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  • 1. 1 1 1 U.S. FOOD AND DRUG ADMINISTRATION 2 CENTER FOR DEVICES AND RADIOLOGICAL HEALTH 3 MEDICAL DEVICES ADVISORY COMMITTEE 4 5 + + + + 6 7 GASTROENTEROLOGY AND UROLOGY DEVICES PANEL 8 9 + + + + 10 11 WEDNESDAY, 12 JUNE 8, 2005 13 14 15 The Panel in the Walker/Whetstone Room of 16 the Holiday Inn Gaithersburg, 2 Montgomery Village 17 Avenue, Gaithersburg, Maryland at 9:00 a.m., MARK A. 18 TALAMINI, M.D., Chair, presiding. 19 20 PRESENT: 21 22 MARK A. TALAMINI, M.D. Chair 23 ABDELMONEM AFIFI, Ph.D. Voting Member 24 GEORGE R. ARANOFF, M.D. Voting Member 25 CHRISTOPHER BLAGG, M.D. Consultant 26 WILLIAM DUFFELL, JR., Ph.D. Industry Representative 27 CHRISTOPHER HOY, M.D. Consultant 28 RICHARD GIBSON, M.D., M.P.H. Consultant 29 ROBERT GILLESPIE, M.D. Consultant 30 SUSAN J. KALOTA, M.D. Voting Member 31 ROBERT LOCKRIDGE, JR., M.D. Consultant 32 CHRISTINE MOORE Consumer Representative 33 JOHN MORAN, M.D. Consultant 34 JOHN SADLER, M.D. Consultant 35 GERALD SCHULMAN, M.D., FASN Consultant 36 MATT WEINGER, M.D. Consultant 37 38 NANCY C. BROGDON, Director, Division of 39 Reproductive, Abdominal, and Radiological 40 Devices 41 JEFFREY W. COOPER, DVM, Executive Secretary 42 2 3 NEAL R. GROSS 4 COURT REPORTERS AND TRANSCRIBERS 5 1323 RHODE ISLAND AVE., N.W. 6 (202) 234-4433 WASHINGTON, D.C. 20005-3701 www.nealrgross.com
  • 2. 1 1 1 FDA PRESENTERS: 2 3 SUSAN S. ALTAIE, Ph.D. 4 Scientific Policy Advisor, OIVD/CDRH 5 6 SUSAN GARDNER, Ph.D. 7 Director, OSB/CDRH 8 9 CAROLYN Y. NEULAND, Ph.D. 10 Branch Chief, GRDB/DRARD/ODE/CDRH 11 12 JOSHUA C. NIPPER, M.E. 13 Biomedical Engineer, GRDB/DRARD/ODE/CDRH 14 15 MICHAEL MENDELSON, D.D.S., M.S. 16 Biomedical Engineer, Director Health Promotion 17 Officer, Human Factors Science and Engineering 18 Branch 19 20 CLAUDIA C. RUIZ-ZACHAREK, M.D. 21 Medical Officer/Nephrologist, GRDB/DRARD/ODE/CDRH 22 23 24 PUBLIC SPEAKERS: 25 26 ROD KENLEY 27 Aksys, Ltd. 2 3 NEAL R. GROSS 4 COURT REPORTERS AND TRANSCRIBERS 5 1323 RHODE ISLAND AVE., N.W. 6 (202) 234-4433 WASHINGTON, D.C. 20005-3701 www.nealrgross.com
  • 3. 1 1 1 I-N-D-E-X 2 3 AGENDA ITEM: PAGE 4 5 CALL TO ORDER: 4 6 7 Introductions 4 8 9 FDA's Critical Path Initiatives, presentation 12 10 Susan S. Altaie, P.D., Scientific Policy 11 Adviser, Office of In Vitro Diagnostic 12 Device Evaluation and Safety 13 14 Post Market Study Design 19 15 Susan Gardner, Ph.D., Office of Surveillance 16 and Biometrics 17 18 OPEN PUBLIC HEARING: 32 19 20 OPEN COMMITTEE DISCUSSION: 33 21 22 1. Regulatory Briefing - 34 23 Carolyn Neuland, Ph.D., Branch Chief of 24 the Gastro-Renal Devices Branch 25 26 2. Overview of Conventional Hemodialysis 47 27 Systems - Josh Nipper, M.E. 28 29 3. Human Factors - Mike Mendelson, D.D.S., 61 30 M.S., Biomed Eng 31 32 4. FDA Presentation - Claudia Ruiz. M-D., 80 33 Nephrologist 34 35 5. Questions for the Panel 103 36 37 OPEN PUBLIC HEARING: 309 38 39 7. Final Comments 322 2 3 NEAL R. GROSS 4 COURT REPORTERS AND TRANSCRIBERS 5 1323 RHODE ISLAND AVE., N.W. 6 (202) 234-4433 WASHINGTON, D.C. 20005-3701 www.nealrgross.com
  • 4. 1 P-R-O-C-E-E-D-I-N-G-S 2 (9:04 a.m.) 3 CALL TO ORDER 4 CHAIRPERSON TALAMINI: I would like to 5 call to order this meeting of the Gastroenterology and 6 Urology Devices Panel. 7 My name is Dr. Mark Talamini. I am the 8 chairperson of the Gastroenterology and Urology 9 Devices Panel. I am currently professor of surgery at 10 the Johns Hopkins University School of Medicine and 11 Director of Minimally Invasive Surgery there. 12 If you haven't already done so, I would 13 request that everyone in attendance at this meeting 14 sign in on the attendance sheet that is available on 15 the table outside the door. 16 At this time I would like each panel 17 member at the table to introduce him or herself, state 18 your specialty, position title, institution 19 affiliation, and status on the panel. And we'll start 20 over here on the right. 21 INTRODUCTIONS 22 MS. BROGDON: Good morning. I'm Nancy 23 Brogdon. I'm not a member of the panel. I'm the 24 director of FDA's Division of Reproductive, Abdominal,
  • 5. 1 and Radiological Devices. 2 DR. HOY: Chris Hoy, a clinical 3 nephrologist from upstate New York affiliated with the 4 Rubin Dialysis Center. And we have a nocturnal 5 program for seven years. I'm a consultant. 6 DR. LOCKRIDGE: Bob Lockridge. I'm a 7 clinical nephrologist from Lynchburg, Virginia. I 8 started the first nightly program in Lynchburg in '97. 9 I've trained over 57 patients and have over 159 hours 10 of experience in nocturnal patient care years. 11 DR. MORAN: I'm John Moran. I'm a 12 clinical nephrologist. I'm chief scientific officer 13 at Satellite Health Care in northern California and 14 consulting professor at Stanford University School of 15 Medicine. I'm also a panel member. 16 DR. BLAGG: Chris Blagg. I'm emeritus 17 executive director of the Northwest Kidney Center in 18 Seattle and professor of medicine emeritus, University 19 of Washington. And I've been involved with home 20 dialysis and nocturnal dialysis for more years than I 21 like to think. I'm a consultant. 22 DR. GILLESPIE: I am Robert Gillespie. 23 I'm a pediatric nephrologist from Corpus Christi, 24 Texas. I'm affiliated with Driscoll Children's
  • 6. 1 Hospital as well as an assistant professor of 2 pediatrics at Texas A&M University. 3 DR. WEINGER: Matt Weinger. I'm a 4 professor of anesthesiology, biomedical informatics, 5 and medical education at Vanderbilt University. And 6 my area of expertise is in human factors engineering 7 and patient safety. And I'm a consultant. 8 DR. GIBSON: Richard Gibson, adult 9 nephrology and psychiatry, Tulane University, 10 consultant. 11 DR. COOPER: My name is Jeff Cooper. I'm 12 the executive secretary of the panel and a veterinary 13 medical officer at FDA. 14 DR. KALOTA: I'm Susan Kalota, a private 15 practice urologist in Tucson, Arizona, panel member. 16 DR. ARANOFF: I'm George Aranoff. I'm 17 chief of the Nephrology Section and professor at the 18 University of Louisville. And I'm a consultant. 19 DR. AFIFI: I'm Abdelmonem Afifi. I'm 20 professor of biostatistics and former Dean of the 21 School of Public Health at UCLA. I'm a 22 biostatistician. I'm a panel member. 23 DR. SADLER: I'm John Sadler. I'm a 24 clinical nephrologist from Baltimore, former head of
  • 7. 1 nephrology at the University of Maryland. I've been 2 involved in dialysis for more than 40 years now and 3 formerly had the privilege of chairing this panel. 4 DR. SCHULMAN: I'm Gerald Schulman. I'm a 5 professor of medicine at Vanderbilt University. I'm 6 the director of hemodialysis for the hospital. And 7 I'm a consultant. 8 DR. DUFFELL: I'm Bill Duffell. I'm an 9 industry rep for this panel. My graduate studies were 10 in sciences and pharmacology. 11 MS. MOORE: I'm Christine Moore, retired 12 executive assistant and dean of students at the 13 Baltimore City Community College, consumer rep. 14 CHAIRPERSON TALAMINI: Thank you very 15 much. 16 I'll now turn the meeting over to the 17 executive secretary, Dr. Jeff Cooper, who would like 18 to make some introductory remarks. 19 DR. COOPER: Good morning. I will now 20 read the record of the conflict of interest statement. 21 "The following announcement addresses conflict of 22 interest issues associated with this meeting and is 23 made a part of the record to preclude even the 24 appearance of an impropriety.
  • 8. 1 "To determine if any conflict existed, the 2 agency reviewed the submitted agenda for this meeting 3 and all financial interests reported by the committee 4 participants. 5 "The conflict of interest statutes 6 prohibit special government employees from 7 participating in matters that could affect their or 8 their employers' financial interests. However, the 9 agency has determined that participation of certain 10 members and consultants, the need for whose services 11 outweighs the potential conflict of interest involved, 12 is in the best interest of the government. 13 "Waivers have been granted for Drs. 14 Christopher Blagg and John Moran for their interests 15 in firms that could be impacted by the panel's 16 deliberation. Copies of these waivers may be obtained 17 from the agency's Freedom of Information Office, room 18 12A15 of the Parklawn Building. 19 "We would like to note for the record that 20 the agency took into consideration certain matters 21 regarding Drs. John Sadler and Gerald Schulman. Each 22 of these panelists reported current and/or past 23 interests in the firms at issue but in matters not 24 related to today's agenda. The agency has determined,
  • 9. 1 therefore, that they may participate fully in today's 2 deliberations. 3 "We would also like to note for the record 4 that the agency took into consideration other matters 5 regarding Drs. Robert Lockridge, Blagg, and Sadler. 6 The panelists reported current and/or past interests 7 in firms at issue in matters related to today's 8 discussion. Since the agenda item for this session 9 involves only particular matters of general 10 applicability, the agency has determined that these 11 panelists may participate fully in the discussion. 12 "In the event that the discussions involve 13 any other products or firms not already on the agenda 14 for which an FDA participant has a financial interest, 15 the participant should excuse him or her self from 16 such involvement. And the exclusion will be noted for 17 the record. 18 "With respect to all other participants, 19 we ask in the interest of fairness that all persons 20 making statements or presentations disclose any 21 current or previous financial involvement with any 22 firm whose products they may wish to comment upon. 23 "The FDA seeks communication with industry 24 and the clinical community in a number of different
  • 10. 1 ways. First, FDA welcomes and encourages pre-meetings 2 with sponsors prior to all IDE and PMA submissions. 3 This affords the sponsor an opportunity to discuss 4 issues that could impact the review process. 5 "Second, the FDA communicates through the 6 use of guidance documents. Toward this end, FDA 7 develops two types of guidance documents for 8 manufacturers to follow in submitting a pre-market 9 application. One type is simply a summary of the 10 information that has historically been requested on 11 devices that are well-understood in order to determine 12 substantial equivalence. The second type of guidance 13 document is one that develops as we learn about new 14 technology. FDA welcomes and encourages the panel and 15 industry to provide comments concerning our guidance 16 documents. 17 "I would also like to remind you that the 18 tentative date for the last 2005 Gastroenterology and 19 Urology Devices Panel meetings is scheduled for 20 Friday, October 21st, 2005. You may wish to pencil in 21 these dates on your calendars, but please recognize 22 that this date is tentative at this time. 23 "On another note, information on 24 purchasing transcripts or videos of today's meeting
  • 11. 1 can be found on the registration table, which is 2 outside of the meeting room." 3 Before I turn the meeting back to Dr. 4 Talamini, please ensure that all cell phones are 5 either turned off or placed in the silent ring mode so 6 that they do not interrupt the business of the 7 meeting. 8 Dr. Talamini will now continue. 9 CHAIRPERSON TALAMINI: Thank you, Dr. 10 Cooper. 11 Dr. Susan Altaie of the Office of In Vitro 12 Diagnostic Devices will now give a presentation to the 13 panel regarding the agency's critical path 14 initiatives. Dr. Altaie? 15 DR. ALTAIE: Thank you and good morning. 16 FDA'S CRITICAL PATH INITIATIVES, PRESENTATION 17 DR. ALTAIE: I am the focal point for 18 Center for Devices under the critical path umbrella. 19 And in my daytime job, I am Scientific Policy Adviser 20 for the Office of In Vitro Diagnostics. 21 Today I will talk to you about what the 22 critical path is, why is this an FDA initiative, and 23 what are the critical path tools that we speak about, 24 what projects we are pursuing at CDRH, and how you can
  • 12. 1 get involved as an interested individual. And then we 2 can answer questions if you have any. 3 Critical path is a serious attempt to 4 modernize the medical products' critical path and 5 market product development to make it more predictable 6 and less costly. 7 If you look at the critical path for 8 device developments, you are looking at basic research 9 prototyping, preclinical, and clinical development, 10 and then hopefully FDA application and large 11 production scales. 12 Well, critical path will cover everything 13 in that life cycle of development except for the basic 14 research. So one might think why FDA gets involved in 15 such a path. It's an industry job to develop. 16 Well, because FDA believes in tremendous 17 benefit of bringing innovative products to the public 18 faster. We also have a unique perspective and 19 understanding of product development. And we see the 20 failures, the successes, and the missed opportunities. 21 And because critical path will help us develop 22 guidances and standards that foster innovation and 23 improve chances of success in the device development. 24 We like to work together with companies
  • 13. 1 and patient groups and academic researchers and other 2 stakeholders to modernize and develop and disseminate 3 tools that will help remove the science hurdles that 4 affect product development. 5 I spoke about tools on the critical path. 6 These are methods and techniques that work in three 7 dimensions of safety, efficacy, and industrialization 8 of the devices. 9 Under safety tools, those are the tools 10 that will predict if potential products will be 11 harmful. And the efficacy tools will determine if a 12 potential product will have medical benefit and 13 industrialization tools. Those will deal with how to 14 manufacture a product at a commercial scale with 15 consistently high quality. 16 So these tools that I describe in three 17 dimensions, these are examples of them. Biomarkers 18 can be one of them by Bayesian statistics, animal 19 models of biomarkers, clinical trial design tools and 20 computer simulations, quality assessment, protocols, 21 and post-market reporting. And we are also open to 22 any suggestions any of you have to add to this list of 23 tools to follow up and ease up the device development. 24 At the CDRH, we deal with an array of
  • 14. 1 devices, anywhere from Band-Aids to stethoscopes to 2 CAT scans and heart valves and infusion pumps and 3 glucose monitoring devices. Everything that you can 4 think of medically are regulated under CDRH. And so 5 there is a tremendous opportunity for developing tools 6 to get these devices faster to the market. 7 However, I want to note that we at CDRH 8 deal with devices that are totally different than the 9 drugs dealt with in CDER. Even though we parallel in 10 paradigm, the paradigms are different. We deal with 11 complex components of the devices, and we deal with 12 biocompatibility. 13 We have to have equipment that is durable 14 and they long-last. And then we also deal with 15 devices that have rapid cycle and turnover to the 16 better model. We deal with malfunctions of 17 instrumentation and user errors. And we study them by 18 actually bench testing them. 19 Our regulations are different. We deal 20 with quality systems in ISO 9000, which is parallel 21 but different than the GMPs that CDER deals with. 22 These are also areas of interest under the 23 three dimensions that I spoke with you about. The 24 safety tools we are dealing with biocompatibility
  • 15. 1 databases, effects of products on disease or injured 2 tissue. When you look at the effectiveness tools, you 3 are talking about surrogate endpoints of 4 cardiovascular device trials, and you're talking about 5 computers simulating modeling of the implanted 6 devices. 7 Under the mass production, we are looking 8 at the practice guidelines for follow-up of implanted 9 devices. We are also looking at validated training 10 tools for devices with known learning curves by the 11 users. 12 These are a few examples of critical path 13 projects that we're pursuing in CDRH. Most of these 14 are not funded. And we're trying to leverage funding 15 from outside stakeholders, whether it's industry or 16 academia or government, other government agencies. 17 We are looking at developing a serum panel 18 to assess sensitivity and specificity of the hepatitis 19 assays. We are looking at computer models of human 20 physiology to test and predict failures of peripheral 21 vascular stents before going into animals or human. 22 We are looking at a clear regulatory path 23 for intrapartum fetal diagnostic devices. We are 24 looking for consensus from a safety community. And
  • 16. 1 under the surrogate markers, we are looking for 2 pathways of statistical validations of these markers. 3 We are looking for development to develop 4 practice guidelines for appropriate monitoring of 5 permanently implemented devices. And we also are 6 looking for knowing the extent of the neurotoxicity 7 testing that is required in the tissue contacting, 8 neural tissue contacting, materials. 9 So, as I said, these are the projects we 10 have picked up with not having funding, but all of 11 these projects are in some steps of development and 12 progress. If you are interested, you can participate 13 in two ways. You could give your views and comments 14 through the open public docket and tell us about areas 15 that benefit from research and development of critical 16 path evaluative tools. 17 You also can help us compile this national 18 critical path opportunities list in the areas that we 19 have missed probably. And there are ways to contact 20 us. You could go on the CDRH Web page under "News and 21 Events," and you can go to the links to the critical 22 path white paper. And then there are links for the 23 docket and the critical path group that you could 24 contact if you have any ideas.
  • 17. 1 I would like to leave you with this 2 thought that at CDRH, we work to ensure the health of 3 the public throughout the total product life cycle of 4 the products. And we believe it is everyone's 5 business. So I request your involvement in critical 6 path. 7 Any questions? 8 (No response.) 9 DR. ALTAIE: All right. Thank you. 10 CHAIRPERSON TALAMINI: Thank you, Dr. 11 Altaie. 12 I need to remind all of the panel members 13 and speakers to talk directly into the microphone when 14 you talk for the transcriptionist's benefit. If they 15 don't hear you, it's like you haven't said it. Are 16 you the transcriptionist over there? Is that person 17 in the room? So if you aren't getting something, 18 raise your hand. And I'll make sure that we have 19 people speak clearly. 20 Next, Dr. Susan Gardner of the Office of 21 Surveillance and Biometrics will give a presentation 22 to the panel regarding the role of OSB in the review 23 of post-market study designs. Dr. Gardner? 24 DR. GARDNER: Thank you and good morning.
