution where there's a 14 dynamic leader who says hypothermia is the way to go, 15 why didn't those people get it? So I'm worried about 16 that. 17 So if one can assure the comparability of 18 the two groups, if they're not randomized, maybe it's 19 just one doctor does it one way on Monday, Wednesday 20 and Friday and the other one does it Tuesday, Thursday 21 and Saturday; that's fine as well. But some sort of 22 way to make sure that one group is not much sicker NEAL R. GROSS COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. (202) 234-4433 WASHINGTON, D.C. 20005-3701 (202) 234-4433 208 1 than the other, the control group, therefore making 2 the intervention look more effective and look safer 3 because the sicker that have more problems. 4 CHAIRMAN MAISEL: Jeff? 5 DR. BRINKER: I would just like to 6 question one piece of this, and that is the concept of 7 the randomized trial cannot be done anymore. In a 8 country where we exist, and I would venture to say 9 that less than 10 percent of patients having cardiac 10 arrest or defib out-of-hospital get hypothermia now. 11 So it seems to me that a randomized trial could be 12 done, if not to normothermia certainly to some form of 13 hypothermia other than this device. And compare the 14 two in terms of a number of endpoints. One, of 15 course, is safety and for the sponsor it might be good 16 to see for them if there were other issues in terms of 17 utility and ease of patient care what device offered 18 advantage. 19 So I think that there is room for that 20 kind of information that would give us some 21 information on safety. 22 The other issue that boggles my mind but NEAL R. GROSS COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. (202) 234-4433 WASHINGTON, D.C. 20005-3701 (202) 234-4433 209 1 in the FDA logic of this probably makes sense, if we 2 accept all the data that shows from the European and 3 Australian studies that hypothermia is good for this 4 situation, basically none of that was achieved with 5 this device, the randomized trials. So we're in a 6 position of potentially recommending an approval of 7 one device on the basis that it is roughly equivalent 8 in action to other devices which are not approved for 9 this, which sort of boggles my mind a little bit. But 10 I assume it's not unreasonable to think that way. 11 But if you do, then it should be equally 12 reasonable to think that you could a randomized trial 13 between those two, this device and other devices, and 14 to see if there's a difference in safety, utility, 15 etcetera. 16 CHAIRMAN MAISEL: As this Panel often 17 encounters a relatively small randomized trial that 18 addresses uncommon safety issues, it's going to be a 19 difficult design to identify rare safety issues. 20 Tom? 21 DR. BROTT: In that regard, I would say 22 that, John Marler's here he's heard this before, but NEAL R. GROSS COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. (202) 234-4433 WASHINGTON, D.C. 20005-3701 (202) 234-4433 210 1 patients like this in terms of a study are like 2 diamonds. They're rare. They will be difficult to 3 enroll. And I think they need to be studied extremely 4 carefully so that a Panel such as ours can be assured 5 we have eight different ways of looking at the 6 comparisons. We have the primary endpoint, but then 7 we have other things. 8 These patients, they all ventricular 9 fibrillation, arrest. I'm not a cardiologist, but 10 they must have coronary artery disease. Many of them, 11 if not 80 to 90 percent. Does ice cold water or more 12 rapid cooling do something to recurrence of coronary 13 artery disease or their infarct? What happens to the 14 EKG? 15 Whatever the design, I think that the 16 surveillance has to be at a different level than what 17 we've been presented, which is why I think we've 18 struggled. 19 DR. BRINKER: As far as being diamonds, we 20 might be more like South Africa than you might think. 21 There are over 100,000 people a year that might 22 qualify for this if it were done in a reasonable way. NEAL R. GROSS COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. (202) 234-4433 WASHINGTON, D.C. 20005-3701 (202) 234-4433 211 1 And Mike was suggesting that they could enroll up to 2 10,000 patients in a three year study. So I think 3 that you could do this if it was done appropriately. 4 But I agree that there are other pieces of information 5 that would be extremely important to have. 6 But the bottom line for our concerns now 7 given the data that we do have, would be simply 8 whether this device is as safe as a comparative 9 device. And while we might not get the very rare 10 things, if there's a general consensus that at least 11 we do away with issues like renal failure and 12 pancreatic problems and maybe infection, then those 13 are big things that I'd like to see settled. 14 CHAIRMAN MAISEL: So if I could try to 15 summarize the Panel's thoughts regarding safety. 16 Most, but not all of the Panel members seem to feel 17 that we need more data with regard to the safety 18 endpoints, specifically with regard to some of the 19 things that we've seen with pancreatic and renal 20 injury as well as bleeding complications with catheter 21 insertion, etcetera. That a randomized trial design 22 would be the best way to establish these issues, but NEAL R. GROSS COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. (202) 234-4433 WASHINGTON, D.C. 20005-3701 (202) 234-4433 212 1 not necessarily absolutely the only way. 2 Does anyone take issue with anything I 3 just said? Okay. 4 Why don't we move on to question number 5 two. 6 DR. YUSTEIN: Dr. Maisel, can I ask you 7 one question. Does the Panel have any concerns about 8 any other specific safety items? You mentioned 9 pancreatitis and renal insufficiency. Dr. Brott was 10 getting at possible recardiac events that occurred 11 secondary. Does this Panel have any other items that 12 particularly stuck out at them or will stick out for 13 them? 14 CHAIRMAN MAISEL: I think certainly 15 anything related to catheter insertion, so bleeding 16 vascular complications would certainly be relevant. 