  • 18. 1 POST MARKET STUDY DESIGN 2 DR. GARDNER: I am going to spend a few 3 minutes this morning telling you about an important 4 programmatic change in CDRH and how that might impact 5 you as panel members. 6 First of all, the basis of the change is 7 the move of the conditions of approval program from 8 the Office of Device Evaluation, ODE, to the Office of 9 Surveillance and Biometrics, which is the office which 10 I'm the director of. 11 Briefly, what we do in OSB is we are 12 involved in pre-market review by virtue of the fact 13 that we have the statisticians in OSB who are almost 14 always involved in PMAs, and we also have the 15 epidemiologists in the office, who increasingly are 16 going to be involved in the PMA review process. 17 We are responsible for adverse event 18 signal detection. Again, we have the post-market 19 monitoring tools in the office, including our medical 20 device reporting program, our Medsun program, and 21 other surveillance tools. 22 We are responsible for risk 23 characterization. By that I mean the analysis of the 24 post-market data and coordination of the center
  • 19. 1 response for health care professionals when we see a 2 post-market problem and we have a solution to get to. 3 We are also responsible for interpreting the medical 4 device regulation. 5 For condition of approval studies, the 6 regulation tells us that in 21 CFR 814, post-approval 7 requirements can include continuing evaluation and 8 periodic reporting on the safety, effectiveness, and 9 reliability of the device for its intended use. 10 Again, this is the basis for a condition of approval 11 studies program. 12 So the impetus for change came from an 13 internal study that we did a couple of years ago. We 14 looked at all of the PMAs that were approved from 1998 15 to the year 2000. There were 127 PMAs. Forty-five of 16 those were approved with condition of approval study 17 orders. 18 So we went back. Actually, the initial 19 effort was to go back and look at the quality of the 20 condition of approval studies, but we ran into a 21 problem because we actually couldn't locate a lot of 22 these studies. It was a real red flag for us. 23 We found out that we had very limited 24 procedures for tracking the progress and results of
  • 20. 1 these studies. There was no automated tracking system 2 or even manual tracking system in many cases. 3 We also found, as you might expect, that 4 many of the lead reviewers for these PMAs had moved on 5 to other jobs, either in the agency in a different 6 division or outside the agency. 7 Finally, the folks in the pre-market, 8 particularly towards the end of an approval process, 9 are really heads down in improving the product, doing 10 the labeling, and all of the other things they need to 11 do to get the product out the door. And they really 12 lack the resources to focus on the condition of 13 approval study. 14 So we have a strategy for change. And 15 obviously the goal of the change is to obtain what is 16 really critical post-market information as the device 17 moves onto the market and to continue to assure the 18 safety and effectiveness of the device. And the 19 important words, of course, are "in real world use." 20 The device is moving from the tightly 21 controlled clinical trials into community use. And so 22 it's really a critical time to know what is going on 23 if we have post-market questions. 24 We want to be able at that point to better
  • 21. 1 characterize the risk-benefit profile of the device 2 and, of course, to add to our scientific database so 3 we can make better decisions. 4 So what did we do? Starting in January of 5 this year, we transferred the condition of approval 6 program to OSB, although I will say this was done 7 after a two-year pilot, where we tested some of the 8 procedures that I am going to tell you about. 9 We have developed and instituted and is 10 now up and running an automated tracking system. So 11 we're going to be able to acknowledge the receipt of 12 study reports and do follow-up of reports if they're 13 not received. 14 We have also added an epidemiologist to 15 the PMA review team when it appears that there is 16 probably going to be a condition of approval study. 17 The task of the epidemiologist is, first of all, to 18 think post-market during the pre-approval process. 19 So during the approval process, their task 20 with developing a post-market monitoring plan, it may 21 or may not include a condition of approval study, but, 22 as I say, sort of when we think there is going to be 23 one, that is when we will have the epidemiologist on 24 the team from the beginning.
  • 22. 1 The epidemiologist will take the lead in 2 developing. And, again, some key words here are 3 "well-formulated post-market questions," important 4 questions. They are going to have the lead in the 5 design of the condition of approval study protocol. 6 And they are going to be responsible for 7 evaluating the study progress and the results of the 8 study once the product is approved. They will 9 continue to work with the PMA team throughout this 10 process. It's just a matter of adding their expertise 11 to the team and changing the lead as the product goes 12 to market. 13 Why do we think these changes will improve 14 the program? Well, first of all, the development of 15 important post-market questions and a good study 16 design should be motivation both for FDA and for 17 industry to get these studies done. 18 We're certainly willing to discuss the 19 design of the studies throughout the conduct of the 20 studies. And if something changes while the product 21 is on the market, we are willing to make those 22 adjustments. Again, it's time, money, and resources. 23 And it's important that we answer the important 24 questions.
  • 23. 1 Second of all, we're committed to 2 acknowledging these studies when they come in to CDRH 3 and giving feedback on the studies. And, again, this 4 is added motivation, both for the agency and for 5 industry to get these studies done. 6 We will have a Web site, where we will 7 post the status of the studies. So for folks who are 8 doing them well, that will show up. And if folks 9 aren't doing them well, that will also be on our Web 10 site. And we do have the ability to mandate a 11 post-market study or order a post-market study if 12 these studies are not being done. 13 So what is the impact on the advisory 14 panel? Post-market questions come up often naturally 15 during the discussion of products as you are looking 16 at them for approval. And sometimes we are going to 17 have them come up intentionally or pose post-market 18 questions during the process. And we are going to 19 look to you. We want your advice, your suggestions on 20 possible approaches and any help that you can give us 21 in thinking about what the post-market strategy might 22 be. 23 During the post-market period, we're 24 committed to having either FDA or industry come back
  • 24. 1 to the panel and give you an update on the progress 2 and results of the condition of approval studies for 3 the approved devices. 4 Thanks. Do you have any questions? Yes? 5 DR. DUFFELL: Will OSB be managing 6 registries as well as post-market surveillance? 7 DR. GARDNER: Yes. The condition of 8 approval studies could have many possible designs. 9 And a registry is certainly one design that could be 10 part of the study. It would be managed somewhere 11 else, but we would be part of looking at the data and 12 doing the analysis. 13 Yes? 14 DR. MORAN: Would it be fair to say that 15 this might expedite the approval process if there are 16 issues that you feel you can deal with after approval, 17 after marketing? 18 DR. GARDNER: Well, certainly the 19 pre-market requirements for safety and effectiveness 20 don't change. But I think, again, thinking hard about 21 what our post-approval questions are, thinking about 22 what a good post-approval study design could be and 23 how we could answer those questions are just going to 24 make us all feel more comfortable with the product.
  • 25. 1 And knowing, again, that these studies are going to be 2 done I think, again, will add to our comfort level. 3 CHAIRPERSON TALAMINI: Dr. Gardner, do you 4 know exactly -- this is Talamini here -- what 5 percentage of post-market studies were completed out 6 of that number? 7 DR. GARDNER: Well, I don't. We had a 8 number that we were using because it was the number 9 that we could find and the ones that were not 10 accounted for. 11 What we did not do was to go back to 12 industry and call them up and say, you know, "We don't 13 have your post-market study. Did you do it or did you 14 not?" It's not a place we would have liked to have 15 been, but just because for resource issues, we made 16 the decision to move forward, rather than to go back. 17 The products, again, were approved between 18 1998 and 2000. So if the studies weren't done, these 19 were products that we had been looking at for a number 20 of years. So it wasn't clear, again, sort of a 21 resource issue, that going backwards would have been 22 as beneficial as going forward in this case. 23 CHAIRPERSON TALAMINI: Any other questions 24 for Dr. Gardner? Yes?
  • 26. 1 DR. AFIFI: I appreciate the increased 2 role for an epidemiologist in post-market studies 3 because of their expertise in data collection and so 4 on. My question is regarding the analysis. How will 5 that be coordinated between the epidemiologist and the 6 statisticians? 7 DR. GARDNER: Well, mostly the analysis 8 should be done by the companies. What they send us is 9 a report, similar to what is sort of done now. 10 They're conducting the study. They should collect the 11 data. They should do the analysis. 12 The data will come in to us. We will 13 review it. If we have any questions, we get to go 14 back to the company and ask them to provide additional 15 information. But the epi person will take the lead in 16 doing the analysis, but they will share this with 17 people who were members of the PMA approval team. So 18 that they will also have input into the condition of 19 approval study. 20 DR. SADLER: You said these things will be 21 posted on the Web site. And obviously a good posting 22 will be the carrot for the company -- 23 DR. GARDNER: Yes. 24 DR. SADLER: -- to encourage them to get
  • 27. 1 the studies done, for which I am very happy to hear. 2 You also said that there might be penalties and other 3 studies if they were not completed. Could you go a 4 little further on the penalties? Who would design 5 subsequent post-marketing studies? 6 DR. GARDNER: Yes. We have a regulation. 7 Well, actually, the law says that we are allowed to 8 impose post-market studies for various reasons. And 9 essentially the easy way to say it is if we have a 10 major post-market question, then we think that there 11 might be a danger to the people using the device. 12 So if we have a well-formulated 13 post-market question for the condition of approval 14 studies that has not been answered, that will 15 translate very well into this requirement that we have 16 to do this post-market study. It's called section 17 522. 18 So when we do this, we go to the company. 19 And we tell them what our question is. It is their 20 job to go back and design a study and come back to us 21 and say, "This is what we are proposing." 22 Now, if we have gotten to this point with 23 the company, obviously we're running into a lot of 24 problems. But at that point if they are still not
  • 28. 1 doing it, we can impose civil money penalties and the 2 product can be labeled as misbranded. 3 DR. SADLER: Okay. Would you expect to 4 consult with the advisory panel members or with some 5 of them in reviewing these subsequent studies? 6 DR. GARDNER: I think it is entirely 7 possible. I mean, we have an appeals process. And, 8 again, if we are sort of to the point where we are 9 ordering a secondary study because the condition of 10 approval study hasn't been done, there's a message 11 here about some real conflict between industry and 12 FDA. 13 So we would go up through the appeal 14 process. That would also include perhaps going to our 15 dispute resolution panel if the company asked to do 16 that. So we would go through all of those mechanisms 17 as we sort of wind our way there. 18 Again, we're hoping that input from the 19 panel if the product is approved, working hard on 20 designing the studies well, whatever, can avoid those 21 kinds of issues. 22 CHAIRPERSON TALAMINI: Any other questions 23 for Dr. Gardner? 24 (No response.)
  • 29. 1 CHAIRPERSON TALAMINI: If not, thank you 2 very much. 3 DR. GARDNER: Thank you. 4 OPEN PUBLIC HEARING 5 CHAIRPERSON TALAMINI: We will now proceed 6 with the first of the two half-hour open public 7 hearing sessions of this meeting. The second 8 half-hour open public hearing session will follow the 9 panel discussion this afternoon. 10 At these times, public attendees are given 11 an opportunity to address the panel, to present data 12 or views relevant to the panel's activities. 13 I would like to remind public observers at 14 this meeting that while this portion of the meeting is 15 open to public observation, public attendees may not 16 participate except at the specific request of the 17 chair. 18 I would ask when persons address the panel 19 now or later, they come forward to the microphone and 20 speak clearly as the transcriptionist is dependent on 21 this means for providing an accurate transcription. 22 If you have a hard copy of your talk 23 available, please provide it to the executive 24 secretary for use by the transcriptionist to help
  • 30. 1 provide an accurate record of the proceedings. 2 No individual has given advance notice of 3 wishing to address the panel this morning. If there 4 is anyone now wishing to address the panel, please 5 identify yourself at this time. Do we have anybody in 6 the audience? 7 (No response.) 8 CHAIRPERSON TALAMINI: It does not appear 9 that we do. Okay. 10 OPEN COMMITTEE DISCUSSION 11 CHAIRPERSON TALAMINI: Since there are no 12 public comments this morning, we will proceed to the 13 open committee discussion. We will start with the 14 FDA's presentation on nocturnal home hemodialysis. 15 The first speaker for the FDA is Dr. Carolyn Neuland. 16 1. REGULATORY BRIEFING 17 DR. NEULAND: Good morning. Thank you, 18 Dr. Talamini. 19 As Dr. Talamini has said, I am the Branch 20 Chief of the Gastroenterology and Renal Devices 21 Branch. And this is the branch within FDA that is 22 responsible for reviewing medical devices for 23 hemodialysis products, which is the main topic of 24 today's session.
  • 31. 1 I would also like to take this opportunity 2 to welcome each of you to the session today and thank 3 you again for taking time out of your busy schedules 4 to share with us your clinical experience and your 5 scientific knowledge in the area of home nocturnal 6 dialysis. 7 Before we get into the in-depth 8 discussion, I would like to cover a few 9 introductory-type issues. The first thing I would 10 like to do is introduce the members of the 11 Gastroenterology and Renal Devices Branch who are 12 present today. These are individuals who review the 13 medical devices related to hemodialysis. 14 I will then discuss with you very briefly 15 an update on the advisory panel that occurred in 16 January 2003 and let you know the outcome of that 17 deliberation that you had at that time. 18 I will then go into the regulation of 19 hemodialysis devices very briefly. I know you covered 20 this last night in your training, but I will just 21 touch upon how we review hemodialysis products in 22 general. And then I will discuss the guidance 23 documents for hemodialysis that currently have been 24 written.
  • 32. 1 Finally, I will give you a working 2 definition today of nocturnal home hemodialysis that 3 you can work from and then bring forth the main 4 meeting objectives for today's meeting. 5 Okay. I am going to announce the members 6 of the Gastroenterology and Renal Devices Branch that 7 are present. If they would please identify themselves 8 when I mention your name? We have present Linda Carr, 9 who was our consumer safety technician, who prepared 10 all of our slides today. I guess Linda hasn't shown 11 up yet. 12 Dr. Jeffrey Cooper, who is our panel 13 executive secretary, sitting at the head table; Linda 14 Dart, who is a biochemist in our group, who reviews 15 dialysis products; Gema Gonzalez, a biomedical 16 engineer, who is very active in the review of our 17 dialysis product; Dr. Irada Isayeva, who is a polymer 18 chemist in our group; Dr. Kristina Lauritsen, who is a 19 biologist; Barbara McCool, our nurse consultant, very 20 active in dialysis; Joshua Nipper, our biomedical 21 engineer. And you will be hearing from Joshua Nipper 22 shortly, who is going to give you an overview of 23 conventional dialysis equipment. 24 Kathleen Olvey, a biologist in our group;
  • 33. 1 Dr. Claudia Ruiz-Zacharek. Dr. Ruiz is going to give 2 the clinical presentation today on our issues related 3 to nocturnal home hemodialysis. 4 Rebecca Stephenson, a chemical engineer in 5 our group. She is the youngest person in our group 6 and the newest to join FDA. Kellie Straughn, our 7 clerk-typist; and then Mr. Richard Williams, a 8 mechanical engineer in our group. I'm sure many of 9 you have talked to these individuals over the history 10 of reviewing these products. Okay. 11 One of the requirements for the advisory 12 panel process is to ensure that the advisory panel 13 members receive adequate follow-up and feedback on the 14 outcome and the status of previous products that have 15 been brought before this advisory panel. Therefore, I 16 will take the next couple of minutes to update you on 17 the status of the PMA that was brought before the 18 advisory panel in 2003, the last session of this 19 group. 20 This device is what's called the Enteryx 21 procedure kit. It is marketed currently by Boston 22 Scientific Corporation. This device is a solution 23 which is injected into the lower esophageal sphincter 24 for the treatment of gastroesophageal reflux disease
  • 34. 1 in patients who currently are responsive to 2 pharmacological therapy. 3 This product, this PMA product, came 4 before the advisory panel in January 17th, 2003. And 5 the recommendation at that time was for approval with 6 conditions. The conditions were related to 7 modifications to the physician labeling; modifications 8 to the patient labeling; and for a post-market study, 9 as you just heard. That was one of the primary 10 recommendations. And the study was to occur for three 11 years post the last injection of the material. 12 Well, I am happy to say we did approve the 13 PMA following that recommendation. It was approved on 14 April 22nd, 2003. A post-approval study was a 15 requirement of the conditions of approval. It was a 16 three-year post-approval study, which required the 17 enrollment of up to 300 patients, some of which were 18 patients that had already been in the initial study 19 and were going to be followed out to three years. 20 Others were new patients that were going to be 21 enrolled. The 300 patients were required. 22 We also were interested in looking at 23 reinjection of the material in that study. And I am 24 also happy to say that study is actively ongoing. We
  • 35. 1 receive annual reports from them. The study is not 2 completed yet because it was only approved in 2003, 3 but the study is actively ongoing. 4 Now, I just wanted to mention briefly that 5 there have been a few MDR reports that have come out 6 on this device which have shown adverse events related 7 to the transmural injection of the Enteryx material 8 from improper implantation techniques. This is 9 typically physician related in how they are injecting 10 the material. 11 This transmural injection has resulted in 12 the placement of the Enteryx material into the aorta, 13 the media steinum, or into the plural space in a few 14 patients. In one example, the material may have 15 through the aorta through a branch of the right renal 16 artery. 17 In addition, one patient who had 18 inadvertent transmural injection into the wall of the 19 aorta developed an aorta or anterial fistula, which 20 that patient then, unfortunately, succumbed to 21 bleeding and passed away. 22 As a result of these types of adverse 23 events, again, I wanted to emphasize this is 24 physician-related. It is a technique that is
  • 36. 1 occurring. It was determined that we needed to have 2 some additional labeling changes to the PMA. And the 3 company has worked extensively with us on this. And 4 we have rewritten the labeling and instructions for 5 use, stressing the proper technique for injection of 6 the material. We will continue to monitor this 7 closely. And I think that with the additional 8 training, this problem should go away. 9 Okay. Now I would like to turn our 10 attention to the main topic of today, which is 11 nocturnal home hemodialysis. How does FDA regulate 12 hemodialysis products? Well, most all of the products 13 for hemodialysis are regulated through a 510(k) 14 process. These products are class II medical devices. 15 The classification process is risk-based. Class II 16 products generally are considered of a moderate level 17 of risk. 18 There are some requirements for class II 19 devices for general controls and special controls to 20 ensure the safety and effectiveness of these products. 21 General controls include such things as registration 22 and listing the submission of a pre-market 23 notification, quality system regulations, and things 24 of that nature. And special controls are such items
  • 37. 1 as guidance documents development following 2 performance standards and other types of safety issues 3 such as those. 4 As I said, these devices, the hemodialysis 5 products, are regulated under a 510(k) process called 6 a pre-market notification. And these devices are 7 determined when they are marketed to be substantially 8 equivalent to a device that is already currently on 9 the market. We call this a substantial equivalence 10 clearance process. 11 I do want to note that currently there are 12 no devices that are currently labeled and approved for 13 the use of nocturnal home hemodialysis in the United 14 States. 15 I said this was a clearance process. 16 Substantial equivalence is determined. And when a 17 device is placed on a market through this 510(k) 18 clearance process, it is determined to be as safe and 19 as effective as the predicate device. 20 Performance data is usually required for 21 these submissions. Typically it is bench studies. 22 However, if there are new modalities, we frequently 23 require clinical studies. And we have required 24 clinical studies for devices in hemodialysis that are
  • 38. 1 going to be put into the home setting. 2 Hemodialysis products are listed in the 3 Code of Federal Regulations under a number of 4 classifications. The primary ones for hemodialysis 5 equipment are under 876.5820 and 876.5860. The 6 difference between these two classifications has to do 7 with whether an ultrafiltration controller is added to 8 the system, and the 5860 is for high flux dialyzers. 9 Both of those types of devices are classified under 10 those classifications. 11 We have a number of other classifications 12 that deal with dialysis products. I am bringing this 13 out so that you realize we don't bulk everything into 14 one classification. We have tried to spread out these 15 different products into different regulations. 16 We have a separate classification for 17 sorbent regenerated dialysis delivery systems for 18 hemodialysis. We also have a separate regulation for 19 water purification systems. Again, we have products 20 for peritoneal dialysis that are separate from 21 hemodialysis. 22 And we have blood access devices and 23 accessories for the dialysis process. I just would 24 note that these currently are class III, but they are
  • 39. 1 still reviewed under the 510(k) process. We are 2 looking into the reclassification of these products 3 currently. 4 We have written a number of guidance 5 documents for hemodialysis products. They have 6 included guidances for conventional high-permeability 7 dialyzers, guidance documents for the hemodialysis 8 delivery systems. We have a guidance on the reuse of 9 hemodialyzers. And we also have a fairly detailed 10 guidance document on water purification systems, which 11 is a significant component that raises a lot of safety 12 issues in the dialysis process. 13 Now, it's important for me to bring these 14 issues out to you because today you are going to be 15 challenged with giving us advice which may lead to the 16 development of a guidance document for nocturnal home 17 hemodialysis. So I would just like to make a couple 18 of comments about guidance documents. 19 Guidance documents are actually listed in 20 the Code of Federal Regulations. And it stated that 21 the guidance documents are documents prepared for FDA 22 staff, applicants, and sponsors, as well as the public 23 that describe the agency's interpretation of or policy 24 on a regulatory issue.
  • 40. 1 Now, guidance documents represent FDA's 2 current thinking on a specific issue or a device. 3 Guidance documents do not establish legally 4 enforceable rights or responsibilities. They do not 5 legally bind the FDA or the public. 6 An applicant may choose to use an approach 7 other than the one set forth in a guidance document. 8 However, the alternative approach must comply with the 9 relevant statutes and regulations that have been 10 written. 11 So just keep that all in mind as you go 12 through your deliberations today and your discussions 13 and give your advice because I do hope that we result 14 in a guidance document for nocturnal home 15 hemodialysis. 16 Okay. Well, this leads us into the 17 discussion of today's main topic: nocturnal home 18 hemodialysis. And I would like to give you what I 19 consider a working definition for this topic today. 20 You may add or take away and discuss this further, but 21 this is the definition that we have come up with. 22 Nocturnal home hemodialysis is a type of 23 hemodialysis performed in the home by the patient 24 while the patient is asleep. Typically this may be
  • 41. 1 done at night. It is done over a six to ten-hour 2 period using slower flow rates for the blood and 3 dialysate or generally slower flow rates and is 4 frequently performed five to seven days per week. 5 Today we would like you all to engage in a 6 discussion of this topic of nocturnal dialysis, and I 7 have here the three main objectives I would see as 8 hopefully coming out of this meeting. 9 The first is to discuss and provide 10 recommendations on the clinical and scientific issues 11 associated with hemodialysis device design, the 12 labeling, and the training for nocturnal home 13 hemodialysis. 14 Second, we would like you to discuss and 15 provide recommendations on the clinical trial design 16 to study nocturnal home hemodialysis in the home 17 setting. 18 And, finally, we would like to obtain 19 scientific feedback, which can be used to help in 20 device evaluation decisions on these products in the 21 future and may lead to the future development of a 22 guidance document for nocturnal home hemodialysis. 23 Again, I thank you for coming and for 24 providing us this feedback. And any suggestions,
  • 42. 1 recommendations, or advice you can give would be 2 greatly appreciated. 3 I would now like to introduce the next 4 speaker, Mr. Joshua Nipper, who will be discussing 5 with you the current conventional hemodialysis 6 equipment that is on the market. 7 CHAIRPERSON TALAMINI: Thanks, Dr. 8 Neuland. I would just remind panel members, jot any 9 questions down because after all of the FDA 10 presentations, we will have the opportunity to ask the 11 FDA specific questions about their presentations. 12 Dr. Nipper? 13 MR. NIPPER: Thank you, Dr. Neuland. And 14 good morning, ladies and gentlemen. 15 2. OVERVIEW OF CONVENTIONAL HEMODIALYSIS SYSTEMS 16 MR. NIPPER: My name is Joshua Nipper. I 17 am a biomedical engineer with the Gastroenterology and 18 Renal Devices Branch. And I am here today to talk to 19 you about conventional hemodialysis delivery systems 20 as they have been currently cleared. 21 Just a brief overview of my talk. Again, 22 I'm going to be talking about conventional systems. 23 I'm going to go over some of the models and parameters 24 that dialysis device is responsible for. I'm going to
  • 43. 1 cover some of the alarms that a standard system would 2 have. I'm also going to go over some of the accessory 3 devices that would be used during a hemodialysis 4 treatment, including water treatment systems, the 5 hemodialysis blood tubing, remote monitoring systems, 6 and blood access devices. 7 Just a very brief disclaimer. I'd like to 8 point out that any examples I give in this 9 presentation aren't an endorsement or criticism of any 10 specific type of technology, device, or company. It 11 is merely to give you an idea of what has been 12 cleared. 13 I would also like to reiterate a point 14 that Dr. Neuland made in that no devices are currently 15 cleared for nocturnal home hemodialysis. 16 As Dr. Neuland mentioned, our hemodialysis 17 delivery systems are cleared under two different 18 classifications: 5820 for low-permeability systems 19 and 5860 for high-permeability systems. I would just 20 like to point out the only real difference between 21 these two classifications for dialysis delivery 22 systems is the fact that the high-permeability systems 23 have an ultrafiltration controller to regulate the 24 amount of fluid that is removed from the patient.
  • 44. 1 We also do have a guidance document 2 available for manufacturers that gives them an idea of 3 what type of information we are looking for in a 4 510(k) submission. This covers the traditional bench 5 testing that we would be expecting. 6 What I have here is basically a schematic 7 of a standard or traditional hemodialysis system. And 8 I'll kind of walk you through it here. I apologize if 9 this is rudimentary review for anyone, but the blood 10 typically is pumped from the patient through a drip 11 chamber by the blood pump, goes through the 12 hemodialyzer, and returns to the patient. 13 Some of the key features that most systems 14 do have is some form of saline pump. This can be a 15 gravity-fed or it can be drawn in by the blood pump or 16 maybe a separate pump itself. Many systems have an 17 anticoagulant pump that administers either a bolus or 18 a rate of anticoagulant through the entire treatment. 19 There is also a series of pressure 20 transducers here, here, and on the venous side. 21 Different systems measure pressure differently. Some 22 measure multiple sites on the arterial side. Some 23 measure pre-pump, as I demonstrated here. Some 24 measure post-pump. And some don't measure on the
  • 45. 1 arterial side at all. However, all systems are 2 responsible for monitoring the pressures during the 3 treatment. 4 On the venous side, I will use the mouse 5 so as not to blind anyone. We do have an air detector 6 that monitors for air embolism and keeps any air from 7 being administered to the patient. You also have a 8 venous clamp that will clamp down on the lines in case 9 of any warning states, any severe warning states, to 10 prevent blood from being returned to the patient in an 11 alarm situation. 12 The system I've demonstrated here is known 13 as a three-stream system because you have the water, 14 acid concentrate, and bicarbonate concentrate all 15 coming into the system, being mixed by the system to 16 form the dialysate of the prescribed conductivity. 17 Systems that use this type of technology would be 18 required to have a conductivity meter to ensure that 19 the appropriate composition of dialysate is being 20 created. 21 The dialysate is pumped by the blood pump 22 in a counter-current fashion through the dialyzer and 23 back out to a waste. I have also demonstrated some 24 patient fluid being removed and would like to point
  • 46. 1 out there is a blood leak detector on the dialysate 2 outline. This blood leak detector does not detect any 3 disconnections or any loose connections in the blood 4 tubing. Rather, it connects broken fibers in the 5 dialyzer itself. Basically it monitors for hemoglobin 6 or any pinkness in the dialysate line and will alarm 7 if there is any blood in that line. 8 Some systems do not use the three-stream 9 and will use either a premixed or some type of sorbent 10 regenerated dialysate. If this is the case, they can 11 get rid of the mixing system that was there because 12 the dialysate coming in is already expected to be the 13 appropriate conductivity and concentrations. 14 These systems may or may not have a 15 conductivity meter, pretty much depending on whether 16 they use the premixed or a sorbent regenerated system. 17 What we have here is just a blow-up of the 18 dialyzer itself. You can see the blood in and out and 19 dialysate in the counter-current fashion. What I 20 would just like to point out here is that if the 21 pressure on the blood side and the dialysate side are 22 approximately equal, your main soluble transfer is by 23 diffusion alone. 24 However, if you do have a higher pressure
  • 47. 1 on the blood side, you have fluid removed of 2 ultrafiltrate removed. And you do have solute 3 transfer by convection as well. 4 During a hemodialysis treatment, the 5 machine is responsible for monitoring the parameters 6 listed here. You can see that it monitors the blood 7 and dialysate flow rates. Typically does this by 8 measuring the pump speeds or rotation permitted of a 9 pump. Again, it measures pressure in several 10 different areas: arterial, venous, dialysate, and 11 waste. 12 From these pressures, the systems 13 calculate the transmembrane pressure, which is 14 essentially the difference in the blood and dialysate 15 side. 16 Patient fluid removed is also monitored 17 using a variety of methods. And temperatures of blood 18 and dialysate can also be measured. 19 One of the main responsibilities for these 20 machines is alarming in any type of error state. And 21 hemodialysis alarms usually come in two different 22 varieties. The first is a yellow or caution alarm. 23 These are the types alarms that indicate poor trends, 24 high pressures, things of that nature, in the machine.
  • 48. 1 These alarms usually can be mitigated, and 2 the treatment can be resumed. If they aren't 3 mitigated correctly, they can progress to a red or 4 warning alarm. These alarms are more serious and may 5 or may not require the termination of a hemodialysis 6 treatment. 7 Most systems have alarms for the following 8 parameters. And this is not an all-inclusive list, 9 but you do have temperature; blood leak detector, as I 10 mentioned before; any flow rate mismatches, you know, 11 the pump is going either too fast or too slow. 12 You have several different pressure 13 measurements: arterial, venous, TNP, and dialysate 14 lines. You also have warnings if you have excessive 15 ultrafiltration and too much fluid is being removed. 16 Air embolism, one of the more important warnings, 17 prevents air from being returned to the patient. 18 Systems that do mix or regenerate their 19 own dialysate will have a conductivity or pH alarm to 20 ensure that dialysate is of the appropriate 21 conductivity and concentrations. 22 Some systems communicate directly with an 23 individualized water treatment system. These devices 24 may have alarms that generate poor water quality or
  • 49. 1 when components of the water treatment system need to 2 be replaced or serviced. 3 There are also system-level alarms. They 4 include many types of hardware or software failures, 5 power failures, and things of that nature. 6 I have included vascular access 7 disconnection with venous pressure with a question 8 mark. And I've done this because most modern systems 9 rely on the venous pressure to monitor for any type of 10 needle pull-out or vascular disconnection. 11 The problem with using this method is that 12 if a patient's natural venous return pressure is low 13 and you are using small bore needles with long tubing, 14 you can create enough resistance in the system to 15 prevent these alarms from being triggered. And we 16 have had documented cases of needle pull-outs in the 17 clinic, and the systems have filed to alarm. 18 I would now like to move into some of the 19 accessory devices. Again, these include water 20 treatment systems, dialysis blood tubing, monitoring 21 systems, and blood access devices. 22 As Dr. Neuland mentioned, water treatment 23 systems are classified under 876.5665. And we do have 24 a guidance document available for these devices as
  • 50. 1 well. This guidance document tells manufacturers of 2 these devices what type of information we are looking 3 for in a standard water treatment system. 4 The primary job of a water treatment 5 system is to convert potable water meeting EPA 6 standards to purified water that meets AAMI RD:62 7 standards. The AAMI RD:62 standard is not sterile 8 water, but it does give the maximum level of 9 concentrations of contaminants and things like 10 endotoxins and bacterial contaminants. 11 These devices can be designed for multiple 12 patients. And these are the types of water treatment 13 systems that you see in the standard clinics that 14 deliver to multiple patients or they can be single 15 patient, more designed to interface directly with the 16 dialysis system. 17 It's important to note that the single 18 patient systems often have or need some type of 19 pretreatment to remove their sediments or chloramines, 20 things of that nature. 21 This is just a basic schematic or flow 22 chart of a standard water treatment system. These 23 devices are highly customizable. So not every water 24 treatment will have each one of these components or
  • 51. 1 may have additional components as needed. It's a 2 little cut off here because this is the EPA potable 3 water, and you have any amount of pretreatment, 4 sediment filters, or chloramine reduction. 5 You then go to carbon filters, which are 6 generally in two filters in an in series known as the 7 worker/polisher fashion. You then would go to a 8 reverse osmosis and a deionization. 9 The system I have shown here has an 10 altered filter, which would be responsible for 11 removing any residual endotoxins or lower, smaller 12 contaminants. And then you have your AAMI water 13 coming out. The system I have shown also has a data 14 out, which could be used to interface directly with 15 hemodialysis device. 16 Hemodialysis blood tubing serves the 17 simple function of being just the conduit for blood. 18 It interfaces directly with the patient and the 19 dialysis system. It has a larger section of the 20 tubing that is known as the blood pump segment. And 21 it interfaces directly with the blood pump, the 22 device. The blood pump segment has to be fit in very 23 snugly within the blood pump in order to get efficient 24 pumping.
  • 52. 1 The important thing to note about the 2 blood tubing is that there are multiple connection 3 points that the patient or care-giver would be 4 responsible for connecting. That includes the access, 5 arterial and venous, any pressure transducers that 6 have to manually be fit on the machine. They have to 7 make sure that the tubing is securely fit into the air 8 detector and into a roller or peristaltic blood pump. 9 Blood tubing can also be either cassette 10 or cartridge-based, which interfaces directly with the 11 dialysis system. And these types of devices greatly 12 reduce the number of connections that the patients 13 required for making. Generally they only have to do 14 arterial and venous and maybe some priming 15 manipulations. 16 I would also like to point out that kinked 17 tubing is a significant problem, can cause hemolysis, 18 which can lead to death. Again, we have had 19 documentation of kinked tubing in the clinics causing 20 patient death. 21 Remote monitoring systems are basically 22 software that interfaces with the dialysis system. It 23 can be built into the machine or it can be as an 24 accessory or an add-on. They're used for basic data
  • 53. 1 transmission. They connect the machine to the 2 internet by either a modem or some type of broadband 3 connection or a local area network. 4 These devices transmit real-time alarms 5 and/or completed treatment data. So they can be used 6 to transmit things to a nurse's station or over the 7 internet to a remote monitoring station. They can 8 also be used to just send final data, such as amount 9 of blood processed or length of treatment, that type 10 of thing. 11 I would like to point out that current 12 systems are contraindicated as the sole method of 13 monitoring a patient during hemodialysis. So to date, 14 FDA has required that there be some form of partner or 15 some other monitoring for these devices. 16 Finally, I would like to mention some of 17 the blood access devices that are available. They 18 generally come in three different varieties. There's 19 long-term cuffed hemodialysis catheters. These 20 devices are available both in single and double lumen 21 models. 22 Catheters contain alternating luer lock 23 connectors that meet ISO standards for connection to 24 the blood tubing. This is important because catheters
  • 54. 1 are less prone to any type of disconnection and 2 completely remove the possibility of needle 3 disconnection. 4 There is also arterio-venous grafts, which 5 are implanted prostheses that are designed to bypass 6 sections of native vessels. These devices are 7 accessed with a fistula or graft needle. 8 And, finally, there are A-V fistulas. I'd 9 like to point out these are a surgical procedure and, 10 therefore, not a device regulated by FDA. The fistula 11 needles are regulated by FDA, are medical devices, and 12 they use the same luer locks as the dialysis 13 connectors but, again, aren't prone to any type of 14 needle pull-out. 15 This concludes my talk. I'd now like to 16 introduce Dr. Michael Mendelson, who will be talking 17 to you about human factors and dialysis. 18 DR. MENDELSON: Thank you, Josh. 19 3. HUMAN FACTORS 20 DR. MENDELSON: Good morning. I'm Mike 21 Mendelson. And I'd like to thank my FDA colleagues 22 for the opportunity to speak on the impact of human 23 factors on the safe and effective delivery of 24 nocturnal home hemodialysis.
  • 55. 1 Here are the topics I am going to touch on 2 today. First I want to introduce you to human 3 factors. I'm going to talk about the magnitude of use 4 error as a cause of adverse incidence, including 5 deaths. 6 I'll talk briefly about methods used in 7 the field of human factors. And I'm going to talk 8 about based on human factors the types of problems I 9 anticipate in the delivery in the home. And I'm going 10 to give a brief list of the recommendations of our 11 Human Factors Branch. 12 First a definition. This definition of 13 human factors was proposed by one of the pioneers in 14 the field, Alphonse Chapanis. I won't read it to you, 15 but I will mention that the emphasis in our field is 16 on the behavior of humans, their limitations. 17 As I said earlier, we are interested in 18 use error as a cause of adverse incidence. And here 19 is a general definition of error, as found in a 20 popular human factors textbook. 21 You will notice again the emphasis on 22 humans and their behavior. And you will notice the 23 words "effectiveness and safety," which are important 24 to us at the FDA.
  • 56. 1 Do we know if use error is really a 2 significant problem in medicine? Yes, we do. I could 3 spend my entire talk going over data, but here just a 4 couple of pieces that might be interesting, Lucian L. 5 Leape, who is a noted authority at the Harvard School 6 of Public Health, has mentioned in an interview that 7 you could load patients into one jumbo jet every day 8 and crash it, resulting in all of their deaths. And 9 at the end, you would have 120,000 deaths, which is 10 the number of people he estimates who die from medical 11 error. 12 And a more well-known piece of data is 13 this. "To Err is Human" was released by the Institute 14 of Medicine in November of 1999. And it blamed use 15 error for between 44,000 and 98,000 deaths in U.S. 16 hospitals each year. 17 Now, is it necessary for manufacturers to 18 pay attention to human factors? Yes, it is. The 19 quality system regulation, which took effect in 1997, 20 requires that user needs be included in the design of 21 medical devices. 22 And hemodialysis units would be in class 23 II, which is one of the classes to which the supplies 24 -- and you'll notice I'm emphasizing the words "user"
  • 57. 1 and "patient" and "actual" or "simulated" conditions. 2 I'll touch on that a little later. 3 There are three phases in the design and 4 development process of a device where human factors is 5 required to be included: the input phase, where a 6 manufacturer would take into account complaints about 7 previous devices or what is written in the literature 8 or information known about good design; the output 9 phase, where a comparison is made between what is 10 known about design needs and what the design of the 11 device is before it's actually constructed; and, 12 probably the most visible area where human factors is 13 required is -- and let's call it the validation phase, 14 where an actual production unit is tested in a 15 realistic setting with prospective users. 16 Now, what areas in the medical environment 17 do we look at in human factors? Of course, we look at 18 the device as the Center for Devices, but in human 19 factors, we look at it as a system. We look at the 20 environment, where things can be very challenging. We 21 look at the user, whose abilities may be limited; and, 22 of course, the device. The outcome could result in 23 safe and effective care or what we're trying to 24 prevent: unsafe or ineffective care due to use error.
  • 58. 1 Now, if human factors is successfully 2 applied to the design and development of a device, we 3 would like to see the following. Now, these are all 4 areas of what's called the use interface, which is 5 anything a user would interact with in order to 6 deliver care with a device. 7 Of course, we expect intuitive operation, 8 what you'd call user-friendliness, but also applies to 9 all of these areas: the displays, the controls, the 10 connections. You have an adverse incidence associated 11 with all of these: effective alarms. 12 I have clear and effective labeling listed 13 here, but I want to emphasize that by applying human 14 factors, we hope to minimize the burden on labeling as 15 a way of ensuring safety and effectiveness. 16 This is noteworthy. When I say "safe and 17 simple installation, repair, maintenance, and 18 disposal," I would like to point out that users aren't 19 only the people who are operating the device to 20 deliver care. They're also the people whom you may 21 not think about as users, anyone who interacts with 22 the device in any way. People have died because of 23 interaction with cleaning staff, well-meaning 24 relatives, and others.