17 DR. KATO: The traditional ones, 18 thrombosis, bleeding, you know coagulopathy. 19 DR. BRINKER: Infection, since that's a 20 high overall rate. 21 DR. KATO: Oh, infections, sure. 22 DR. SOMBERG: Sepsis was something that NEAL R. GROSS COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. (202) 234-4433 WASHINGTON, D.C. 20005-3701 (202) 234-4433 213 1 came out specifically from the cooling system, 2 although not in the latest studies with this device. 3 DR. KATO: I mean there are, obviously, a 4 lot of mechanical issues that go along with this 5 catheter. You know if the water pressure builds up, 6 balloon rupture, inadvertent administration of the 7 fluid into the patient. You know, the usual 8 mechanical things that would be associated with 9 catheter designs such as this. 10 CHAIRMAN MAISEL: Number two. 11 EXECUTIVE SECRETARY WOOD: Please discuss 12 whether you believe the data provides reasonable 13 assurance of effectiveness for the proposed 14 indication. In your discussion, please specifically 15 comment on whether the issue of nonrandomized data was 16 adequately addressed by the propensity analysis? 17 CHAIRMAN MAISEL: So many of our comments 18 in earlier discussion have addressed this topic. I 19 think many panelist have issues with interpreting the 20 data. The issue of effectiveness, I don't know that 21 we have the data to establish that endovascular 22 cooling is equivalent to surface cooling as was NEAL R. GROSS COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. (202) 234-4433 WASHINGTON, D.C. 20005-3701 (202) 234-4433 214 1 presented in many of the New England Journal studies, 2 etcetera. 3 So I think that my sense is the consensus 4 is that nonrandomized data is not adequate. 5 I would invite other panelists to comment 6 as well. 7 DR. SOMBERG: Well, I'd just make the same 8 point earlier for safety, is that it is conceivable 9 and we have -- I think you've said this yourself, 10 Bill. That sometimes concomitant controls that are 11 comparable could help establish that point as well. 12 So I don't think we have to necessarily demand, 13 although it's preferable to have a randomized placebo 14 controlled trial. 15 DR. MARLER: Well, I guess in response to 16 that, I think that the labor and the effort that goes 17 into doing a registry or a nonrandomized study of 18 sufficient quality to approach being convincing is not 19 that much different from actually introducing one more 20 step of randomization. And I think a clinical trial, 21 I haven't heard anything today that convinces me that 22 it's not possible to do a trial. It may be difficult, NEAL R. GROSS COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. (202) 234-4433 WASHINGTON, D.C. 20005-3701 (202) 234-4433 215 1 but most all of them all. And a registry well done is 2 difficult as well. 3 CHAIRMAN MAISEL: I would also comment 4 that I think they did about as good a job as you can 5 do with a registry and the problems that we're dealing 6 with are just what registries are about, which is 7 they're not randomized and it's difficult to account 8 for what you don't know. 9 Anyone else have any comments on 10 effectiveness? I'm not sure we've absolutely gotten a 11 flavor for -- let me ask this question. Are there 12 Panel members who agree with John that randomized 13 trials are not necessarily necessary? 14 DR. SOMBERG: I'm not sure I said that. 15 CHAIRMAN MAISEL: Didn't you say that? 16 DR. SOMBERG: I said requisite, required. 17 CHAIRMAN MAISEL: Well, that's what we're 18 asking. We're trying to give guidance about whether 19 they must do a randomized trial or whether there is 20 another way out. 21 DR. SOMBERG: Okay. 22 CHAIRMAN MAISEL: Norm? Or Mike, go NEAL R. GROSS COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. (202) 234-4433 WASHINGTON, D.C. 20005-3701 (202) 234-4433 216 1 ahead. 2 DR. WEISFELDT: There are devices that 3 have been -- treatments that have been approved by the 4 FDA without a randomized trial. I mean automatic 5 defibrillators, pacemakers; a lot of them. 6 CHAIRMAN MAISEL: Right. So it's 7 specifically for this device, what nonrandomized 8 information would you need to approve the device? 9 DR. BLUMENSTEIN: This is Brent 10 Blumenstein. 11 A much larger effect size. 12 DR. WEISFELDT: Yes, right. You know, 13 uniform survival. People are unconscious an hour 14 after a cardiac arrest. That would do it, wouldn't 15 it? 16 CHAIRMAN MAISEL: Okay. 17 DR. YUSTEIN: Dr. Page? 18 DR. PAGE: Let me just be clear. Are we 19 talking about -- because my comments in, maybe my 20 pessimism about having the great randomized trial and 21 having to just deal with the data we have, my comments 22 in terms of safety and efficacy were having to do with NEAL R. GROSS COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. (202) 234-4433 WASHINGTON, D.C. 20005-3701 (202) 234-4433 217 1 hypothermia conceptually. Are we now talking about 2 the device? 3 CHAIRMAN MAISEL: Yes. I'm trying to be 4 pragmatic, and we're going to finish this Panel 5 meeting and the FDA is going to need to give advice to 6 the sponsor about if we decide that we're not going to 7 approve it, not that we're voting. They're going to 8 need to give very specific recommendations about the 9 least amount of data that is going to need to be 10 presented to reach the bar that we're setting. So I'm 11 trying to understand. 