  • 59. 1 If there is only one slide that I can 2 present in this talk, it would be this one. It's sort 3 of our human factors mantra that some devices can 4 actually invite people to commit errors because of 5 poor design. And these design deficiencies cannot 6 thoroughly be prevented by labeling changes. 7 There is an easy-to-read paperback called 8 The Design of Everyday Things written by Donald 9 Norman, which is quite often mentioned in the field as 10 a source of seven principles of a well-designed 11 interface. I'm going to touch very briefly on the 12 seven. 13 Here is an example of a device that does 14 not provide good visibility. It's a 15 patient-controlled analgesia device, a PCA pump, which 16 was adapted to go home with pregnant women in order to 17 delay labor. It was used for the delivery of 18 terbutaline. 19 Now, all controls are limited to just 20 these two toggles and a small display, which is about 21 one centimeter by a centimeter and a half. Through 22 that small window, it was necessary to view 23 approximately 50 nested menus. And users quite often 24 became lost and were unable to navigate their way back
  • 60. 1 and have to start the process over again. The authors 2 of this study, Obradovich and Woods, called this an 3 example of dumb automation. 4 The second principle, communicate clearly. 5 Patients have been seriously injured and killed when 6 well-trained operators of medical devices did not know 7 in one case what type of radiation and what the dose 8 of radiation was when they were operating a 9 radiotherapy unit. 10 Mappings. Probably the simplest way to 11 mention mappings is to ask you, have you ever burned 12 an empty pot on the cooktop because you flipped the 13 wrong control? It can have a serious result in other 14 areas, including medicine, but one noteworthy area 15 where mappings was a problem; that is, the 16 relationship between controls and displays or controls 17 and what you're controlling, is in the nuclear power 18 industry. 19 Don't be arbitrary. Be consistent. We 20 all expect to turn a valve counterclockwise when we 21 want to water our lawns. This is actually a principle 22 that is violated occasionally in medicine. Older 23 style anaesthesia vaporizers used in the operating 24 room sometimes would require opposite turning of the
  • 61. 1 concentration controls in order to accomplish the same 2 thing, which is increased concentration. 3 Simplifying tasks. When Dr. Cooper asked 4 us to please silence our cell phones, I was amazed at 5 the number of steps people had to take in order to 6 accomplish that task. Both consumer devices and 7 medical devices are filled with unnecessary features 8 that increase their marketability but interfere with 9 safe and effective use. 10 Here is an example of poor constraints. 11 This is probably the most well-known human factors 12 disaster in medicine. Well-meaning family members and 13 cleaning staff accidentally severely burned and 14 electrocuted some infants when they plugged the 15 electrode pins for infant apnea monitors into either a 16 receptacle or an extension cord. 17 FDA responded by requiring something 18 called protected pins. These pins on the ends of the 19 cables could only be plugged into a dedicated 20 connector for use with a monitor. That's an example 21 of a principle called protective incompatibility. 22 Last principle, design for error. If 23 there's a critical step that needs to be performed, 24 the user should be reminded in order to make sure that
  • 62. 1 he or she doesn't accidentally perform that step. For 2 example, when you delete a file or a folder on your 3 computer, you are asked if you really want to do that. 4 Now, when we take a medical device into 5 the home, there are reasons why human factors are 6 particularly critical. Looking first at our users, 7 working at home, they do not have the support that one 8 would have in a hospital. They don't have biomedical 9 engineers available to sort out problems. They don't 10 have supplies and repair parts. 11 The users range in education from perhaps 12 elementary school level to doctorate. Bear in mind 13 that the typical reading level of a person in the 14 United States, you will hear different numbers, but I 15 guess a good average is the sixth grade. 16 For the very reason that users need to use 17 their medical devices, their ability to operate them 18 is compromised, particularly in the areas of vision 19 and sense of touch and memory. 20 This is a diverse country. Many languages 21 other than English are spoken, another reason why 22 dependence on labeling may not be the wisest approach. 23 And even because of cultural differences, people do 24 not look at devices the same way.
  • 63. 1 This bullet is a little complex. I'll 2 explain it. There are papers that we have read that 3 indicate that hemodialysis can be delivered at the 4 same level of safety as in the clinical environment. 5 But these authors, D'Amico and Bazzi, pointed out that 6 based on their research, the clinical level of safety 7 found in the home is due to the fact that the 8 healthiest patients are doing this at home and they 9 can better withstand the adverse outcomes that 10 sometimes occur. 11 Looking at the environment, when patients 12 go into the clinic, they no longer have to take care 13 of other people or accomplish other things. In the 14 home, they still have to take care of their families. 15 They have to worry about children and pets. There are 16 many stresses that they still face in the home. Of 17 course, the physical environment in the home is not as 18 well controlled as it is in a hospital. 19 Things as simple as the proper placement 20 of device are often not possible because of crowding 21 or unstable furniture. Voltage and grounding can be 22 problems because of old wiring. Temperature and 23 humidity are not well-controlled. The home 24 environment is probably more dusty. And there is
  • 64. 1 variance in water quality. Some homes do not have 2 municipal water. 3 Now I'm going to touch on two examples of 4 problems with hemodialysis equipment that were not 5 found in the home environment. The reason I'm 6 pointing these out is to show that in the clinical 7 environment, where you have all of this backup, the 8 results, the outcomes of these problems were 9 minimized. 10 We have to keep in mind that problems like 11 this are going to occur in the home. No device is 12 perfectly designed. And we have to be extra vigilant 13 in order to prevent adverse outcomes. 14 In the first example, one piece of 15 hemodialysis equipment instructed the user that in the 16 event that transmembrane pressure automatic control 17 failed, the user would be alerted with a code that 18 began with the letters "FL," and it would be possible 19 to manually control it. 20 Well, the users actually tried to do this, 21 but for three of the fault codes, it was not possible 22 to operate the device. The result was a recall. And 23 the manufacturer's solution was labeling. And I 24 mentioned earlier how that can be unsatisfactory.
  • 65. 1 With a second device, if a device was not 2 plugged into a ground fault circuit interrupter, which 3 frequently may not be found in the home, and certain 4 other conditions existed; that is, certain other 5 settings with the hemodialysis unit, it resulted in 6 overheating. Again, the manufacturer sent an 7 important advisory letter to the users. 8 Now, what I am going to do now is list 9 some of the concerns I have with medical devices used 10 in the home, particularly hemodialysis units. 11 Hygiene is extremely important in the 12 setup of a hemodialysis unit. The unit should be 13 designed to minimize the exposure to connections where 14 hygiene is critical. Josh Nipper mentioned the choice 15 of using cassettes, rather than multiple connections. 16 I understand that some units may require 15 17 connections. 18 As I said before -- and I will probably 19 say it again -- we need to minimize the need for 20 labeling. Also, because both health professionals and 21 lay users can easily forget their training and develop 22 habits that may not be desirable, manufacturers may 23 consider the need for retraining. 24 Thick manuals are difficult to deal with
  • 66. 1 for common needs. It's more advisable to rely on 2 on-screen help or laminated cards attached to the 3 machine. 4 It's not certain at this point how the 5 prescribed dialysate will be prepared. The 6 opportunity for error if it's there should be 7 monitored so a user does not cause injury by using an 8 inappropriate dialysate. 9 The setup and adjustment of the device 10 should be as simple as possible. What I mean here, 11 "ensure safety of consumables," I'm reflecting back on 12 infusion pumps, which are a rich source of human 13 factors disasters in medicine. 14 There was an infusion pump which had an 15 administration set; that is, a tubing set, which 16 included an automatic valve that would pinch shut if 17 the tubing were removed from the infusion pump. 18 In one hospital, a woman in labor had an 19 after-market inexpensive tubing set attached. And 20 when the tubing was disconnected from the infusion 21 pump, this after-market tubing did not have this 22 safety device. And she was a victim of what's called 23 runaway infusion. She was overdosed on the 24 medication, and she died.
  • 67. 1 It's critical to prime the blood lines; 2 that is, purge them of air. And users in the clinical 3 environment know how to respond to symptoms of air 4 embolism. Now, when a patient is asleep, we need to 5 minimize the chance of this occurring and to alert the 6 user of this particular problem. 7 Interruptions in the delivery of 8 hemodialysis occur in the clinical environment. And 9 users in the clinical environment know how to respond. 10 We have to be certain that the home user will know how 11 to do this also. 12 I may have mentioned before the 13 possibility of inadequate room or opportunities for 14 proper mounting of a device. I know of cases where 15 dialysis units were mounted on the floor, even though 16 the manufacturer intended to mount them on a table 17 because the user wanted to operate them from a bed and 18 was unable to view the display. 19 I mentioned that users are typically 20 medically compromised. And in end-stage renal 21 disease, they face the comorbidities of, of course, 22 renal failure but quite often heart failure and 23 diabetes as well. 24 Touch screens are critical. Users should
  • 68. 1 not be probing for different controls. Quite often, 2 they are not using their glasses at night. And they 3 should not have to look up error codes. They should 4 learn what particular failure has occurred with their 5 device without the need for separate labeling. 6 Progressive disclosure refers to the 7 principle of allowing users to get just the right 8 amount of information. If they're technophobes and 9 they only want the device to operate, then they should 10 not have to deal with a lot of technology. 11 If, however, they want a device that is 12 very transparent; that is, a device that lets them 13 know exactly what is going on, particularly when the 14 device is not operating properly, they should be 15 allowed to get more information. 16 And a critical problem with hemodialysis, 17 of course, is the risk of exsanguination. Based on 18 the evidence available, it seems that a single-needle 19 system would allow the greatest protection from that 20 because during the phase when blood is drawn from the 21 patient, air would be detected in the line and the 22 system would shut off. 23 Patient abilities may be lowest at the 24 start of the session. What I mean by that is these
  • 69. 1 patients are toxic at the beginning of their 2 hemodialysis session. Consequently, we should not 3 expect their abilities to be as high as even those of 4 an average patient. 5 I mentioned in the home, power supply is 6 not as dependable. There are medical devices which 7 have been tricky and caused problems that were 8 difficult to detect because error codes were generated 9 or the device went back to defaults that may not be 10 appropriate. 11 Design in virtual guardrails. What that 12 refers to is the principle of protecting the user from 13 entering dangerous settings. When a patient is 14 asleep, of course, we want an alarm that is loud 15 enough or produces the kind of auditory signal 16 appropriate for awakening them. But that doesn't mean 17 that once they are awakened, their abilities are the 18 same as they are in mid-morning. Things should be 19 particularly clear for them. 20 The human factors engineering process is 21 what occurs when a medical device is designed from the 22 concept stage taking into account the human factors 23 needs of the user. 24 In order to do it properly, manufacturers
  • 70. 1 need to apply human factors from the time they first 2 conceive of a new design. The advantages are it's 3 very easy to design in the needs of the user. During 4 their iterative process, it's easy to make changes. 5 It won't be as necessary to stick on warnings and 6 increase the thickness of manuals. And research shows 7 that users appreciate devices designed this way. And 8 they last longer in the market. 9 As I mentioned earlier, the validation 10 phase refers to actually testing a sample finished 11 device. And I want to touch on something that I feel 12 is critical: the difference between a usability study 13 and a clinical trial. 14 The purpose of the useability study is to 15 make sure that the risk of dangerous use error is 16 minimized when a device is used by typical users in a 17 realistic setting. This contrasts with a clinical 18 trial, where we are trying to demonstrate that a 19 device is operating safely and effectively when used 20 exactly as directed because, as we know, in an actual 21 environment, devices may not be used where or how 22 exactly they're directed to be used. 23 And in my conclusion, I have five points. 24 We should not assume that users are using the devices
  • 71. 1 in the exact environment that they are intended for. 2 There are compromises in the user and the environment. 3 We need to minimize the burden of training 4 and labeling and ensuring safety and effectiveness. 5 We should not leave the patient or user home alone 6 without support. They need the same kind of support, 7 perhaps more, than is present in a clinical 8 environment. 9 When I mentioned design needs, I mentioned 10 complaints from users were one area where information 11 can be found to improve design. I think it is 12 critical to obtain as much feedback as possible from 13 the users of the device so the next device can be 14 better designed. And our bottom line I'm just going 15 to reiterate is we want to protect our users from 16 dangerous use error. 17 Thank you. And I would like to introduce 18 our nephrologist, Dr. Claudia Ruiz-Zacharek. Thank 19 you. 20 4. FDA PRESENTATION 21 DR. RUIZ-ZACHAREK: Good morning. My name 22 is Claudia Ruiz-Zacharek. The reason for meeting here 23 today is to ask for your help on nocturnal home 24 hemodialysis devices regarding optimal device design
  • 72. 1 for actual use conditions, adequate labeling for 2 minimizing error, appropriate training for successful 3 treatments, risk analysis to minimize unforeseen 4 problems, and clinical study design to demonstrate the 5 safety and effectiveness of the nocturnal dialysis 6 device under actual use conditions. 7 Currently, as has been mentioned before, 8 there are no devices that are specifically labeled to 9 perform nocturnal dialysis. In my talk, I will cover 10 some background information on this issue, specific 11 issues on nocturnal home hemodialysis. And I will ask 12 for your help for an optimal design of the clinical 13 studies to address our concerns related to this 14 modality. 15 The background information will break it 16 down in demographics, a brief review of the 17 literature, definitions, and nomenclature. The most 18 common form of renal replacement therapy in the United 19 States is in the form of hemodialysis. This typically 20 takes place in a center four hours per treatment three 21 times per week. This is what we call conventional 22 dialysis. 23 One of the main features of conventional 24 dialysis that I would like to point out is the
  • 73. 1 presence of medical personnel. A patient has a 2 passive role during the treatment from measuring the 3 patient's vital signs to accessing the access or 4 getting the weight to initiating treatment, 5 troubleshooting through treatment, ending the 6 treatment. All of this is done by medical personnel. 7 This is significantly different to our 8 subject today, which is nocturnal home hemodialysis, 9 where the treatment is actually performed at home by 10 the patient, typically at night and while he sleeps. 11 This is done in the absence of medical personnel. And 12 that is one of our main concerns today. And a patient 13 is usually the performer of the treatment. 14 The interest is shifting to different 15 treatment schedules, away from the conventional 16 hemodialysis described previously. And the most 17 promising change with strongly favorable literature 18 accumulated over the last few years is daily 19 hemodialysis. 20 One of the forms of daily hemodialysis 21 could be short daily. Basically it is all in the same 22 modality of providing more frequent, more intense 23 hemodialysis than the conventional dialysis as we know 24 it.
  • 74. 1 Nocturnal hemodialysis also is referred as 2 nightly hemodialysis. The subject today specifically 3 is the home, the nocturnal home, hemodialysis, which 4 could be long nocturnal or sometimes also called slow 5 nocturnal. 6 In-center nocturnal hemodialysis is not 7 going to be considered today as the presence of 8 medical personnel is still available. So it's not 9 much of a concern to us. 10 So nocturnal home hemodialysis is 11 performed at home by the patient in the absence of 12 medical personnel. Frequency has been reported to 13 range from five to seven nights a week. The length of 14 treatment is about six to ten hours per night 15 depending on the prescription. 16 Blood flows tend to be also slower than 17 conventional hemodialysis with blood flows reported to 18 be 200 to 300 mL per minutes. Dialysate flows range 19 from 100 to 800 mL per minute, also depending on 20 prescription, but the usual dialysate flows are about 21 300 mL per minute. 22 According to the United States renal data 23 system, the prevalence of patients on hemodialysis in 24 the United States is about 281,000 patients, out of
  • 75. 1 which 843 have home dialysis, are home dialysis 2 patients. 3 According to a publication by Dr. 4 Lockridge in 2002, there are 115 nocturnal 5 hemodialysis patients distributed in about 13 centers 6 in North America. 7 The characteristics across this population 8 in North America, it's about 14 percent of diabetic 9 nephropathy. And I would like to compare this with 10 the U.S. demographics of about 45 percent of diabetic 11 nephropathy in the dialysis population. Let me point 12 out also that diabetes is the leading cause of 13 end-state renal disease patients leading to the need 14 for renal replacement. 15 This is important for us to consider 16 because diabetic nephropathy or patients with diabetic 17 nephropathy tend to have more comorbidities than 18 patients with other etiologies. 19 So there is a merging body of evidence 20 that more frequent hemodialysis offers superior 21 treatment than conventional hemodialysis. And this is 22 just a small sample of the body of literature 23 available, but the reason I included this slide is to 24 point out that these studies or these publications are
  • 76. 1 non-randomized trials. Most of them are prospective. 2 Some of them are retrospective. And the majority have 3 a small number of patients. Most of them are single 4 arm, although there are a few of them that have 5 matched controls. 6 Both modalities of short daily or 7 nocturnal dialysis have been associated with 8 significant clinical benefits, including blood 9 pressure controls. Most of them report or, in fact, 10 all of them report an improvement in blood pressure 11 control to the point where patients need to decrease a 12 lot of the anti-hypertensive medications they're 13 already taking. 14 Calcium-phosphorous control is also 15 improved. Some of the patients actually need to 16 reduce the phosphate binders that they are taking. 17 Some reports also suggest that additional phosphorus 18 is necessary to keep a normal phosphorus level. That 19 is actually a new thing for hemodialysis patients in 20 which calcium-phosphorus control is actually very 21 difficult to control. 22 Anemia, on the other hand, has not shown 23 significant improvement on the patients on these 24 studies. Some of them have actually reported
  • 77. 1 increased epoetin and iron mean. 2 Other benefits associated with this type 3 of more frequent dialysis include the reduction of 4 number and severity of dialysis symptoms and the 5 fatigue associated with the hemodialysis. And the 6 time to recuperate from a dialysis treatment is also 7 reduced. 8 Improved serum albumin. This is also a 9 good thing. End-stage renal disease patients tend to 10 have low albumin. And that is a poor prognostic 11 factor. 12 There are also no fluid or dietary 13 restrictions reported in certain patients. This is 14 also in terms of improving the quality of life for a 15 patient. They also have improved the sleep patterns. 16 Pierratos in 1999 reported a reduction or correction 17 of sleep apnea. 18 So now we will concentrate on nocturnal 19 hemodialysis issues that we would like you to 20 consider. Let me just remind you things that we are 21 going to cover are the device design and components, 22 human factors issues, water quality, use of a partner, 23 and remote monitoring vascular access and 24 extracorporeal circuit connections, labeling, and lay
  • 78. 1 user training. 2 Let me remind you again that our concerns 3 with a conductor in home hemodialysis compared to 4 conventional hemodialysis is the role of the patient 5 in conventional dialysis is actually the passive 6 recipient of hemodialysis while in nocturnal home 7 hemodialysis, the patient has an active role. He is 8 the performer of the treatment. The patient needs to 9 troubleshoot. Basically while he is asleep, he needs 10 to wake up to the alarms. 11 To review what Dr. Mendelson said on human 12 factors, the objective to include this in the device 13 design would be to improve human performance. And for 14 this, the device may need to be user-friendly, reduce 15 the likelihood of user error and patient injury, and 16 to reduce the burden in training and labeling. So 17 please keep this in mind when considering device 18 design. 19 So we would like for you to consider the 20 following features in the device design, such as 21 redundancy to have a back-up system in case a safety 22 feature fails. 23 What would be the right adequacy of the 24 alarms? The loudness and sensitivity and ease of
  • 79. 1 understanding and correction and the possibility of 2 additional safety alarms that are not present in 3 conventional hemodialysis. 4 Another important aspect in nocturnal 5 hemodialysis is to consider water quality. This is 6 because the exposure to water is a lot higher in 7 nocturnal hemodialysis. Compared to conventional, 8 hemodialysis patients are exposed to about 360 liters 9 for week in form of dialysate. Nocturnal hemodialysis 10 doubles this amount to 600 to sometimes more than a 11 liter a week depending on the device and depending on 12 the prescription and the flow of dialysate. 13 Just to let you know on the review of the 14 standard water quality is a total viable microbial 15 count of less than 200 colony-forming units per mL and 16 an endotoxin concentration of less than two endotoxin 17 units per mL. So should higher standards of water 18 quality be required for nocturnal hemodialysis since 19 the exposure to the dialysate is a lot more than 20 conventional dialysis? 21 So other issues to consider in regards to 22 the modality itself are going on with water quality 23 concerns, the type of water systems available right 24 now, treatment systems, is reverse osmosis,
  • 80. 1 deionization, or a combination of both. So which 2 system would be appropriate for a patient to take home 3 and perform nocturnal hemodialysis? 4 The water source on how to manage changes 5 in the quality of municipal -- in the case of 6 municipal water suppliers, another issue that is 7 concerning to us is monitoring. Raija in 2003 8 suggested that nocturnal dialysis could be done 9 without a partner. His study was 59 patients, 10 prospective study. Out of these 59 patients, 13 of 11 them were actually in nocturnal dialysis without 12 assistance. 13 The conclusion was that there were no 14 increased technical difficulties or increased alarms 15 or safety issues in regards to this. He based this 16 conclusion in about 115 patient-month experiences. 17 In center hemodialysis, there is constant 18 monitoring by medical person. In home hemodialysis, 19 we understand by that a patient that is awake. So 20 it's also not too concerning in regards to home 21 dialysis. 22 The London daily nocturnal hemodialysis 23 study in 2003 suggests or the conclusion was that 24 monitoring is essential for the initial three months
  • 81. 1 of nocturnal hemodialysis therapy until the 2 hemodialysis team is convinced the patient is stable 3 and compliant. 4 Now, they base this -- again, as I 5 mentioned earlier, this is a prospective comparative 6 non-randomized study of about 23 patients with 22 7 matched controls. However, only 14 of them were in 8 nocturnal hemodialysis. The rest were in daily 9 dialysis. 10 Their treatments ranged from 13 to 602 11 treatments based on these 14 patients. There were 12 reported in the time of the study about 4,000 patient 13 nights, out of which there were about 5,000 alarms, 14 reported alarms. These resulted in calls, but most of 15 the alarms were due to either slow response by the 16 patient to the alarms or non-response. 17 Most of the alarms were due to arterial or 18 venous pressure alarms due to the patient obstructing 19 the blood tubing. So there were not emergencies. 20 There was no need to call the designated contact 21 person or emergency services. 22 The average number of alarms per night 23 decreased significantly over time. So each 24 progressive decrease from month 3 through month 18 was
  • 82. 1 statistically significantly lower than the value at 2 one month. And that's why they concluded at three 3 months. After three months, monitoring may not be 4 necessary. 5 Our discussion wouldn't be complete 6 without talking about vascular access. Let me just 7 review what is available right now for the 8 hemodialysis and conventional in-center or home 9 dialysis. 10 Long-term cuffed catheters, it's actually 11 very convenient in terms of using it immediately after 12 placement. But there is a disadvantage in the 13 increase of thrombosis, increase of clotting, increase 14 of infection. So this is actually not recommended by 15 the DOQI guidelines. 16 The next vascular access available is a 17 synthetic graft. And this is a surgical graft. 18 Usually it's PTFE. And it's usually available within 19 weeks of placement. It's superior. It has a superior 20 performance than the catheter but not as good as 21 arterio-venous fistulas. And that's actually the 22 recommendations by DOQI guidance. 23 A-V fistulas need some time to mature, 24 sometimes up to three months and sometimes recommended
  • 83. 1 to let mature longer depending on the surgeon. But 2 they have a much better rate, a superior rate of low 3 infections compared to the other, to vascular access. 4 The concern with the A-V fistulas and 5 daily dialysis, though, is that with increased 6 punctures, would that affect the life of the fistula? 7 Quintaliani in 2000 reported an observational study of 8 24 patients in daily dialysis, follow-up of 3.6 years. 9 They concluded that the life of the fistula is really 10 not affected by the daily puncture, requiring daily 11 dialysis. 12 However, they used dual technique, rather 13 than the single button hole technique. Also, they 14 were using different sites for puncture, rather than 15 the same puncture, as the button hole technique does. 16 Other things that we would like you to 17 consider when it comes to nocturnal dialysis devices 18 are vascular access location. Would these have an 19 effect in terms of disconnections, infections, or 20 thrombosis? 21 Connection to the device and the use of 22 locking devices or interlinked devices, the 23 self-cannulation technique, the training that gets 24 involved for the patient to self-cannulate, full
  • 84. 1 detection locking devices, as I mentioned earlier, 2 with a connection to the device on fluid detection 3 alarms to detect either blood or dialysate leaks. 4 Pierratos in one of his papers and many 5 others have reported the use of enuresis alarms to 6 detect blood leaks or dialysate leaks. In the same 7 way, moisture sensors should be included or discussed 8 and the technique of using single versus dual needle 9 technique. A lot of literature supports the use of 10 the button hole technique because of the ease of doing 11 it. 12 So these are additional features which we 13 think should be addressed by the device manufacturer 14 as either part of the device or part of labeling. 15 Now, labeling is the operator manual that includes the 16 warning, precautions, device specifications, 17 instruction for maintenance, cleaning, and 18 disinfection. 19 This includes the physician's instruction 20 for use, which it should also include relevant data 21 from clinical studies and instructions for use in the 22 caring of the device. 23 This is basically the same thing as the 24 patient instruction for use with the main difference
  • 85. 1 and important to remember is that this is written for 2 a person with no medical training or we should assume 3 that they have no medical training. 4 So training is defined as the teaching 5 provided by the manufacturer. So the medical expert 6 can train the lay user. And the lay user is able to 7 use the device successfully. 8 So the aim for the training should be to 9 be able to conduct safe and effective nocturnal 10 hemodialysis treatments. The length of training has 11 been reported to be from two to eight weeks. 12 Agar in Australia in 2003 and Leitch in 13 the London daily in nocturnal hemodialysis, NHD, this 14 also depends on the past experience of the patient and 15 prior exposure to home dialysis or hemodialysis in 16 center or at home. 17 Let me add this now. For the purpose of 18 testing the adequacy of the training, it would be 19 ideal to have patients who have no exposure to 20 hemodialysis prior to entering the trial. The main 21 reason for it is to test the adequacy of the training. 22 So what we would like to see at the 23 completion of the training is an appropriate use of 24 the hemodialysis device, interpretation and use of
  • 86. 1 safety features and accessory hemodialysis treatment 2 itself, on evidence or a test to confirm the adequacy 3 of the training. 4 So, yet, we would like to minimize the 5 burden on labeling and training. So we have come up 6 with a list of risk analysis that we would like you to 7 consider and see the completeness of this list. And 8 maybe there are a few things that we might be missing. 9 Inadvertent disconnections, blood loss 10 from increased frequency of treatment, potential 11 increased rate of vascular access infection, and the 12 psychological effects. 13 Let me tell you that none of this has 14 actually been reported in the literature with the 15 exception of blood loss. And that might be one of the 16 reasons why anemia has not shown a significant 17 increase or a significant change, a clinically 18 significant change in the daily treatments. 19 Inadvertent disconnections have not been 20 reported. However, once the treatment goes into the 21 broader marketing population, would the adverse events 22 reported be still applicable to the wider population 23 and the marketing population? Would that be still 24 reflective of the results of the trials and the
  • 87. 1 publications? 2 So disconnection could, as we all well 3 know, be life-threatening and if the patient is asleep 4 may not even realize that he is bleeding. 5 The potential increased rate of vascular 6 access infections again has not been documented. And 7 the psychological effects could be positive or 8 negative. That is another thing that we need to 9 assess. 10 So now we are going to go into the 11 clinical studies. And I will divide this into the 12 purpose of what we think a clinical study is needed, 13 patient selection, inclusion, and exclusion criteria, 14 to ask for your help, to ask for your help in the 15 optimal design to test the device in actual use 16 conditions. 17 So the purpose is to demonstrate the 18 safety and effectiveness of the nocturnal hemodialysis 19 device under actual use conditions. This is not 20 intended to evaluate the long-term morbidity and 21 mortality of nocturnal hemodialysis as a therapeutic 22 modality compared to conventional hemodialysis. 23 So our concerns are the patient selection 24 for trial. Can this be reflective of the patient
  • 88. 1 selection when the device goes for marketing? Again, 2 for the trial, in order to test the adequacy of 3 training, we would like patients that do not have 4 prior training or prior exposure to home dialysis. 5 And this is just to test the training. Once it goes 6 to marketing, of course, patients with prior 7 experience would probably be preferable. 8 We would like to make sure that the 9 patient is able to perform the entire treatment and 10 that the patient is actually able to attend the 11 alarms. So, again, the adequacy of the alarms becomes 12 an issue. 13 In terms of patient selection, there is 14 different literature. And let me go through these 15 three citations. Agar in 2003 -- he's from Australia. 16 He included in his prospective study 16 patients. The 17 selection criteria was they must be clinically stable 18 for more than three months on hemodialysis. They 19 should be psychologically sound, technically adept, 20 stable and have a supportive home and a history of 21 compliance. So this is already excluding a large part 22 of the population. 23 Alloati in Italy in 2002 also had a 24 non-randomized prospective study, including 18
  • 89. 1 patients. Let me point out here the important thing 2 is the diabetic nephropathy. It's only one patient of 3 18 patients. And the U.S. population, as I mentioned 4 earlier, is 45 percent. So, again, this type of 5 selection is not representative of the marketing 6 population in the U.S. 7 Covic, this is a retrospective 8 observational study of 286 patients in the U.K. He 9 basically started his analysis since 1960. Initially 10 the patients in nocturnal dialysis excluded older and 11 frailer patients, exclusively excluded patients with 12 diabetes, cardiac failure, and multiple myeloma, 13 although that plan has changed. And now they are 14 including about 33 percent of diabetic patients. 15 So should the following be incorporated 16 into the selection criteria? And that is availability 17 of a partner or the possibility of monitoring. 18 Patient compliance, psychological well-being, and home 19 environment, which most of these items are already 20 addressed by Medicare, to have an adequate water 21 supply, adequate sewage, adequate electricity, 22 adequate space, and social interaction. 23 So once patient selection is discussed in 24 regards to an optimal study design, what would the
  • 90. 1 clinical endpoints be the best to assess this study 2 design in terms of effectiveness and safety and 3 adverse events? 4 In addition to what is conventional 5 dialysis, should a control group be necessary? And 6 should it be randomized or should the patient be their 7 own control? The length of follow-up is also an issue 8 and the sample size. 9 Let me just briefly tell you that on home 10 hemodialysis studies, what we have done is a small 11 number of patients, less than 30. The time frames are 12 an observational period during in center; then the use 13 in center of the device in question; then a wash-out 14 period, where the patient doesn't have this device. 15 And then they go home with the device, and there is 16 continuation of the study. 17 So these are treatment-related issues 18 include the dialytic composition, which may change 19 with more intense and more frequent hemodialysis, the 20 additives on the possibility of using phosphate, as 21 reported by several of the clinical studies I've 22 mentioned, administration of anticoagulation and the 23 type of anticoagulation, what kind of dialyzer to use, 24 and whether monitoring should be encouraged or
  • 91. 1 required, and what type of monitoring, vascular access 2 and what type of access would give the safest 3 connection to the device and the practice of reuse. 4 In conclusion, we would like your help for 5 eventually creating a guidance document in creating an 6 optimal device design for actual use conditions, 7 adequate labeling to minimize error, appropriate 8 training for successful treatments, risk analysis to 9 minimize unforeseen problems, and clinical study 10 design to demonstrate safety and effectiveness of the 11 device itself under actual use conditions. 12 Thank you. 13 CHAIRPERSON TALAMINI: Thank you very much 14 for very clear presentations from all of the FDA 15 personnel. 16 I would like to now offer the panel the 17 opportunity to question the FDA regarding these 18 presentations. In the interest of a smooth day, I 19 would encourage you to not ask questions that we know 20 are going to be discussed or are already within the 21 scope of the questions that we are going to be going 22 through as a panel, but try to ask questions that are 23 either outside of that scope or are clarification 24 questions about that which has been presented.
  • 92. 1 So, with that caveat, are there any 2 questions? Dr. Blagg? 3 5. QUESTIONS FOR THE PANEL 4 DR. BLAGG: I would like to raise an issue 5 about the definition of nocturnal home hemodialysis 6 because there are patients -- 7 CHAIRPERSON TALAMINI: A little bit closer 8 to the microphone, sir, if you could. Thank you. 9 DR. BLAGG: Okay. I would like to raise a 10 question about the definition of nocturnal home 11 hemodialysis, which in this case is limited to a 12 treatment frequency of five to seven days a week. 13 There are patients in this country and elsewhere doing 14 it three times a week or alternate nights. 15 And I think that the difficulty comes. 16 What we need to do is define nocturnal dialysis as 17 dialysis which is done overnight to any frequency and 18 define five or more times a week dialysis as nightly 19 dialysis to clarify the difference. 20 CHAIRPERSON TALAMINI: So noted. And I 21 think through the day today, it appears to me as a 22 non-nephrologist, that there really are two global 23 issues that we need to deal with. One is the fact 24 that this is being done at home, as opposed to in a
  • 93. 1 center. And the second is the issue of frequency and 2 whether it's better for patients to have more frequent 3 dialysis. 4 But with that question, do any of the FDA 5 speakers have a response to the issue of the 6 definition? 7 DR. MITCHELL: Hi. My name is Dr. Dianne 8 Mitchell. And I'm the chief medical officer for this 9 division. 10 I think those two definitions are fine. 11 What we need to keep in mind, though, is that we will 12 be asking you to give us guidance for both types of 13 dialysis you identify. 14 CHAIRPERSON TALAMINI: Other questions for 15 the panel? Dr. Sadler? 16 DR. SADLER: I would just like to make the 17 point that a couple of presenters considered the 18 material provided by the manufacturer to be the 19 training or a large component thereof. And the 20 training actually is the responsibility of the medical 21 team in the dialysis facility doing the training. 22 And the manufacturers will provide 23 background information, but my experience would say 24 that the further the manufacturers go with the details
  • 94. 1 of clinical steps to be taken by the team, the more 2 they see themselves exposed to liability. And so 3 they're fairly reluctant to do that. 4 And I don't think we should assign them 5 this responsibility except for characterizing their 6 product, its operation, and the rational hazards 7 associated with it. 8 CHAIRPERSON TALAMINI: So noted. Dr. Hoy? 9 DR. HOY: Dr. Mendelson said he felt that 10 patients might actually be more toxic pre-nocturnal 11 dialysis than patients in the center. In fact, that's 12 not. Perhaps I misunderstood what you said, that 13 they're certainly not more toxic. They're 14 well-dialyzed, much better dialyzed than our own 15 center patients. And their cognitive function is 16 markedly improved. 17 DR. MENDELSON: Yes. I think they didn't 18 explain it correctly. At the beginning of each 19 session at night, they are more toxic than they would 20 be at the end of the previous session. I wasn't 21 comparing the clinical setting to the home setting. 22 I was simply saying their abilities may be 23 compromised at the beginning of a treatment session 24 relative to the end of the treatment session.
  • 95. 1 DR. HOY: I certainly -- 2 DR. MENDELSON: Or relative to their 3 recovery from the treatment session. 4 DR. HOY: In my experience, that is not 5 the case. These patients don't seem to show a major 6 cognitive difference between the morning and the 7 evenings because they are dialyzed 48 hours a week. 8 So I'm not sure that that is a real concern. 9 DR. MENDELSON: Okay. Thank you. 10 CHAIRPERSON TALAMINI: Other questions? 11 Dr. Lockridge? 12 DR. LOCKRIDGE: Yes. On the issue of the 13 human factor -- and you cited the part about the 14 hospital error. There wasn't anything discussed about 15 the fact that when you empower a patient, they become 16 much more adept and much more responsible for their 17 care. 18 The factors of the 98,000 deaths per year 19 in hospitals are based purely on the fact that 20 personnel in the hospital are making mistakes. And I 21 think we have to be very aware that there is something 22 that is very positive about empowerment of patients. 23 DR. MENDELSON: Yes, there is. Now, we do 24 know that error involving medical devices probably
  • 96. 1 plays a -- it's not even half of those reported 2 deaths. It accounts for a minority of those deaths 3 because so many of these deaths involve medication 4 errors. 5 But in looking at home use devices, we 6 feel that the compromises of the patient in the 7 environment need to be considered to the point where 8 they play a significant role, just as the fact that 9 although in the clinical role you'll have a highly 10 trained, experienced person delivering care, that 11 person may be overtired or may be distracted because 12 of many different responsibilities or many devices, 13 which pose conflicting operation methods. 14 I realize there are patients who are so 15 adept at use of their home use devices they sort of 16 fall into a pattern. Actually, some patients fall in 17 love with their home devices, and they will not part 18 with them, even though there are better designed, 19 safer, perhaps even more friendly devices on the 20 market. I recognize that. 21 CHAIRPERSON TALAMINI: Dr. Aranoff? 22 DR. ARANOFF: I would like to come back to 23 something that Dr. Blagg brought up, and that is the 24 definition of this therapy because, especially if, as
  • 97. 1 Dr. Neuland pointed out, we want to perhaps come up 2 with a new document, advisory document, I think we 3 need to think differently about the way that this 4 therapy is defined because if we define it on the 5 basis of blood flow, 200 versus 400, that is the wrong 6 pathway because you can exsanguinate very quickly at 7 200 milliliters a minute, just as you can at 600 8 milliliters a minute, or if we define it by starting 9 the machine after sundown versus at sunrise, that's 10 also the wrong pathway. 11 This therapy is fundamentally different 12 than in-center hemodialysis or previous home 13 hemodialysis in the way that it is monitored, not how 14 fast the blood goes or the dialysate flow rate or the 15 time of day or the duration of the therapy. It has to 16 do with the way the treatment is monitored at home. 17 Traditional home hemodialysis, not too 18 differently than traditional in-center hemodialysis, 19 is monitored by more than one individually usually, by 20 somebody who is awake and alert and can respond to 21 traditional kinds of alarms and so forth. This form 22 of therapy is defined differently in that patients 23 will be unconscious when the therapy is performed, 24 largely. And, therefore, the whole concept of how we
  • 98. 1 view this therapy needs to be different than simply 2 the superficial markers of blood flow, dialysate flow 3 rate, duration, or time of day. 4 Bob? 5 DR. LOCKRIDGE: I agree with you, but I 6 think that the lower the blood flow rate, limiting the 7 ultrafiltration, and going slow and long impacts on 8 all the things that you're trying to monitor that we 9 keep hearing are very bad in center. 10 When you run somebody at a blood flow rate 11 of 500, dialysis flow rate at 600, and you pull 6 12 kilos in the first 3 hours, they're going to all get 13 sick. The autonomic system is cranked up, and they 14 get sick. When you do at a 2 to 3 hundred ratio and 15 you only pull 300 cc's an hour, they never get sick. 16 So I think it's clearly a difference. 17 CHAIRPERSON TALAMINI: Hold it. Time out. 18 This is all valuable stuff, but I want to make sure 19 that we ask the questions of the FDA that we want to 20 ask them during this time period. So this is all very 21 valuable, but I want to make sure we take this time 22 for clarifications or things that are outside the 23 scope of the questions that we will already be 24 discussing.