12 We certainly all would love to have a 13 randomized trial here. I'm asking whether we 14 absolutely need an randomized trial or whether there 15 is some other form that is easier to achieve that 16 would satisfy us. 17 DR. YUSTEIN: Dr. Page, all these 18 questions are written with respect to this particular 19 advice and the data that you've seen before you. If 20 you need to take other things into account in order to 21 answer those questions, that's fine. But all these 22 questions are written specifically for this product or NEAL R. GROSS COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. (202) 234-4433 WASHINGTON, D.C. 20005-3701 (202) 234-4433 218 1 this device for this application. 2 DR. PAGE: Thank you. 3 DR. BRINKER: I think we should also be 4 aware of the fact that sometimes even if you had a 5 large number of patients in a nonrandomized situation, 6 you'll find yourself no closer to the answer than you 7 are now. So, for instance, what if they did a 100 8 patient trial, registry and found that the incidence 9 of renal failure measured by a half of milligram 10 percent elevation in creatinine was 6 percent? What 11 would we say at the end of that line unless we had a 12 comparison? 13 DR. BROTT: One thing. It may not be that 14 a randomized trial would have to be strictly one-to- 15 one randomization if there were two arms. I think 16 some of our safety concerns could be compatible with 17 the different randomization ratio that would provide a 18 panel in the future the information that they would 19 need. 20 CHAIRMAN MAISEL: Henry? 21 DR. HALPERIN: I'm still a little 22 perplexed on the safety issue. Because I'm still NEAL R. GROSS COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. (202) 234-4433 WASHINGTON, D.C. 20005-3701 (202) 234-4433 219 1 trying to get it clear in my own mind what the 2 differences in the post-cardiac arrest state are from 3 just using the device for its other already approved 4 indications. 5 For instance, all the mechanical issues 6 with the catheter in terms of catheter integrity and 7 replacement, it's hard to believe there's a difference 8 in the post-cardiac arrest state than there is in 9 general use of the catheter. However, with the renal 10 failure there actually might be differences because 11 the added insult of ischemia during cardiac arrest 12 might be a covariable that would not necessarily be 13 taken into account by just general use of the device. 14 So I guess part of the question, and we 15 can still ask the sponsor's questions, but is there 16 any renal failure data on just inducing hypothermia in 17 general with this catheter? And is it any different 18 in the cardiac arrest state? 19 DR. COLLINS: There's no randomized 20 controlled trial on that question. 21 In terms of the effects of hypothermia on 22 renal clearance of that level of creatinine, no. We NEAL R. GROSS COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. (202) 234-4433 WASHINGTON, D.C. 20005-3701 (202) 234-4433 220 1 have examined vessel on post-mortem samples and not 2 seen any obvious indication that there's a problem. 3 And within the normothermia treatment in a controlled 4 trial where the catheter is too cold, but often there 5 was a small subgroup -- most of them are actually -- 6 there was no effect there, although there were daily 7 bloods drawn. So it seems to be isolated. 8 DR. HALPERIN: The other comment is is 9 that I think we should all say or realize once again 10 that these trials are very difficult to do and this 11 particular disease has a very high lethality. So I'm 12 not certain that this scrutiny should be exactly 13 identical to every other situations because of the 14 enormous lethality of this particular disease. 15 CHAIRMAN MAISEL: Bill? John? 16 DR. SOMBERG: With that said, I think it's 17 important to measure the risk versus the benefit. 18 First you're going to introduce cooling to patients. 19 We would like to know that cooling works. And then 20 you're going to introduce cooling by the catheter, and 21 there are modalities of cooling. Now we've heard that 22 some of them are inconvenient. But what happens in a NEAL R. GROSS COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. (202) 234-4433 WASHINGTON, D.C. 20005-3701 (202) 234-4433 221 1 controlled trial and it could be a randomized or 2 nonrandomized and we can discuss that, but in a 3 controlled trial there was cost associated with this 4 device. And I'm not saying an economic cost. But a 5 safety cost. You might say that maybe it's better to 6 go back to basics and have the interns and residents 7 carry the ice bags. 8 And I'm not demanding a large randomized 9 trial with a very sensitive. But this committee has 10 for many lesser devices asked for some sort of 11 demonstration of the risk; and that's the third 12 question they're going to ask in a minute. Is the 13 risk/benefit ratio. And just because something works, 14 doesn't mean you're going to use because it may have 15 tremendous risk. And because it has risk, it may not 16 work. So I just don't think it's been shown, although 17 the data from this reanalysis is more moving than I 18 first thought. The trouble is I'm still not sure if 19 the control group because of the selection process was 20 a lot sicker, therefore it makes the efficacy look 21 better and the toxicity look less. If you can show me 22 some sort of comparable control group or go out and do NEAL R. GROSS COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. (202) 234-4433 WASHINGTON, D.C. 20005-3701 (202) 234-4433 222 1 that and show that the efficacy is greater and the 2 toxicity is minimal, and I know it's a very lethal 3 disease, then you would say but go ahead and do this. 4 And I think that's the FDA is going to have to make 5 this balancing judgment. And the data is half there, 6 but not sufficient for -- obviously there's a lot of 7 difference here. So it's demonstrating it's not 8 sufficient. 9 CHAIRMAN MAISEL: Norm? 10 DR. KATO: I have to agree with Dr. 11 Somberg. And I think that the randomized perspective 12 trial, as difficult as it's going to be to do this and 13 given the lethality of this disease and I don't think 14 anybody's questioning that, but what we've seen 15 recently in some of the more higher profile issues 16 facing the FDA, I mean we've learned okay, even simple 17 drugs like ibuprofen have the same cardiovascular risk 18 as, let's say, as Vioxx or Celebrex which have been -- 19 one of those drugs have now been pulled from the 20 market. But you wouldn't have know that unless you 21 actually did that trial. 22 So I think the comparison between the NEAL R. GROSS COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. (202) 234-4433 WASHINGTON, D.C. 20005-3701 (202) 234-4433 223 1 catheter and alternative forms of cooling I think is 2 important. I think randomization, some type of 3 clinical trial, some type of rigorous trial is 4 important in order to satisfy not only the Panel, but 5 also the public's demand for safety and efficacy. 6 CHAIRMAN MAISEL: Why don't we move on to 7 question three. 8 Geretta? 9 EXECUTIVE SECRETARY WOOD: Taking into 10 account all pertinent clinical information available 11 as well as your responses to the above questions, 12 please comment on whether you believe the data 13 provides an overall risk/benefit ratio which supports 14 marketing clearance of the device in the United States 15 for the proposed indication. 16 CHAIRMAN MAISEL: So we're not taking a 17 formal vote today, however I would like to hear all 18 Panel members on this question, and I'll start with 19 Dr. Marler? 20 DR. MARLER: No. I don't think that the 21 data provided gives an adequate estimate of the 22 overall risk and benefit for the reasons that we've NEAL R. GROSS COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. (202) 234-4433 WASHINGTON, D.C. 20005-3701 (202) 234-4433 224 1 delineated. 2 CHAIRMAN MAISEL: Dr. Brinker? 3 DR. BRINKER: I'm optimistic about the 4 device, but I don't think it meets the level of 5 evidence that I feel comfortable with approving myself 6 at this time. 7 CHAIRMAN MAISEL: Dr. Page? 8 DR. PAGE: And I think we're all wrestling 9 with the same problem with the data. 10 Looking at it from a slightly different 11 perspective, I tip over just slightly to saying yes. 12 CHAIRMAN MAISEL: Dr. Brott? 13 DR. BROTT: I'm optimistic about the 14 device as well. And the data that we've looked at 15 today is not new. And physicians in this country have 16 not accepted it for the reasons that we've proposed. 17 And I think that this study that has the rigorous 18 study that's been proposed might not just help the 19 Panel, but if the therapy is in fact effective with 20 this device and shown to be that, I think our peers 21 will be much more likely to accept it and use it. 22 CHAIRMAN MAISEL: Dr. Somberg? NEAL R. GROSS COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. (202) 234-4433 WASHINGTON, D.C. 20005-3701 (202) 234-4433 225 1 DR. SOMBERG: I'm not yet there but moving 2 in the right direction. 3 CHAIRMAN MAISEL: Henry? 4 DR. HALPERIN: I'm very optimistic about 5 hypothermia and I think the data for the device is 6 borderline. And I would give a slight positive bent. 7 CHAIRMAN MAISEL: Dr. Blumenstein? 8 DR. BLUMENSTEIN: No. 9 CHAIRMAN MAISEL: Dr. Kato? 10 DR. KATO: I would vote no. Again, I 11 think that the data on hypothermia is interesting, but 12 not -- but I really would like to see -- you know, if 13 it's so obvious that this is going to be a benefit, 14 then it should be easy to run the trial and you're 15 going to have obvious positive results. 16 CHAIRMAN MAISEL: Mike? 17 DR. WEISFELDT: No, on the count of 18 safety. But whether the safety concern was met, then 19 I would be in favor. 20 CHAIRMAN MAISEL: I, too, feel that we're 21 moving in the right direction but don't have 22 everything that we need. NEAL R. GROSS COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. (202) 234-4433 WASHINGTON, D.C. 20005-3701 (202) 234-4433 226 1 So why don't we move on the next question, 2 Geretta? 3 EXECUTIVE SECRETARY WOOD: If you believe 4 that the data currently submitted is adequate and 5 sufficient to support marketing clearance: 6 (a) Please comment on what specific elements 7 should be included in the labeling to 8 accurately reflect the risks, benefits, 9 and proper use of the device including any 10 modifications to the proposed: 11 I. Indications for use 12 statement. 13 II. Contradictions. 14 III. Warnings/precautions, and 15 IV. instructions for use. 16 For the latter, please comment on what 17 specific rates of cooling, duration of 18 cooling, optimal target temperatures, 19 rewarming rates, and optimal time to 20 initiation of therapy are supported by the 21 data or whether the general treatment 22 guidelines proposed by the sponsor (32 to NEAL R. GROSS COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. (202) 234-4433 WASHINGTON, D.C. 20005-3701 (202) 234-4433 227 1 34 degree centigrade for 12 to 24 hours) 2 are sufficient for labeling purposes. 3 ((b) Please comment on whether you believe a 4 post-market study should be required and 5 if so, what the critical components and 6 design of that study should be. 7 CHAIRMAN MAISEL: So it's difficult to 8 comment on the labeling issues without knowing exactly 9 what data or the study design, which will obviously 10 have implications for instructions for use. 11 My comment about the labeling is that I 12 found it very verbose. I mean, there were dozen of 13 pages before you got to any clinical data regarding 14 the device. 15 I think it needs to be explicitly stated 16 when surface cooling rather endovascular cooling for 17 hypothermia is used. 18 I think the term "hypothermia" was used 19 liberally without clarifying what type of hypothermia. 20 So I think that in whatever instructions for use 21 eventually come of this, that will need to be 22 explicitly spelled out. NEAL R. GROSS COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. (202) 234-4433 WASHINGTON, D.C. 20005-3701 (202) 234-4433 228 1 It's also difficult to comment to comment 2 on a post-market study at this time. 3 Dr. Yustein, do you have any other 4 comments? 