  • 99. 1 Yes? 2 DR. MITCHELL: This is Dr. Dianne Mitchell 3 again. I was just wondering if I could make a comment 4 in response to Dr. Sadler's comment about device 5 training versus clinic training. 6 We at the FDA do recognize that there is a 7 difference between those two. I think there was a 8 reference to it in one of Dr. Zacharek's slides. 9 The purpose of the discussion today 10 regarding training is indeed for you to address what 11 you think is appropriate for the device manufacturers 12 to do in conjunction with training on their device. 13 Thank you. 14 CHAIRPERSON TALAMINI: Thank you. 15 Other questions for the FDA? Dr. Weinger? 16 DR. WEINGER: Yes. I think many of the 17 issues with regard to the use of these by patients is 18 going to depend somewhat on what percentage of this 19 280,000 patients ultimately would be subject to this. 20 So are there any estimates from the FDA of 21 what kind of patient population? Right now there are 22 100 or 150 or something. When these devices become 23 available, how many are going to be on this? 24 DR. RUIZ-ZACHAREK: Yes. It's hard to
  • 100. 1 predict. Right now I wanted to mention that there is 2 a very limited number of patients. And these are 3 highly selective in each trial. When it goes to the 4 marketing, that selection may or may not still be 5 there. 6 What I wanted to point out is the patients 7 in the general population on dialysis in the United 8 States have a lot more comorbidity than the patients 9 included in these studies. With the impact of a device 10 going into the market, specifically labeled for 11 nocturnal home hemodialysis, we don't know. 12 But we want to make sure we take the 13 safety precautions to deliver safe and effective 14 treatment among that population. 15 CHAIRPERSON TALAMINI: Thank you. 16 Who has not? I think let's go back to Dr. 17 Hoy. 18 DR. HOY: Just a comment, Dr. Ruiz. I 19 think there has been an evolution of the selection of 20 these patients, which isn't perhaps apparent in some 21 of the published literature since it's usually two to 22 three years behind what actually has occurred. 23 In our center, we have trained 49 24 patients. Seventeen of them are diabetics. They have
  • 101. 1 all of the diabetic complications, including 2 peripheral neuropathy and difficulty with manual 3 dexterity, blindness. We have one legally blind 4 patient hose husband is deaf. The two of them can run 5 this machine at home. We have a matched set there. 6 The patients, 41 out of 49 of our patients 7 were over 200 pounds. These are the hardest patients 8 to dialyze adequately. They were all excluded from 9 the hemo study. These are patients that we're using 10 nocturnal dialysis as salvage therapy for. They're 11 the ones who have the unquenchable thirst, you know, 12 who gain six to eight kilos between treatments and 13 cardiomyopathies with ejection fractions in 5 of our 14 patients with less than 25 percent. 15 So I think that you have to be careful 16 concluding that we are self-selecting these patients. 17 There is only one absolute criterion that our patients 18 have to have. And that is they have to want to learn 19 this. And we have not yet found a single patient we 20 could not train if they wanted to learn it. 21 And our most difficult patient was a child 22 psychiatrist. She took 79 days to learn how to do 23 this. 24 DR. RUIZ-ZACHAREK: Yes. As you said, the
  • 102. 1 trends have changed. In fact, most of the benefits or 2 the people, some of the patients that most benefit 3 from this type of modality are overweight patients, 4 patients with sleep apnea. Pierratos have included 5 patients with overweight that demand a lot more 6 dialysis than the conventional hemodialysis can 7 provide. 8 That's why sometimes diatolic flows go up 9 to 800. Sometimes the blood flows can go higher than 10 what nocturnal dialysis tends to have, slower than 11 conventional. 12 So yes, the benefits, you know nobody can 13 deny that the benefits will, the suggested benefits by 14 the published literature, the patients that most will 15 benefit from that are the patients that may have 16 already been excluded by other clinical trials or by 17 other publications. But we cannot deny that they're 18 probably going to be the ones that most benefit from 19 it. 20 CHAIRPERSON TALAMINI: I would warn the 21 panel our time for asking questions is running very 22 quickly. So succinct if you can, please? Dr. 23 Lockridge? We'll just go around one more time, and 24 then we'll --
  • 103. 1 DR. LOCKRIDGE: This is to Dr. Neuland. 2 It really comes out that the guidance document is one 3 of the things that appears to be that we are going to 4 try to develop here today. Is there any direction 5 that you would give to us as panelists of how to help 6 you do that? I mean, I think that's a critical issue 7 that we are trying to develop. Tell us what are our 8 directions or try to educate us a little bit more 9 about that. 10 DR. NEULAND: Well, I think that the two 11 main issues have already been brought out, and that is 12 whether you have any recommendations on design of a 13 device that would make it safer for the medical 14 community. 15 Because in the guidance document, our 16 overall plan is to put in issues that need to be 17 addressed in a submission to the FDA for marketing 18 clearance. And that would include anything to do with 19 specific issues related to the design of the device or 20 with the clinical trials that we hope to have done to 21 support these marketing clearances. 22 DR. AFIFI: Dr. Talamini? 23 DR. NEULAND: Plus, you're going to be 24 addressing these, I think, --
  • 104. 1 CHAIRPERSON TALAMINI: I'm going to go 2 around real quick. 3 DR. NEULAND: -- in the questions that 4 you're going to cover today. 5 CHAIRPERSON TALAMINI: Dr. Blagg? 6 DR. BLAGG: I don't know whether we're 7 going to cover more about the question of patient 8 selection later on. Are we or not because I would 9 like -- 10 CHAIRPERSON TALAMINI: Yes. 11 DR. BLAGG: Okay. 12 CHAIRPERSON TALAMINI: It is certainly 13 within the questions. 14 DR. BLAGG: I will save the comment for 15 later. 16 CHAIRPERSON TALAMINI: Yes, Dr. Gibson? 17 DR. GIBSON: Just a clarification. Josh 18 Nipper said that FDA labels current systems as 19 contraindicated as the sole method of monitoring 20 patients during hemodialysis. Is that aimed at 21 nocturnal hemodialysis? Is the FDA now regulating 22 that in some way or is this -- 23 MR. NIPPER: Well, that was in relation to 24 any remote monitoring systems. That was part of our
  • 105. 1 initial concern that the current information we had 2 was limited to in-center type devices. So we were 3 concerned when we see devices that connect to the 4 internet and can transmit data remotely. That was one 5 of our concerns for nocturnal or just general home 6 use. 7 So both of those were contraindicated or 8 all of the devices have been contraindicated as the 9 sole method. So as long as there is a partner there, 10 we kind of are hands off on whether a device goes home 11 under practice of medicine, but it is contraindicated 12 without a partner. 13 DR. GIBSON: So you label it for that. 14 And if someone sends a patient home now without a 15 partner, you would if you found out about it take some 16 steps? 17 MR. NIPPER: Well, I mean, that would be 18 right there under practice of medicine. A physician 19 can send any device home that they want to. It does 20 provide guidance to the physician that we do not think 21 that the remote monitoring should be the only way to 22 monitor the patient. 23 CHAIRPERSON TALAMINI: Perhaps I could ask 24 somebody from the FDA at this juncture to clarify for
  • 106. 1 us the practice of medicine issue versus FDA 2 guidelines because that is going to play so vitally 3 into the discussions today. 4 MS. BROGDON: The guidance that we will 5 eventually be developing is guidance for the 6 manufacturers, what they should submit to us in order 7 to get the labeling and the clearances that they 8 desire. Regardless what gets cleared, it's the 9 physician's right to use a device as he sees fit in 10 his professional judgment. So we regulate the 11 manufacturers on what information and what devices 12 they can supply. 13 CHAIRPERSON TALAMINI: Thank you. 14 Dr. Afifi? 15 DR. AFIFI: I have a fundamental question 16 about policy that relates to a 510(k) pre-market 17 notification. The question is probably for Dr. 18 Neuland. 19 When we are required to see whether 20 something is demonstrated to be substantially 21 equivalent to an existing device, the process is 22 similar to an evaluation process. And the question, 23 then, are we evaluating just the process; in other 24 words, the delivery of whatever the product is
  • 107. 1 supposed to deliver, or also the outcome? 2 And that, then, relates to a slid that Dr. 3 Ruiz-Zacharek presented, where she said that we need 4 to demonstrate the safety and effectiveness of NHD but 5 not evaluate the long-term morbidity and mortality of 6 NHD as compared to conventional procedures. 7 DR. NEULAND: Okay. Hemodialysis 8 equipment currently and all of the other medical 9 device components are regulated under the 510(k) 10 process. 11 When those products are cleared, -- 12 they're not actually approved; they're cleared -- we 13 are determining whether the product is as safe and as 14 effective as the other devices that are currently on 15 the market. It's more of a comparison. 16 What Dr. Zacharek was trying to say in 17 that slide -- and she can add to it if she would like. 18 Basically we did not feel that this equipment, that it 19 was FDA's role to determine whether nocturnal dialysis 20 as a modality in general was better than or worse than 21 current conventional practice of medicine with the 22 equipment that is currently used. We were looking at 23 whether the equipment as designed can do a safe and 24 effective treatment basically or series of treatments
  • 108. 1 for the patient. 2 So that's why the studies for morbidity 3 and mortality to us are more of a broad scope study, 4 one the NIH might sponsor or something like that 5 nature, not an individual manufacturer would have to 6 demonstrate and prove before their product could go to 7 market. 8 DR. AFIFI: I see. I see. And with that, 9 Dr. Talamini, I have another point, but I think it can 10 wait for the later discussion. And that is the role 11 of redundancy in the design. That is something that 12 can wait. Is that correct? 13 CHAIRPERSON TALAMINI: Yes. We will 14 certainly be covering that later. 15 Dr. Sadler? 16 DR. SADLER: I think I am remiss in not 17 commending all of the speakers for being lucid and 18 clear and making good presentations. But I do have a 19 few points to bring up that I think are important. 20 I think this is still intermittent 21 hemodialysis therapy. It's a different application. 22 And it's a different site in some ways. But it is not 23 a completely different therapy. It is possibly 24 improved, but it is still the same thing.
  • 109. 1 The point in that is that if someone 2 should come forward and ask to have their device 3 labeled for nocturnal hemodialysis, you can be sure 4 that almost everybody who has one that's already 5 approved for other hemodialysis applications will be 6 in the same queue very shortly. So we're still 7 talking about hemodialysis and what goes on. 8 When Dr. Mendelson talked about alarms, he 9 talked about the sound and what goes on with them, but 10 we have to realize that probably the worst thing about 11 alarms is false alarms. It frightens patients. It 12 frustrates patients. And it causes them not to 13 respond appropriately to alarms. 14 As a former chair of the AAMI committee, I 15 would be remiss if I didn't point out that in our 16 comments about water, you must recognize that the 17 increasing water quality requirements have nothing to 18 do with problem-solving. 19 There is no one who has ever been harmed 20 by water that met the original standard enunciated in 21 1982. The standard has risen as our capability to 22 purify water and to monitor what we have accomplished 23 has increased. 24 So that there really hasn't been any
  • 110. 1 rational force for problem-solving. It's just a 2 matter of admiring our capacity and responding to 3 that. 4 And the final point, I want to remind you 5 that passive restraint levels of safety are still not 6 absolute. If you have an air bag, you still have to 7 learn to wear your seat belt. You have to learn to 8 drive. We have to build safer highways and avoid 9 distractions. There is no single passive restraint 10 that is going to create safety in an automobile or 11 when you are attached to a hemodialysis machine. 12 And one last point, it's always been my 13 experience since Dr. Blagg and I both did overnight 14 hemodialysis with our patients almost 40 years ago 15 that the patients dialyzing at home asleep had the 16 same kind of sensitivity that the mother of a young 17 child. When the alarm goes off, they rouse, much 18 better than someone who doesn't recognize that it is 19 important to them. 20 CHAIRPERSON TALAMINI: Comment? You can 21 respond as if it were a question. 22 DR. MENDELSON: The time I had for my 23 presentation was quite limited. And one of the points 24 I wanted to make about alarms -- well, several -- was
  • 111. 1 it's my understanding that the false alarms outnumber 2 the legitimate alarms. 3 And what I am concerned about in the home 4 at night is the effect on the patients psychologically 5 and physiologically if he or she is roused over and 6 over and over again. 7 We know that interrupted sleep has an 8 adverse effect on the patient's health. And whether 9 this problem is limited to the patient's health or the 10 patient's health and their ability to operate the 11 therapy, I'm wondering if people knowledgeable about 12 the physiology of sleep can address that. 13 Thank you. 14 CHAIRPERSON TALAMINI: Thank you. So I 15 think we will close the questions to the FDA and again 16 thank the FDA presenters for very clear presentations. 17 What I would like to do is call for a 18 ten-minute break, but let me just frame the rest of 19 the day quickly before we do that. We have a 20 Herculean task to cover these eight questions. We 21 could probably spend one day on each question. So 22 it's going to be absolutely vital that we move along 23 quickly. And hopefully everybody will not hate me by 24 the end of the day in driving the committee towards
  • 112. 1 doing so. 2 But I would like to take a quick 3 ten-minute break. My objective is going to be to do 4 two questions and then break for lunch. I would 5 remind the committee not to discuss the issues that 6 are at play here outside of the room, as all of the 7 proceedings here do need to be public and on the 8 microphones. 9 So we will reconvene in exactly ten 10 minutes, at 11:34. Thank you. 11 (Whereupon, the foregoing matter went off 12 the record at 11:24 a.m. and went back on the record 13 at 11:34 a.m.) 14 CHAIRPERSON TALAMINI: I would like to 15 call the panel back to order. Dr. Ruiz asked for the 16 opportunity to respond to some of the comments and 17 questions. So, Dr. Ruiz, if you could do so now? 18 Sixty seconds, if possible, please. You could use 19 this one over here perhaps. 20 DR. RUIZ-ZACHAREK: I would like to make 21 some comments on the concerns you raised about 22 nocturnal dialysis and hemodialysis being basically 23 the same modality. It could be. It's basically 24 hemodialysis.
  • 113. 1 And, as Dr. Pierratos said in one of these 2 publications, any type of conventional hemodialysis 3 machines could be used for nocturnal hemodialysis. 4 The concern comes when we send these 5 devices home with a patient that may or may not have 6 the experience or the appropriate training. So that's 7 our concern. It's not the fact that they have 8 hemodialysis itself because this is the same modality, 9 but, as somebody else pointed out earlier, it is the 10 monitoring. That's significantly different from 11 conventional dialysis and home nocturnal dialysis. 12 The other thing that I would like to point 13 out is on the quality of the water. Before all of 14 these standards, actually, patients were being 15 dialyzed with a little bit higher content of aluminum. 16 And they were having a lot of problems. 17 So the question is now we haven't had any 18 problems with the new standards, but would this be 19 still applicable for patients that are exposed to a 20 much higher volume of water in terms of dialysis or do 21 we need to regulate that or do we need to change the 22 quality in the water in former dialysis for patients 23 that are undergoing nocturnal dialysis? 24 And those are the issues that we would
  • 114. 1 like to raise and have you discuss on them. 2 CHAIRPERSON TALAMINI: Thank you. 3 DR. RUIZ-ZACHAREK: Thank you. 4 CHAIRPERSON TALAMINI: So all of those are 5 points that we will be getting to. So this meeting 6 now continues with the panel discussion portion of the 7 meeting. Although this portion of the meeting is open 8 to public observation, public attendees may not 9 participate except at the specific request of the 10 panel. 11 Now, again, some comments on our task 12 today. We have eight questions, which all of the 13 panel members had the opportunity to study prior to 14 the panel meeting today. And if you take the time 15 remaining, the number of panel members, and the 16 questions, that leaves about a minute and a half to 17 two minutes per panel member per question. 18 And, again, we could probably spend a day 19 on each of these questions. So I'm going to have to 20 be very tough with folks, unfortunately. 21 I would like to begin, however, by 22 offering the opportunity for each panel member to 23 offer any general comments. I would ask you please to 24 limit them to about 60 seconds, really the most
  • 115. 1 important points. 2 And I think since we have already had a 3 fair bit away from the right side of the table, I'm 4 going to start over on the left side. If you don't 5 have any general comments, feel very free to pass. We 6 would love you for it, but we would also love to hear 7 your comments. 8 Ms. Moore? 9 MS. MOORE: Yes. My only comment is that 10 in reading the material, my major concern was that we 11 have this technology, which is customarily used in a 12 hospital setting or a clinic of some sort, with 13 professionals in charge. And I was still concerned. 14 And I was very much interested in the 15 doctors over there who mentioned the fact, you know, 16 that they had had experience with patients who were on 17 nocturnal programs, but I know that we are going to 18 have patients with varying amounts of abilities, ages, 19 all kinds of conditions that may mitigate against some 20 of these people using the technology to the best that 21 the technology could offer. 22 And so I guess my major concern was some 23 kind of safeguards so that these people who may not be 24 as educationally able or the elderly persons or people
  • 116. 1 of that sort would be able to use this treatment to 2 the best of his or her ability. 3 And one other thing, the contact, you 4 know, what happens if things go wrong. I was looking 5 to see if there was any consideration given to making 6 contact with someone without being automated. In 7 other words, if there is an emergency, who do you 8 contact and will not get an automated message but you 9 would get a person? 10 CHAIRPERSON TALAMINI: Thank you. You 11 mean not get caught in a voice mail trap. 12 Dr. Duffell, your general comments? 13 DR. DUFFELL: Yes. I think one thing that 14 is going to be important when considering the 15 questions today, which has already come up briefly in 16 Dr. Neuland's remarks, is about the design of these 17 products. 18 CHAIRPERSON TALAMINI: A little closer, 19 please. 20 DR. DUFFELL: And we need to be mindful in 21 our deliberations that we probably shouldn't be trying 22 to actually design products here at this panel but, 23 instead, raising the issues which the manufacturers 24 need to address in their designs because they may have
  • 117. 1 creative ways that we haven't considered. 2 And then my second point is also to keep 3 in mind that it also seems like from one of the prior 4 FDA speakers is that the issue that we are really 5 looking at here, in addition to safety and 6 effectiveness of the products, is also the useability 7 of the products. 8 I think that one of the speakers brought 9 to mind the difference between a clinical trial and a 10 useability study. So I think what we are really 11 looking at here is making sure that these things are 12 useable more than they are effective. 13 CHAIRPERSON TALAMINI: Thank you. 14 Dr. Schulman, general comments? Sixty 15 seconds, please, if possible, or we can come back to 16 you. 17 DR. SCHULMAN: If you can come back, that 18 would be good. 19 CHAIRPERSON TALAMINI: Sure. 20 Dr. Sadler? 21 DR. SADLER: I think I made mine, but in 22 response to Dr. Ruiz, I do believe that if you look at 23 the water standards, the 1982 standard was fairly 24 complex and comprehensive. And what we have done is
  • 118. 1 to incrementally approve it. 2 But, as I say, there hasn't been a problem 3 to force those increments. We have only improved it 4 as our ability to do so occurred. And I guess in 5 admiration of our accomplishments, we raised the 6 standard. 7 You said in your comments that you worry 8 about the training. And I'm afraid that FDA has to 9 relax about that because you can't regulate it. And 10 we just have to get that done. And that becomes our 11 responsibility in our field. 12 CHAIRPERSON TALAMINI: Thank you, Dr. 13 Sadler. 14 Dr. Afifi? 15 DR. AFIFI: I have no general comments at 16 the moment. I will have several relating to design 17 especially later on. 18 CHAIRPERSON TALAMINI: Thank you. 19 Dr. Aranoff? 20 DR. ARANOFF: One additional thing that we 21 haven't mentioned is that although there are no 22 predicate devices for nocturnal home hemodialysis, 23 there is a great deal known about nocturnal peritoneal 24 dialysis.
  • 119. 1 And some of the concepts, although the 2 consequences of failure of the treatment or danger of 3 the treatments are very different with peritoneal 4 dialysis and less so, but some of the concepts about 5 design of monitoring and so forth might be applied 6 from that, might be drawn from that. 7 CHAIRPERSON TALAMINI: Great. Thank you. 8 Dr. Kalota? 9 DR. KALOTA: I think we need to keep in 10 mind that this technology is never going to be for 11 everyone. And we can't try and make it for everyone. 12 There are still physicians who are going to make the 13 decision whether a patient they feel is competent or 14 not and then in the training, are they still competent 15 to do it and that we need to make it safe for those 16 who both patient and physician feel are appropriate to 17 do so. 18 CHAIRPERSON TALAMINI: Thank you. 19 Dr. Gibson? 20 DR. GIBSON: Just very briefly. In most 21 of the material that we have when psychological is 22 mentioned, it's mentioned in terms of risk and 23 monitoring for detrimental effects. 24 I would like to congratulate Dr.