5 DR. YUSTEIN: Maybe if Dr. Page and Dr. 6 Halperin, since they were more on the favorable 7 risk/benefit ratio item, if they can add any comments 8 to that if they were to see anything as far as the 9 labeling that would help us your view of the 10 risk/benefit question. 11 DR. PAGE: There's a lot there. And, of 12 course, I'd rather especially since it's not going to 13 have happen immediately, I'd like to think about that 14 a little bit and get back to you. 15 DR. YUSTEIN: These questions were of 16 course written before we knew what you were going to 17 responding to the first three. 18 DR. PAGE: Right. Right. 19 CHAIRMAN MAISEL: Dr. Halperin, do you 20 want to address the -- 21 DR. HALPERIN: I don't really have 22 anything more to say, except that I think that clearly NEAL R. GROSS COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. (202) 234-4433 WASHINGTON, D.C. 20005-3701 (202) 234-4433 229 1 if one were to fall slightly on the positive side, a 2 post-market surveillance of any potential 3 complications would be critical. 4 CHAIRMAN MAISEL: John? 5 DR. SOMBERG: I also think that in any 6 labeling there has to be some mention of fluids, 7 sedatives, paralytics, paralyzing agents and such 8 because I don't think that this is a therapy that's 9 really taken out of context. And a physician making 10 this choice or a team making this choice may not have 11 not studied as thoroughly as the expert groups that 12 have been applying it so far. So I think you have to 13 have an little bit of -- and I agree with Dr. Maisel 14 that it has to be a user friendly explanation for it. 15 Because the only reason I read it was that you guys 16 made me do it. But otherwise, you know, like all docs 17 you just read the dose and the PRD, and that's about 18 it and you go for it. And, you know, I hate to think 19 of somebody -- you know, if fluids were essential, if 20 the sedatives were essential and which ones was 21 essential. And the person wasn't suffering. So it's 22 sort of tied in together. NEAL R. GROSS COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. (202) 234-4433 WASHINGTON, D.C. 20005-3701 (202) 234-4433 230 1 DR. BRINKER: I would hope that if a 2 further study is agreed upon that some of these issues 3 actually would be prospectively addressed in that 4 study to make it less of a guess work as to what kind 5 of ancillary cocktails the patients need and how 6 they're rewarmed, and things of that nature. 7 CHAIRMAN MAISEL: Next question, Geretta? 8 EXECUTIVE SECRETARY WOOD: If you do not 9 believe that the data presented today met the 10 threshold for marketing clearance, please discuss what 11 additional type and amount of clinical data would be 12 required to meet this level of assurance. In your 13 discussion, please comment on: 14 (a) The appropriate endpoints including 15 assessment scales and timing of 16 assessments which should be used to 17 evaluate the effectiveness of endovascular 18 cooling catheters for this indication. 19 CHAIRMAN MAISEL: Tom, do you want to try 20 to tackle that one? 21 DR. BROTT: As far as the time, we do have 22 the HACA study which I think was six months. And it's NEAL R. GROSS COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. (202) 234-4433 WASHINGTON, D.C. 20005-3701 (202) 234-4433 231 1 always nice to be able to compare. But with brain 2 injury we do have evidence that with focal brain 3 injury, anyway, measures of three months are almost 4 identical to measures at a year. And so I would say 5 that in terms of time, I think three or six months in 6 terms of the time of the assessment would be 7 appropriate. 8 I do think that we require an ordinal 9 scale at this point in time. But I would think that 10 the ordinal scale will be more objective if a detailed 11 inventory of activities of daily living is performed 12 first at the time of the blinded evaluation. 13 Because the trial will not be huge and 14 because Panel members and physician peers need to be 15 persuaded of this concept and this device, I think 16 that secondary endpoints would be beneficial be 17 beneficial, including cognitive endpoints that we've 18 discussed before that would be widely accepted by our 19 peers, such as a standardized test of some sort that's 20 brief in patients who don't tolerate long neurological 21 psychological investigations. 22 I would not require brain imaging, but the NEAL R. GROSS COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. (202) 234-4433 WASHINGTON, D.C. 20005-3701 (202) 234-4433 232 1 standard of care is shifting, I believe, in my talks 2 and in my institution where we are obtaining more 3 brain imaging in these patients than we were obtaining 4 before. To require brain imaging in a study such as 5 this could be overly burdensome and expensive for the 6 sponsor. But if it were possible to do so, it could 7 supplement the other endpoints. 8 In the brain imaging literature that we 9 have thus far, there are some surprises. And, again, 10 I think that could be useful. 11 CHAIRMAN MAISEL: Any other comments 12 regarding endpoints? Jeff? 13 DR. BRINKER: Well, I think that somewhere 14 in the discussions between the FDA and the sponsor 15 there needs to be resolution of something that we 16 haven't come to resolution with here, and that is 17 after all is said and done is the concept of 18 hypothermia accepted and unquestionable? So that if 19 that's the case, then much of the endpoints that you 20 are suggesting might be overkill and that the real 21 issue is the safety, which would have to be done with 22 a comparator of another cooling device. NEAL R. GROSS COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. (202) 234-4433 WASHINGTON, D.C. 20005-3701 (202) 234-4433 233 1 So I think conceptually there needs to be 2 some decision and it's not going to be resolved at 3 this Panel meeting about whether the FDA feels that 4 that hypothermia for out-of-hospital cardiac arrest 5 with defib is a done deal. 6 DR. BROTT: I would agree with those 7 points with regard to the importance of safety. 8 CHAIRMAN MAISEL: John? 9 DR. SOMBERG: I just would say the optimum 10 study would be a three-on study where there is a 11 comparative of, say, topical cooling versus a noncool 12 group. I think the experience in Minnesota, the 13 experience in Illinois is such that so few people get 14 this procedure of cooling by the device, that I think 15 there's still room at this juncture -- there may not 16 be room in a few weeks in a few months if people -- if 17 all societies make this the standard of care. And I'd 18 like to hear from some of the experts in resuscitation 19 on that issue. 20 But the optimum protocol would be to have 21 two comparative groups. And it also might be optimal 22 for the sponsor in that if you only have to treat six NEAL R. GROSS COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. (202) 234-4433 WASHINGTON, D.C. 20005-3701 (202) 234-4433 234 1 patients to show a survival benefit of one, that is 2 very very profound. And if I knew that, you know, I 3 would make a lot of noise in my institution if there 4 was a patient missed that. I mean, ACE inhibitors, 5 ARBs, beta blocks don't really approach those numbers 6 in most instances. And we make a lot of noise about 7 not giving those. 8 So that could be very impressive or it may 9 work out that in the United States given all the 10 response times, there's no benefit from almost 11 anything. And it'll be troubling to do this sort of 12 thing. 13 So I would hope that type of ideal study 14 could be done. 15 CHAIRMAN MAISEL: Now you've touched on 16 questions 5(b) and 5(c). So why don't we put them on 17 the table. 18 EXECUTIVE SECRETARY WOOD: Okay. 19 (b) Whether a randomized controlled trial 20 would specifically be required and if so, 21 what the appropriate control groups would 22 be. If not, please comment on what other NEAL R. GROSS COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. (202) 234-4433 WASHINGTON, D.C. 20005-3701 (202) 234-4433 235 1 types of trial design would be adequate. 2 (c) Whether, due to the potential differences 3 in standard of care between the 4 international community and the United 5 States, data collected in the U.S. would 6 be required. 7 CHAIRMAN MAISEL: Okay. I think we've 8 discussed 5(b) to a certain degree. And it seems that 9 most of the Panel feels that a randomized controlled 10 trial would be required, although that's not an 11 absolute. 12 Any one have any other comments regarding 13 the question 5(b) regarding the trial design? 14 DR. BRINKER: I make a proposal that 15 probably won't be accepted, but I would think that the 16 people that wrote today's presentation should have a 17 discussion with the people responsible for the writing 18 of the AHA and ILCOR guidelines and see if there's 19 something being missed between the diametrically 20 opposed opinions of what the data show. And maybe 21 that could help resolve part of this issue. 22 CHAIRMAN MAISEL: I'm not sure I NEAL R. GROSS COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. (202) 234-4433 WASHINGTON, D.C. 20005-3701 (202) 234-4433 236 1 understand your comment. Can you -- 2 DR. BRINKER: Well, I think the analysis 3 of the same data by the FDA suggests that there's no 4 assurance of efficacy with hypothermia in general. On 5 the other hand, the same data while interpreted by 6 people with expertise in this field suggests that that 7 has been demonstrated to a degree in which no other 8 study is necessary. 9 And the points brought out by the FDA 10 seemed very convincing as to whether this data should 11 stand or not. And I'd like to know maybe they're 12 missing something that these experts have resolved and 13 maybe it would make our job and their job a lot easier 14 to have that kind of interaction. 15 CHAIRMAN MAISEL: I understand your point. 16 Now I think it's an excellent point. I think clearly 17 the bar by which the FDA measures things is different 18 than the international community than the AHA and 19 they're asking different questions and answering 20 different questions. 21 I do think that the proposal, actually, is 22 a good one of having a meeting similar to what has NEAL R. GROSS COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. (202) 234-4433 WASHINGTON, D.C. 20005-3701 (202) 234-4433 237 1 been done with any other topics where representatives 2 of the AHA, ILCOR, industry, the FDA could get 3 together and discuss in an open public forum some of 4 these issues that we've struggled with. 5 DR. YUSTEIN: Dr. Maisel, can I ask just 6 one question? Throughout the discussion today various 7 different control groups were suggested. People 8 suggested endovascular versus surface, endovascular 9 versus normothermia and then also some people have 10 actually even brought up the topic of a three-armed 11 with each of those. 12 Does the Panel feel strongly or suggest 13 one over the other? 14 DR. BROTT: I would just say that, and 15 this is repetition, that I believe that many IRBs 16 would allow a three-arm trial to go forward. And as 17 Dr. Somberg mentioned, and as the sponsor has 18 presented, the NNT for this therapy in some of these 19 trials was suggested to be less than ten. And if 20 that's the case, not only would such a three-arm trial 21 be very persuasive to the FDA, but also the American 22 public and our peers in intensive care units and in NEAL R. GROSS COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. (202) 234-4433 WASHINGTON, D.C. 20005-3701 (202) 234-4433 238 1 cardiology. 2 DR. PAGE: And I'd agree. It would be 3 great to have a three-arm trial. My only concern is 4 whether it can or will be done. 5 The second best would be an active 6 comparator with just the external and internal 7 cooling, I suppose. 