  • 120. 1 Ruiz-Zacharek for mentioning the possible benefits of 2 home dialysis, which may be considerable and which I 3 don't think we should lose sight of during the 4 deliberations today. 5 CHAIRPERSON TALAMINI: Thank you. 6 Dr. Weinger is our panel expert on human 7 factors. So I would void my 60 seconds and offer you 8 a few minutes if you need them for your introductory 9 comments. 10 DR. WEINGER: I'll just make two short 11 comments. First, the data that I have reviewed on 12 this shows tremendous promise. And I think that this 13 methodology and the devices associated with it are 14 going to be a superior method for a subset of 15 patients. 16 But the data that to date is based on 17 experience of individuals who have many years who have 18 evolved a practice -- and the reality in the future 19 with these devices is they are going to be 20 aggressively potentially marketed to clinicians who 21 don't have those years of experience. And they are 22 going to be trying it for the first time. 23 Our obligation as advisers to the FDA is 24 to promote patient safety. And I think that we need
  • 121. 1 to develop guidance, strong guidance, to industry 2 about the design indications and training that 3 maximize safety under those circumstances. 4 I have to disagree with Dr. Sadler about 5 training. In fact, training is well within the FDA's 6 purview. And, in fact, carotid stents is a good 7 example, which there are now regulations that say 8 every user, in this case clinicians, rather than 9 patients, every user, must undergo rigorous 10 simulation-based training before they can use the 11 device. And it's within the FDA's purview to make 12 similar requirements for patients, not that I am 13 necessarily advocating that at this time. 14 The last point I wanted to make in 15 response I think to Dr. Lockridge was that clinicians 16 make user errors. In fact, there's a study by Baden 17 in 2001 involving all of France where they showed the 18 use errors were the most frequent cause of all medical 19 device incidents and the second most common cause of 20 deaths associated with medical devices. 21 Now, these are experienced, highly 22 trained, highly educated individuals using a full 23 range of medical devices. Now we're talking about 24 patients, who are going to be far less educated and
  • 122. 1 perhaps less well-trained, but the issue is how 2 trained should they be, going to be using the complex 3 device. 4 So use error is clearly a problem. And we 5 have to help industry and the clinicians deal with it. 6 CHAIRPERSON TALAMINI: Thank you. 7 Dr. Gillespie? 8 DR. GILLESPIE: I would just like to say I 9 hope people will keep in mind as we go through this 10 the potential pediatric applications of these 11 machines. And I hope that the pediatric uses will be 12 considered part of the kind of overall design of the 13 machine, part of the initial labeling, and not an 14 afterthought or an off-label use because there are a 15 number of good reasons why children would be excellent 16 candidates, in some cases even better than adult 17 candidates for this. And certainly there is a 18 question all the way back to the first home nocturnal 19 dialysis patient. 20 CHAIRPERSON TALAMINI: Thank you, Dr. 21 Gillespie. 22 Dr. Blagg? 23 DR. BLAGG: I would just like to remind 24 you as we talk about these machines, that the first
  • 123. 1 home dialysis machine developed in 1964 was the first 2 single patient machine. It was the first machine 3 which was monitored. And it's really the basis of all 4 of the machines we use now. So a home dialysis 5 machine is where it all started. 6 And the second comment, just a brief one 7 in terms of patients, we did a study once when we had 8 a psychologist come in and do IQs on 100 successfully, 9 consecutive successfully, home-trained home patients. 10 And the IQ ranged from 87 to 147, with an average of 11 103, which he told us is just where it ought to be as 12 we did not take the really low-level effectives. 13 Like some of the previous speakers over 14 here, I think almost anybody technically can do this 15 if they are motivated and everything else falls into 16 place. 17 CHAIRPERSON TALAMINI: Thank you, Dr. 18 Blagg. 19 Dr. Moran? 20 DR. MORAN: I would like to echo Dr. 21 Kalota's comments. There are two places where you can 22 make a choice about sending the patient home. First 23 of all, the health care team can look at the patient 24 and say, "Does this patient look suitable for home
  • 124. 1 therapy?" 2 And then you have the training period, 3 which is two or four or six weeks. And, again, the 4 patient can be assessed every day during that training 5 period. And we can abort the home decision at any 6 time during that training period, and we do. 7 I think that the other point that I would 8 like to make is we keep on talking about professionals 9 doing it in the center and nonprofessionals doing it 10 at home, but at home you've got one person operating, 11 one device on one patient. And that is very, very 12 powerful. The same person is sticking the same 13 access. 14 It's very different from a patient coming 15 into a center, who could have any one of 20 16 professionals who may or may not have seen this access 17 before. 18 CHAIRPERSON TALAMINI: Thank you, Dr. 19 Moran. 20 Dr. Lockridge? 21 DR. LOCKRIDGE: Well, I think to me the 22 most overall comment would be that the FDA has invited 23 the clinicians who are doing this and that this whole 24 process is a process of physician-patient
  • 125. 1 decision-making to see whether or not it's better or 2 worse for the patient. And we are looking for the FDA 3 to give guidance to manufacturers to try to certainly 4 make things safe, but it's that balance. 5 I need to have the choice with the years 6 of experience that I have to choose with patients the 7 FDA needs to protect the overall public. So we need 8 to work together to come up with conclusions. 9 CHAIRPERSON TALAMINI: Thank you. 10 Dr. Hoy? 11 DR. HOY: Just I'm more confused than ever 12 as to whether the jurisdiction is simply the concerns 13 with the machines or access or ROs or water or 14 dialysate or what or monitoring. I mean, it sounds 15 like the FDA -- in fact, you could go in any direction 16 you wanted, but it's to go to the manufacturers 17 ultimately I guess, right? 18 CHAIRPERSON TALAMINI: Well, I think that 19 that is actually a good way to conclude this part 20 because what we really do need to figure out is what 21 the objective of the day is and how we are going to 22 get there. 23 So we have this set of eight questions, 24 and we need to go through them. You have all looked
  • 126. 1 at them. And they do cover a broad array of topics 2 and issues, some of which are directly on point of the 3 machines and how they work and some of them have to do 4 with access and other issues related. So our job for 5 the rest of today is to do our best to answer those 6 questions and to provide the information. 7 Now, again, that is a Herculean task. Let 8 me tell you how I hope that we can do it. And we will 9 try this with the first question. What I hope to do 10 is go around the table, give everybody a minute and a 11 half to address some piece of the question, hopefully 12 a piece that has not already been addressed earlier 13 going around the table. 14 If you've got nothing to say, a pass is 15 just fine. By doing that, hopefully we will get all 16 the way around and have most of the information and 17 still have time to go back and see if there are things 18 that we have missed or other things that we need to 19 discuss. 20 I would also make it clear to the panel 21 and to the audience that we are not voting for 22 approval or disapproval of any specific device today. 23 There may be times where I as the chair ask for a 24 straw vote from the panel to gauge opinion of the
  • 127. 1 panel as a whole, but I don't want in any way for that 2 to be construed as any sort of official panel vote of 3 approval or disapproval. If we do that, it would only 4 be to try and get the temperature of this group here 5 today. Now, if that strategy does not work as we move 6 along through the day, we'll modify it as best we can. 7 So the way we will actually go through 8 this is to read these questions one by one and then go 9 around the panel. And we'll start at a different spot 10 with each question and go clockwise so that everybody 11 has an opportunity as much as possible to respond. 12 So with that, if we could put up the first 13 panel discussion point, which is on device design? 14 And I will read this question, "Standard hemodialysis 15 delivery devices contain monitors and alarms to assess 16 blood pressure, pulse, venous and arterial pressures, 17 blood and air leaks, temperature, dialysate and blood 18 flow, ultrafiltration rate, acid and bicarb pumps, end 19 of treatment, and other parameters particular to the 20 specific device. 21 "Please consider and discuss the need for 22 the following additional safety features in nocturnal 23 home hemodialysis, NHD, treatments and provide 24 suggestions for additional features. You should take
  • 128. 1 into consideration the importance of human factors 2 when discussing these features." 3 Next slide. "Blood Access, a) additional 4 safeguards to prevent blood access disconnections; b) 5 alarms to detect fluid, blood or dialysate, leaks, and 6 a moisture detector at the site of hemodialysis 7 access." 8 Next slide. "Central monitoring, c) 9 software incorporated into the NHD device allowing 10 connection to the internet for remote monitoring; d) 11 central monitoring of treatment and patient 12 parameters, such as blood pressure, pulse, venous and 13 arterial pressures." 14 Next slide. "User-friendly design, e) 15 instructions displayed on the machine itself that are 16 clear and easy to follow for treatment setup, 17 discontinuation, troubleshooting, and disinfection of 18 the device; f) sensitive and loud alarms with clear 19 explanations of what they mean and how to respond; g) 20 a justification for leaving out any standard alarms or 21 features found in traditional hemodialysis equipment." 22 So that's quite a mouthful. It's probably 23 the biggest question, but our goal is to try and 24 answer that question over the next 30 minutes or so.
  • 129. 1 So, Dr. Hoy, if you could pick a spot in 2 there? 3 DR. HOY: Do them all or just a through -- 4 CHAIRPERSON TALAMINI: Well, I think it 5 would be impossible to go a through and still be on 6 time. So perhaps if you could think about what piece 7 of that you would like to address? 8 And if it has already been addressed, 9 please try and pick another piece. And that way, 10 hopefully we will get all the way around and get back 11 to the place where we can summarize and rediscuss some 12 of the points. 13 DR. HOY: So I guess I get to select one 14 out of those. I would like to comment on remote 15 monitoring since we do remote monitoring over the 16 internet in real time and collect the data from the 17 dialysis and the alarms. 18 We allow the patients to respond to the 19 visual and audio alarms. And our observer who is 20 watching the screen for 33 patients at the current 21 time responds after two minutes if the patient doesn't 22 fix the alarm. 23 I believe that remote monitoring is 24 useful. I don't think it is absolutely necessary.
  • 130. 1 And I know that there are definitely circumstances 2 where it is not going to be feasible in patients who 3 are too poor to have a second phone line and an 4 internet connection. 5 For us, we find it very helpful. It's a 6 very useful way to download information about patients 7 and what is going on with their treatments and 8 maintain a clear sense of where they are having 9 problems. It also helps us with some preventive 10 maintenance on the machines. 11 It also allows us to have some sense of 12 who is running and not running each night because 13 patients when they are well-dialyzed may tend to take 14 time off. 15 I don't believe that you need a partner at 16 home if you have remote monitoring with an observer. 17 The New York State Department of Health, which is, 18 believe it or not, harder on us than the FDA or CMS, 19 feels that we meet the criteria for a partner at home 20 using this as a virtual partner. 21 CHAIRPERSON TALAMINI: Dr. Hoy, just to 22 address Ms. Moore's question, do your patients have a 23 human they can get in touch with at night? 24 DR. HOY: There is a human being at the
  • 131. 1 other end of that alarm system from 9:00 p.m. to 7:00 2 a.m. every night. And if they do not respond to that 3 alarm within two minutes, he or she will call them up 4 on their second phone and talk to them. 5 Remote monitoring does not prevent bad 6 outcomes of catastrophic events. And we have had one 7 patient have a cardiac arrest on dialysis. Within 15 8 minutes, the emergency squad was there, called both by 9 the patient's wife and by the observer. The patient 10 was taken to the emergency room and died. 11 We have had one patient have a ruptured 12 kidney while on dialysis. And he was at home alone. 13 And the patient was saved by the observer, who had the 14 emergency squad called and had the door broken down so 15 that they could get in. 16 And we have had one patient who had -- 17 that's another issue. Never mind. That's it. 18 CHAIRPERSON TALAMINI: Okay. Thank you 19 very much. 20 Dr. Lockridge? 21 DR. LOCKRIDGE: I would address the blood 22 access. First of all, I think it's the physician and 23 the patient should decide the blood access associated 24 with the types of dialysis. It's not the manufacturer
  • 132. 1 or FDA I don't think. 2 I think there are really three different 3 types of blood access that need to be addressed: 4 number one, a catheter. Certainly about 27 out of 33 5 people or 25 out of 33 people I have at home now have 6 a catheter. The infection rate is much less because 7 of an interlink device and a disconnect device and how 8 the patient is handled. 9 So I think standard insulin or catheter 10 use is different in center versus at home. I think 11 it's a safer modality. I'm not saying that that 12 should be the primary access, but I think that FDA 13 needs to have the companies look at some way of 14 assuring a disconnect. A simple clam shell, a simple 15 interlink device would be of significant benefit. 16 As far as the A-V fistula and the 17 discharge of the needle or the graft, I think that the 18 A-V fistula using a button hole technique and just 19 simple tapering does prevent the needle from coming 20 out. 21 We have done 41,000 treatments at home. 22 We had never a needle come out in 41,000 treatments 23 with a simple taping procedure, the arm wrapped with a 24 fishnet, and then the lines anchored to the upper arm.
  • 133. 1 So there are real techniques that make 2 needles in the arm, whether it be in a fistula in the 3 lower arm in the upper arm, safe. The same thing that 4 goes with a graft. 5 So I think, in summary, vascular access 6 should be chosen by the physicians with the patient. 7 I think all three are safe. The real focus is on 8 whether or not, how we assure the connection. And 9 there are techniques out there with clam shells that 10 can prevent that. 11 Thank you. 12 CHAIRPERSON TALAMINI: So, Dr. Lockridge, 13 then just looking at point A, do I hear you saying 14 that additional safeguards are not needed to -- 15 DR. LOCKRIDGE: No. I think that clearly 16 in the home setting, Fresenius has developed a 17 disconnect system that clamps on the tube. We have a 18 clam shell. There is a disconnect device or a tape. 19 But if you use that and the patient 20 applies it -- and I think human error does happen. In 21 one case, I had a gentleman not go to sleep but put 22 himself on and did not put his clam shell on. He was 23 watching TV. And his catheter became disconnected. 24 And he had to stop the treatment.
  • 134. 1 So that's out of 41,000 treatments. But 2 it's a patient error. So if the manufacturer can 3 create a way, a red thing that has to be taped around 4 the catheter or there's a connection device that is 5 built into the tubing that connects to the catheter or 6 the needle, the needles once they are taped are okay. 7 So I think we just have to emphasize that the patient 8 should be responsible in that way. 9 CHAIRPERSON TALAMINI: How about alarms, 10 which is the second point of the access? 11 DR. LOCKRIDGE: In the 41,000 treatments, 12 when the patient puts or sets up or builds the unit, 13 they screw the blood line into the top of the kidney 14 and in the bottom of the kidney. And then there are 15 valves that connect to the kidney, the dialysate. 16 We have had one experience where the 17 person over-screwed the tubing arterial. They went 18 on, went to sleep, and through the night, there was a 19 slow drip of blood that resulted in about a unit of 20 blood loss over a night. 21 We have and Pierratos and everybody now 22 has a water detection, moisture detection, device, 23 which I think should go under the kidneys or where it 24 is or under the kidney machine, which would alarm and
  • 135. 1 prevent that from happening. 2 Once again, that is human error and if the 3 manufacturer can figure out a way that when you anchor 4 those lines in place there is a pop or something like 5 that. So the machines that are built with cartridges 6 or kind of packed in there, that decreases the number 7 of connections the patient has to make. 8 But I think that a moisture detector 9 device underneath the kidney would prevent that. 10 CHAIRPERSON TALAMINI: Great. Thank you. 11 Dr. Moran? 12 DR. MORAN: I think in view of the 13 eloquence of my colleagues, I should yield my 60 14 seconds. 15 CHAIRPERSON TALAMINI: Thank you. 16 Dr Blagg? 17 DR. BLAGG: I would just like to comment 18 again on central monitoring because I'm pleased that 19 Chris doesn't think it's essential because I don't 20 think it's essential at all. And many of the programs 21 that are doing nocturnal hemodialysis at this point in 22 time do not use central monitoring. 23 I think to have an internet connection so 24 that you could download information as to what
  • 136. 1 happened during dialysis at a convenient time would be 2 a nice addition where it's available, but it's nothing 3 essential. And in our program, we have one of the 4 training nurses on call 24 hours a day to answer all 5 patient questions. And we haven't seen any problems. 6 So I don't favor central monitoring. 7 Another point I would like to make is that 8 there are state issues here, too. I was at a meeting 9 recently where somebody from Texas was explaining that 10 for nocturnal hemodialysis in Texas, they're supposed 11 to take half-hourly blood pressures throughout the 12 dialysis, which would certainly not help patients 13 sleep. Apparently the Medicare surveyors in Texas 14 will actually want to find evidence that this is being 15 done. So there may be state regulations which may 16 have different effects on some of these things. 17 Thanks very much. 18 CHAIRPERSON TALAMINI: So we have already 19 heard two different opinions on central monitoring. 20 Perhaps I could just get the temperature of the panel 21 on that one issue. How many would favor central 22 monitoring being a requirement of such systems? 23 (No response.) 24 DR. GIBSON: Could we make that dependent
  • 137. 1 on whether the patient is alone or has a partner, 2 which I think makes a big difference? 3 CHAIRPERSON TALAMINI: I don't want to 4 make it too complicated, but -- 5 DR. SCHULMAN: I think that's essential. 6 I think you should make that difference. 7 CHAIRPERSON TALAMINI: Okay. So let's say 8 if the patient does have a partner. How many think 9 monitoring is -- 10 DR. WEINGER: Just to get more 11 complicated, are we assuming the partner is in the 12 same bed or in some room at the other end of the 13 house? 14 CHAIRPERSON TALAMINI: Present in the 15 house. 16 DR. WEINGER: Just in the house? 17 CHAIRPERSON TALAMINI: Yes. So how many 18 with that stipulation, a partner present in the house, 19 think central monitoring should be a requirement? 20 (Whereupon, there was a show of hands.) 21 CHAIRPERSON TALAMINI: Okay. Now, without 22 a partner in the house, how many think it should be a 23 requirement? 24 (Whereupon, there was a show of hands.)
  • 138. 1 CHAIRPERSON TALAMINI: So I think there 2 were six who said yes to that. Okay. So, again, just 3 a straw poll to get the temperature of the group. 4 Dr. Gillespie, you're -- 5 DR. LOCKRIDGE: Can I comment on the 6 central monitoring since the experience I have -- 7 basically we have not done central monitoring. I 8 would like to have ability to download it, but in 9 those 41,000 treatments, we have not identified a 10 single event that central monitoring would impact on 11 the safety of the patients or the response time to the 12 patients. And I think that is critical. 13 We have a 24-hour nurse on call that 14 directly is called and talks to the person. And we 15 have 8 of our 33 patients at home dialyzing by 16 themselves at home with nobody else in the home. 17 So I'm saying that it appears to be safe, 18 but I understand the viewpoint of the panel. 19 CHAIRPERSON TALAMINI: Thank you. 20 Dr. Gillespie? 21 DR. GILLESPIE: Just a quick comment on 22 alarms. I think we have to think very differently 23 about alarms than we do in in-center dialysis, where 24 we have alarms going off all the time, but because of
  • 139. 1 the slow blood flow and slow ultrafiltration rates, 2 it's much less common. So it may not be as much a 3 concern about disturbance of sleep and everything. In 4 the studies we were given, they said there were an 5 average of about one to two alarms a night. 6 I think in patients after they kind of 7 completed the initial training and got used to it but 8 certainly an important concern that we should look at 9 when we are evaluating these systems is, how often do 10 they alarm? And what does that do to the patients' 11 sleep? 12 CHAIRPERSON TALAMINI: Terrific. Thank 13 you. 14 Dr. Weinger, again I would offer you more 15 than a minute and a half since so many of these issues 16 are human factor issues. 17 DR. WEINGER: Well, thank you. Thank you 18 for the comment on alarm. I don't have to say as much 19 about that. So I'll just say that what alarms are 20 present need to have a high positive predictive value. 21 And false alarms are almost as concerning 22 as the absence of an alarm. In the presence of a 23 false alarm, at best, they're disruptive. At worst, 24 they're ignored or even disabled in some way that can
  • 140. 1 impair safety. And alarms need to be designed and 2 evaluated on any device. And IEC 60601-1-8 is perhaps 3 the best source for that. 4 More generally, I want to talk about -- 5 there's this whole section on user-friendly design 6 here. And I wanted to talk about that in a general 7 way. And that is that -- and I know this point has 8 been made, but I think it's critical that useability 9 testing is absolutely critical for these devices. And 10 it has to occur before the clinical trials and, in 11 fact, needs to occur throughout the design phase. 12 The process results and documentation of 13 the human factors engineering for the device need to 14 comply with current national and international 15 standards, which include ANSI AAMI HE 74, IEC 16 60601-1-6, and ISO IEC 62366. 17 The final thing with regard to design is 18 that there are a lot of questions later about labeling 19 and training, but I want to emphasize the importance 20 of designing the product right in the beginning to 21 minimize the need for patients to have training on how 22 to attach all of these connections, on how to run the 23 session, on how to respond to alarms. 24 The design should be sufficiently robust
  • 141. 1 that errors are prevented wherever possible, that when 2 errors occur, that there is safe and easy recovery, 3 that when the device fails, it fails safe. And then 4 you have issues of alarms. 5 The other thing to think about we will 6 talk about more is just-in-time training, where, 7 rather than just a beep going off, that the device 8 provides information about what is wrong and what one 9 needs to do to fix it at the time the event occurs. 10 And I think I will stop there. 11 CHAIRPERSON TALAMINI: Thank you. 12 Dr. Gibson? 13 DR. GIBSON: The only other thing I want 14 to add is that consideration should be given to having 15 instructions displayed, not just clearly in English 16 but clearly in other languages. At least in New 17 Orleans, we have many people who might well benefit 18 from this who do not speak English very well and don't 19 read English at all. 20 CHAIRPERSON TALAMINI: Thank you, Dr. 21 Gibson. 22 Dr. Kalota? 23 DR. KALOTA: Nothing more to add. 24 CHAIRPERSON TALAMINI: Thanks.