8 And somehow fitting in the ongoing 9 question of duration and depth of cooling. And then 10 suddenly the trial gets a little bit bigger, but if we 11 had the three-arm trial, we'd be done already. 12 DR. HALPERIN: But if this would be a 13 three-arm trial and powered enough to show relatively 14 small potential incidences of complications, it's 15 going to be an enormous trial. And you know, an 16 enormous difficult trial of a very lethal disease is 17 going to take a long time. 18 DR. SOMBERG: The FDA is -- well, I should 19 talk for the FDA. I apologize. 20 My study of the subject is that they've 21 never asked to power a trial toxicity. You're 22 powering the trial for the predominant efficacy NEAL R. GROSS COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. (202) 234-4433 WASHINGTON, D.C. 20005-3701 (202) 234-4433 239 1 endpoint. And there's a very potent -- as your 2 research and as people have suggested say. But what 3 you do is at least have a sample size to see if there 4 are any obvious differences. And sometimes surprises 5 come out. 6 So we don't want to see something that 7 comes one in 10,000 or one in 1,000. But you want to 8 see a problem that would come in maybe one in 50. So 9 if there's a host of different problems with the 10 catheter, nothing with topical cooling. And topical 11 cooling is better. That's not necessarily the reasons 12 to withhold approval for the device. But it's 13 something that the general medical community can know 14 about and make risk/benefit decisions. 15 DR. HALPERIN: AHA is very, very 16 enthusiastic about working with the FDA on this as 17 well as other issues. It's actually come from the AHA 18 side as well. 19 Also when AHA reviews stuff, animal data 20 and cellular data can be a major part of that which 21 could in some ways explain some of the differences and 22 points of view on this subject. NEAL R. GROSS COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. (202) 234-4433 WASHINGTON, D.C. 20005-3701 (202) 234-4433 240 1 DR. MARLER: I guess I'd like to add that 2 I think -- I don't know, I'm always a person who wants 3 to rip the bandage off quickly; it hurts less long. 4 I think that by encouraging the sponsor 5 and the community to think that there's some 6 nonrandomized easy way to get around answering the 7 question is to do a disservice to the patients and the 8 community. I think that if you pitch in, get this 9 trial done, that you'll have the answer that you want, 10 particularly if your estimates of the effect of this 11 are accurate or anywhere close to accurate. This is 12 not going to be this large extremely expensive trial 13 that you seem to be imagining. And I don't think 14 you're going to have to convince the community until 15 this actual comparison is made. 16 The three-arm trial, I mean is nice 17 because it tests two different modalities. But I 18 think the basic trial that you may not be able to do 19 in five years, which you still won't have the 20 convincing data to look at if you continue with 21 registries or some nontrial methods. They may become 22 progressively more difficult to perform. But right now NEAL R. GROSS COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. (202) 234-4433 WASHINGTON, D.C. 20005-3701 (202) 234-4433 241 1 I think you have the opportunity to have a randomized 2 controlled trial where you have essentially a placebo 3 arm. 4 CHAIRMAN MAISEL: And can we comment on 5 question (c) the differences in standard of care 6 between the international community and the United 7 States and is U.S. data required? 8 DR. BRINKER: Yes, I think that that's 9 been addressed. I think because of differences in 10 rapidity with which people get resuscitated as well as 11 different forms of up front therapy that's 12 administered to patients, I think U.S. data is 13 necessary for this. 14 CHAIRMAN MAISEL: Norm? 15 DR. KATO: Yes, I would agree with that. 16 I think that the chain of survival parameters can be 17 different. 18 The other advantage of having multiple 19 centers in the United States is pretty obvious. I 20 mean, you get thought-leaders at various institutions 21 trying this device, drug out, whatever it is protocol. 22 If it works great, then you have that many more NEAL R. GROSS COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. (202) 234-4433 WASHINGTON, D.C. 20005-3701 (202) 234-4433 242 1 people on board when you're facing the FDA again. 2 DR. MARLER: I don't think it's easy to 3 generalize about international centers, having just 4 visited the center in Helsinki a couple of weeks ago 5 where the door-to-needle time for acute stroke is 12 6 minutes they're working on right now. 7 I think you could probably include some 8 international centers if you set up criteria. I think 9 you should probably also be sure that -- there may be 10 more variability I'm saying between U.S. centers than 11 there are between high quality U.S. centers and high 12 quality international centers. 13 DR. YUSTEIN: Yes. I think this question 14 wasn't meant to say do all the sites need to be in the 15 U.S., but would U.S. data be required in addition to 16 any international sites. 17 DR. SOMBERG: But it's not really U.S. 18 versus Europe or U.S. versus anyplace else. It's 19 really comparability. 20 DR. YUSTEIN: Right. 21 DR. SOMBERG: And generally speaking 22 there's a very long latency between downtime, NEAL R. GROSS COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. (202) 234-4433 WASHINGTON, D.C. 20005-3701 (202) 234-4433 243 1 resuscitation and resuscitation to intervention. And 2 that may play a role in the efficacy of the therapy. 3 So if you took not good centers of Europe, 4 but bad centers in Europe and good centers potentially 5 given our logistics and all, you may get a better 6 comparability. 7 I'm saying you need some information about 8 the times. And maybe you recommendation might say is 9 that if you resuscitate in such a time and if you're 10 able to cool them in such a -- you know, like tPA, you 11 have a three hour window, you're able to do that 12 fine. But if someone comes to you and the resident 13 gets an idea 24 hours later, let's cool this person. 14 This is totally inappropriate and only doing harm. So 15 I think that's maybe in the labeling. 16 CHAIRMAN MAISEL: Any other Panel 17 comments? 18 Dr. Yustein, any unanswered questions from 19 the FDA questions. 20 DR. YUSTEIN: No. 21 CHAIRMAN MAISEL: Okay. So at this point 22 we'll move on to the open public hearing session for NEAL R. GROSS COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. (202) 234-4433 WASHINGTON, D.C. 20005-3701 (202) 234-4433 244 1 the afternoon. Is there anyone who wishes to address 2 the Panel in the audience. 3 Seeing none, we will close 4 the open public hearing. 5 I'll once again ask Mr. Yustein any other 6 questions from the FDA? 7 DR. YUSTEIN: No. I think the team is 8 satisfied. Thank you. 9 CHAIRMAN MAISEL: Does the sponsor have 10 any additional comments or questions that they would 11 like to address to the Panel? 12 DR. COLLINS: No. 13 CHAIRMAN MAISEL: I'd like to ask Michael 14 Morton, our industry representative to comment. 15 MR. MORTON: Thank you. No comments about 16 the particular sponsor that we've heard from today. 17 But just in general, it's important that the industry 18 and the FDA work together on utilizing the 510(k) 19 process to bring devices to patients. And I certainly 20 appreciate the attention that the Panel has given 21 today and the focus on the 510(k) process, because 22 it's not typical of what this Panel reviews. NEAL R. GROSS COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. (202) 234-4433 WASHINGTON, D.C. 20005-3701 (202) 234-4433 245 1 Also, appreciate the efforts of the 2 sponsor and the fact that there were physicians who 3 traveled trans-Atlantic flights to come here. 4 And also note that the FDA did a very 5 concise and good review today. 6 Thanks. 7 CHAIRMAN MAISEL: Thank you. 8 And I'll ask our consumer rep Linda Mottle 9 to comment, please. 10 MS. MOTTLE: Thank you, Dr. Maisel. 11 I concur that it would be wonderful to 12 have a device that will increase survivability and 13 neurological outcome for this devastating condition. 14 I also concur with various Panel members 15 that we don't quite have the data yet to prove that to 16 us. But I really hope that the sponsor will endeavor 17 to conduct these clinical trials with the input from 18 the FDA and the Panel here today so that we can move 19 forward in this arena. 20 And having worked with IRBs in acute 21 emergency type clinical trials, I don't see it as the 22 impediment that has been presented. And I do think NEAL R. GROSS COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. (202) 234-4433 WASHINGTON, D.C. 20005-3701 (202) 234-4433 246 1 that, hopefully, the FDA will be able to get that 2000 2 ER research guidance revision done soon to facilitate 3 that process. 4 I would also like to see a little bit more 5 instruction in the operational manuals. Coming from 6 a clinician standpoint I saw some inconsistencies in 7 that at one point it says 5-cc irrigation syringe and 8 other 10. I mean, just little inconsistencies like 9 that. And I would hope that the FDA would look that 10 over. 11 Thank you. 12 CHAIRMAN MAISEL: Thank you very much. 13 Are there any other comments from any of 14 the Panel members? John? 15 DR. SOMBERG: I just have one more thing 16 to add, and I'm not sure this is something the FDA or 17 the Panel can fix. But the burden is very high for 18 the sponsor because if they do all these studies we 19 recommend, do everything well, the next sponsor will 20 have a much easier pathway. And therefore, the 21 incentive for them to bear or their role just to be 22 there just a hair ahead of someone else is very NEAL R. GROSS COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. (202) 234-4433 WASHINGTON, D.C. 20005-3701 (202) 234-4433 247 1 difficult. 2 So I think to do a studies like we're 3 recommending, and that's one of the things that I 4 agonized with when I review this, you know, it's not 5 a patent, it's not a unique approach. Cooling, there 6 are many ways to do that, etcetera. So how do you 7 incentivize the process. And I heard that the NIH is 8 working this area has developed these centers. And I 9 think it's most important to try to do something like 10 with advocating piggyback on a larger project in some 11 way. Because I do not think that all in the meetings 12 that the FDA has with this sponsor, would be able to 13 overcome some of these problems of the lack of 14 incentive to do the proper pathway to get a whole 15 series of which devices, only one of which the sponsor 16 has renumeration from. 17 It's a real conundrum. 18 CHAIRMAN MAISEL: Additional comments? 19 DR. YUSTEIN: Dr. Maisel, before you close 20 out, I just wanted to thank all the Panel members for 21 assembling today on relatively short notice. Usually 22 this is much shorter than our usual pre-panel NEAL R. GROSS COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. (202) 234-4433 WASHINGTON, D.C. 20005-3701 (202) 234-4433 248 1 preparation. 2 And also Dr. Blumenstein for being able to 3 fill in for our statisticians on a very very short 4 notice. We appreciate that. 5 CHAIRMAN MAISEL: Does the sponsor have 6 any final comments? 7 Okay. This concludes the -- oh, I'm 8 sorry. Go ahead. 9 DR. COLLINS: Just to say thank you. 10 CHAIRMAN MAISEL: You're welcome. 11 This concludes the recommendations of the 12 Panel regarding the Alsius Corporation CoolGard 3000 13 Icy Catheter System K040429. 14 We are adjourned. 15 (Whereupon, at 2:33 p.m. the meeting was 16 adjourned.) 17 18 19 20 NEAL R. GROSS COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. (202) 234-4433 WASHINGTON, D.C. 20005-3701 (202) 234-4433