  • 142. 1 Dr. Aranoff? 2 DR. ARANOFF: A couple of brief comments 3 on each section. When it comes to the choice of blood 4 access, that's going to have to be a medical decision 5 based on the physical characteristics of whether the 6 patient can have a fistula conduit or a catheter. And 7 the devices should be designed to function equally 8 well with all three blood access, potential blood 9 access. 10 When it comes to monitoring the blood 11 access, redundancy has to be the key. However it is 12 monitored, there have to be redundant systems because 13 it is inevitable that a blood disconnection will occur 14 at some time. And there must be multiple system 15 failure before someone exsanguinates. 16 Central monitoring, whether or not it's 17 mandatory or not, it should never be allowed to be 18 used as the only way of monitoring patients. 19 With regard to user-friendly design, Dr. 20 Mendelson's talk could be used as a check-off list for 21 the design of these devices. They should be as 22 automated as possible. 23 They should not be designed in a way that 24 allows for use error. And patients should not be
  • 143. 1 allowed to move from one point of setup from treatment 2 to cleanup without completing all of the steps 3 sequentially in order. 4 And the devices should be designed in a 5 way so that alarms or the appropriate process cannot 6 be short-circuited, as they so frequently are in 7 dialysis units or in intensive care units. 8 CHAIRPERSON TALAMINI: Terrific. Thank 9 you, Dr. Aranoff. 10 Dr. Afifi? 11 DR. AFIFI: Yes. I would like to look at 12 it from the point of view of a public health 13 professional. The concern I think should be for 14 taking the optimistic view that Dr. Blagg offered that 15 this could actually be better than existing current 16 available technology. 17 I hope this will be the case, in which 18 case, though, what we want to pay special attention to 19 is something that Dr. Weinger said a minute ago. And 20 that is, if the device fails, we want to design it so 21 that it fails safe. 22 And that I think is a fundamental point 23 from the point of view of looking at the overall 24 results when analyzed on a population-based level that
  • 144. 1 building in the redundancy that Dr. Aranoff is 2 something that perhaps the FDA could think about 3 requiring in some way. I don't know what the actual 4 implementation of that would be. 5 CHAIRPERSON TALAMINI: Thank you, Dr. 6 Afifi. 7 Dr. Sadler? 8 DR. SADLER: Two quick points. One of the 9 items on here says, should we justify leaving out 10 standard alarms? I would say no. The standard alarms 11 are good, and we need them. 12 Secondly, the blood access is the greatest 13 source of anxiety and the greatest opportunity for 14 improvement. This is the one place where a central 15 catheter without needle access would be desirable. 16 And if product development is going to take place, a 17 central catheter that is more securely attached less 18 prone to thrombosis and infection would be an 19 advantage. 20 CHAIRPERSON TALAMINI: Just prerogative of 21 the chair here, does anyone disagree with Dr. Sadler 22 with regard to point G, justification for leaving out 23 any standard alarms or features found in traditional 24 equipment, just so we can be clear on that point? Dr.
  • 145. 1 Lockridge? 2 DR. LOCKRIDGE: Yes. I think the 3 traditional alarms, there's so much that has been on a 4 dialysis machine: sodium modeling; conductivity; 5 Kt/V, which has become standard modeling. All of that 6 stuff needs to go. It needs to be very simple for the 7 patient. And that's built into a lot of alarms there. 8 So that needs to go. 9 But as far as the standard alarms, we need 10 to keep them. 11 CHAIRPERSON TALAMINI: Any other comments 12 on leaving out alarms? Dr. Hoy? 13 DR. HOY: Our patients don't have a 14 problem with the alarms. We only have about 1.3 15 alarms per patient per night. What they have a 16 problem with is that sometimes they're more sensitive 17 than they need to be. And specifically for a 18 catheter, they would like a longer time before the 19 alarm goes off. And for a fistula, we would like a 20 shorter time before it goes off. 21 So we would like some variability built in 22 that allows us to set the alarms to go off dependent 23 on the access. 24 CHAIRPERSON TALAMINI: Great comment.
  • 146. 1 Dr. Lockridge? 2 DR. LOCKRIDGE: The other issue that we 3 found in training, hearing is a big issue as you get 4 older. And none of the machines are designed to deal 5 with a hearing deficit. We have developed a vibrating 6 connector to the machine that vibrates and puts under 7 the pillow. 8 So I think technology is out there. The 9 manufacturers need to look at that to deal with 10 hearing deficit. 11 CHAIRPERSON TALAMINI: Thank you. 12 Dr. Weinger? 13 DR. WEINGER: Just like any other feature 14 on these future devices, the alarms that are chosen 15 need to be tested in the end users. And so one can 16 vote in favor, as I would, of retaining alarmable 17 conditions, but the specific alarms and how they are 18 triggered and what they sound like probably will be 19 very different for a home device than for a device in 20 a dialysis unit. 21 CHAIRPERSON TALAMINI: Dr. Hoy? 22 DR. HOY: One last comment. When we asked 23 our patients how they would approve the alarms, some 24 of them have already done it. We use a Fresenius
  • 147. 1 2008H machine, which has buttons, not a touch screen. 2 And they have put tactile felt or something else on 3 the buttons to identify the ones that most commonly go 4 off, the arterial pressure button, so they can reach 5 out and just shut it off as they turn over and go back 6 to sleep. 7 Tactile probably is helpful, not useful 8 with a touch screen. 9 CHAIRPERSON TALAMINI: Great. Thank you. 10 Those are great comments. 11 Dr. Schulman? 12 DR. SCHULMAN: Well, I would also agree 13 with Dr. Sadler that the most worrisome issue is 14 worrying about a blood disconnect. And I think that 15 to the extent that the manufacturers can provide us 16 with a way to have these safeguards be set so that the 17 machine can't, the patient can't be treated unless 18 their force should be an important feature of design. 19 Secondly, I think I would like to know 20 about the quality of the treatment. So in central 21 monitoring, I think you can have a memory stick with a 22 USB port on the machine to capture it with the 23 parameters of the treatment, including things like Kt/ 24 V, that could be brought in for review periodically.
  • 148. 1 CHAIRPERSON TALAMINI: Thank you, Dr. 2 Schulman. 3 Dr. Duffell? 4 DR. DUFFELL: I'll pass. 5 CHAIRPERSON TALAMINI: Ms. Moore? 6 (No response.) 7 CHAIRPERSON TALAMINI: That is terrific. 8 Great job. We did that in 20 minutes. 9 So just a couple of other issues. I don't 10 think anybody discussed specifically point C in 11 central monitoring, and that is software as involved 12 with central monitoring. 13 Do any of the panel members have a 14 specific comment with regard to software? Dr. 15 Lockridge? 16 DR. LOCKRIDGE: Yes. I think that the 17 point about bringing in and clinically monitoring 18 these people, if you could have the machine designed 19 to be able to just take a phone line and plug it in, 20 hit a button, and it dials up and downloads the stuff 21 to my computer in the home training area, then I can 22 monitor each treatment each day, the nurse can, and 23 look at that. 24 The other thing is central monitoring is
  • 149. 1 critically -- in my population, I looked at it. Forty 2 percent of the people that I've sent home could not 3 afford two lines of internet connection. So when we 4 basically create a central monitoring, we're going to 5 select out the people, the haves and the have nots. 6 And that is not who is doing dialysis. 7 So I think we have to figure out a way to 8 not do that. 9 CHAIRPERSON TALAMINI: Dr. Hoy? 10 DR. HOY: A comment on this issue of the 11 software. This is done very differently all over the 12 world. About half of the units that are doing 13 nocturnal dialysis in the world are doing monitoring. 14 Let me take that back. It's about a third of the 15 units, but they constitute half of the patients. 16 For example, in Holland, their monitor, 17 their observer, is Lifeline. They find so few alarms 18 and so few problems that they outsource it to 19 Lifeline. They use people who are not trained in any 20 way, shape, or form to know anything about dialysis. 21 In Toronto, Dr. Pierratos brings people in 22 off the street who have no contact at all with 23 dialysis and trains them to be the observers. 24 This isn't rocket science. It really is
  • 150. 1 safe to do. And you can do it. And you can have a 2 set of protocols that allow us to know when to call 3 the nurse on call, when to call the doctor on call, 4 when to call the technician on call, and how to 5 intervene. 6 So that there are definitely software that 7 is useful. Fresenius has come up with a wonderful 8 system called Eyecare. There is another system out 9 there by Sebernius, which is what we use. These are 10 very good systems. They're not perfect, but they 11 work. And then you have protocols which are 12 implemented by the people watching. 13 CHAIRPERSON TALAMINI: Let me do Dr. Blagg 14 first. Then I will come around to Dr. Sadler. Dr. 15 Blagg? 16 DR. BLAGG: A couple of quick comments. 17 If you actually use central monitoring and add it to 18 the cost of the treatment process -- and that may be a 19 concern -- the same thing is that Dr. Pierratos does 20 not feel that remote monitoring is essential to all. 21 CHAIRPERSON TALAMINI: Thank you. 22 Dr. Sadler and then -- 23 DR. SADLER: I just wanted to make the 24 point that among the issues we raise, this is of
  • 151. 1 interest, but this is secondary to the more important 2 ones. 3 CHAIRPERSON TALAMINI: Dr. Aranoff? 4 DR. ARANOFF: We're actually talking about 5 two aspects of monitoring here. One is the safety of 6 the treatment. And the other one is to access 7 clinical information about adequacy and the 8 characteristics of the dialysis treatment. 9 My comments about safety and monitoring 10 are that we should never use central monitoring as the 11 only way of monitoring safety. And others have 12 recognized that it may not be necessary at all. 13 And, secondly, I would point out that the 14 majority of home hemodialysis or peritoneal treatments 15 now done in the United States do not download 16 information to any central source. And, in fact, the 17 vast majority of in-center hemodialysis treatments 18 provided in the United States do not download this 19 information electronically to any central source. 20 CHAIRPERSON TALAMINI: Terrific. 21 Dr. Kalota? 22 DR. KALOTA: He answered my question. 23 CHAIRPERSON TALAMINI: Okay. I would just 24 like to ask the FDA -- this might be a spring on these
  • 152. 1 folks -- if there are other issues that the panel had 2 either missed or that you would like us discuss in 3 more depth with respect to device designs. 4 MS. BROGDON: Thank you. I was checking 5 with the staff on that question. And Dr. Ruiz would 6 like to ask something. 7 CHAIRPERSON TALAMINI: Okay. Dr. Ruiz, 8 please? 9 DR. RUIZ-ZACHAREK: And I'll be very 10 quick, too. This question is for Dr. Hoy. You said 11 that partners are not required among your patient 12 population. You reported also some patients that have 13 some serious events, not treatment-related but 14 basically a kidney rupture, which is pretty danger and 15 you need to act quickly on it. 16 What would happen if there is no central 17 monitoring, no partner, and someone who lives far 18 away? In the cases that you presented, emergency 19 personnel showed up in 15 minutes. If these patients 20 live in remote areas, what type of safeguard would we 21 have or should we restrict the nocturnal dialysis to 22 patients who live close to hospitals? How would we 23 address patients that live far away? 24 DR. HOY: This is a perfect technique for
  • 153. 1 people who live far away from a dialysis unit in a 2 hospital. If a catastrophic event takes place in an 3 in-center dialysis unit and the emergency squad gets 4 there in 15 minutes, which is about what it takes, it 5 doesn't change the outcome most of the time. 6 Those events, we have incredibly sick 7 patients, you know, and they die. And they die 8 suddenly sometimes. The fact that we have had a mixed 9 bag, we had one patient die, despite the observer, the 10 partner, and emergency response quickly. We had one 11 patient whose life was probably saved by the observer 12 and the rapid emergency response. 13 We send out a video to the emergency squad 14 for every patient. And we have the number of that 15 emergency squad. And that video shows them, this 16 machine, and how to disconnect it because that is all 17 they need to know. 18 If the patient has a partner who wants to 19 learn how to do this, we teach the partner to do it. 20 But the main reason that there are only 98 people in 21 New York State on home hemodialysis out of 20,000 and 22 less than 1,000 in the entire country is because of 23 care-giver burnout. 24 CHAIRPERSON TALAMINI: So would you
  • 154. 1 contend, then, that the emergency response system of 2 the country in general as it exists is already 3 sufficient for whatever would happen with this 4 population? It sounds like that is what you are 5 saying? 6 DR. HOY: Yes. I don't think this 7 population is any different than any other population 8 that's at home and sick or in center and sick. 9 CHAIRPERSON TALAMINI: Other opinions, 10 particularly contrary opinions, on the panel? Dr. 11 Sadler? 12 DR. SADLER: I simply refer to my earlier 13 remarks about passive restraint levels of safety. 14 There are some things you cannot guarantee. The worst 15 thing that can happen to one of these patients is not 16 to get his dialysis. 17 So that to be remote from a hospital and a 18 dialysis center and to have the ability to get it done 19 at home without having to travel, it may involve some 20 risk, but it avoids that very large risk. 21 DR. RUIZ-ZACHAREK: Thank you. 22 CHAIRPERSON TALAMINI: Dr. Duffell? 23 DR. DUFFELL: Similar to the last comment, 24 I just think FDA needs to keep in mind that we really
  • 155. 1 can't regulate totally the use of these things. I 2 mean, clinical judgment has to come into play here. 3 Patients are very complicated. So there may be 4 extenuating circumstances. 5 I think the most you can do is probably in 6 the professional labeling give the benefit of the 7 wisdom of the things that you see in MDR reports and 8 complaints and stuff that come through of points to 9 consider. But the clinical judgment has to come into 10 play. 11 So if that patient is 100 miles away from 12 an emergency response team, there may still be 13 compelling reasons to do this. 14 CHAIRPERSON TALAMINI: Yes? 15 DR. BLAGG: Just one rapid comment. 16 Patients may go home with a helper, but the helper may 17 not stay around. And, for example, our patient with 18 an IQ of 87, measured by a psychologist, not by me, we 19 didn't find out until he was transplanted that for the 20 last 15 months, his roommate had not been with him. 21 He had been dialyzing alone very successfully. 22 So we can't control that the helper stays 23 there. 24 CHAIRPERSON TALAMINI: Yes. Thank you.
  • 156. 1 So that will close question one. 2 DR. LOCKRIDGE: There is the issue about 3 the water I don't think we really addressed. That is 4 in this section. I think as far as design purposes 5 for the machine, I think AAMI standards are very 6 critical and we need to be able to have a 7 patient-friendly port that looks at the water post -- 8 CHAIRPERSON TALAMINI: That is actually 9 question two. 10 DR. LOCKRIDGE: I'm sorry. 11 CHAIRPERSON TALAMINI: So we're about to 12 get to that. So let me be the ugly surgeon and get 13 you guys to do one more question before we break for 14 lunch. So if we could do question two, which refers 15 to device design with respect to water? 16 "The quality of the water to be used to 17 prepare dialysate is crucial for any dialysis 18 treatment. Please discuss the water purification 19 needs for the NHD procedures, including the following: 20 a) type of water treatment equipment for preparation 21 of water and verification of its quality appropriate 22 for nocturnal home use; b) due to the potentially 23 higher exposure of patients to the processed water, 24 consideration as to whether the water quality
  • 157. 1 recommendations should be different for nocturnal home 2 use, as opposed to conventional, in-clinic use; and c) 3 procedures on how to handle changes in the water 4 quality and composition by municipal water suppliers. 5 Dr. Lockridge, since you have started in, 6 go ahead. 7 DR. LOCKRIDGE: All right. I think water 8 deals with 60 percent of the problems that I have with 9 the patient at home. I think it is a major issue that 10 we have to address. I think we have to meet the AAMI 11 standards. And I think that if we do that, that is 12 where we need to be. 13 Clearly, I think whether we choose to do 14 an RO versus a DI is not the issue. I think what we 15 do need to have is the highest quality water because 16 these people are seeing more water per week than they 17 are when they are doing three times a week in-center 18 dialysis. 19 There needs to be, you know, the carbon 20 filter, a pre-filter that protects the sediment that 21 gets into the water, well water, before the carbon 22 tank, the carbon tank to do with the chloramines, and 23 then a post-DI or if you use DI microfilter. And then 24 you need to have another filter to do the dialysate or
  • 158. 1 to create ultra-pure water, I think. 2 So I think that we need easy ports for the 3 patients to access the water at each one of those 4 points so that we can test the water so it meets AAMI 5 standards and the clear CMS requirements once a month 6 for colony counts and LALs and how often we need to 7 look at the dialysate. 8 So I think it's critical, easy for patient 9 to access. We're not going to send technicians to go 10 out and do that. We need the design to do that. 11 CHAIRPERSON TALAMINI: Terrific. 12 Dr. Moran? 13 DR. MORAN: I think the new AAMI standards 14 have it specifically the same for in-center and home 15 use. And I would agree with that. I think I disagree 16 about the concern about the potentially higher 17 exposure of patients to processed water. I think if 18 they make the AAMI standards, that should be fine. 19 Procedures how to handle changes to the 20 water quality, that's a never-ending saga, both for 21 centers and for home patients. And it's one of the 22 biggest things we struggle with at home. 23 We have to have redundancy in the system. 24 That's why we have two carbon tanks. They're testing
  • 159. 1 the water between the two carbon tanks. And when the 2 first carbon tank shows evidence of a breakthrough, 3 then they change that tank. It's a fail-safe system, 4 but it is a big issue. 5 One of the concerns I have about AAMI is 6 saying that the water should be tested once a month at 7 home. That's much more difficult to do than it is in 8 center, especially for some of the machines. I think 9 at home, where you are dealing with a single 10 established system which doesn't have storage tanks, 11 as you do in center, no blind loops, as you do in 12 center, there is much less risk of water problems. 13 And, therefore, the testing should be done at some 14 period less than once a month. 15 CHAIRPERSON TALAMINI: Terrific. Thank 16 you. 17 Dr. Blagg? 18 DR. BLAGG: Just a brief comment, 19 following up on Bob. I think that there is a tendency 20 to move towards ultra-pure water for dialysate, 21 particularly in Europe but coming in this country, 22 too. And it's something that we should think about. 23 I agree with Dr. Moran that it is very 24 difficult. The way we handle our home patients is we
  • 160. 1 try to contact the local water company, wherever they 2 may live, every six months and also make sure that 3 they know our phone number. But it's a problem you 4 can't always solve. 5 CHAIRPERSON TALAMINI: Thank you, Dr. 6 Blagg. 7 Dr. Gillespie? 8 DR. GILLESPIE: I think I'll pass and 9 defer to my colleagues on this. 10 CHAIRPERSON TALAMINI: Thanks. 11 Dr. Weinger? 12 DR. WEINGER: Just a general comment. To 13 the extent that patients have processes, procedures, 14 and devices related to water purification and 15 assessment, those need to be designed for patients and 16 evaluated for their ability to use them effectively. 17 CHAIRPERSON TALAMINI: Thank you. 18 Dr. Gibson? 19 DR. GIBSON: Yes. This is more in the 20 nature of a question for those of you who know more 21 than I now do about the technical aspects of 22 hemodialysis since I haven't taken a dialyzer apart or 23 set up a water treatment system in a long time. 24 But it used to be at least theoretically
  • 161. 1 possible for back diffusion to occur in a high-flux 2 system. And by that, of course, I mean dialysate 3 passing into the blood compartment. 4 So my question is, is that a real 5 possibility? And would that make a difference in your 6 view of whether AAMI's standards are essential or 7 whether we should recommend ultra-pure water? 8 CHAIRPERSON TALAMINI: Dr. Sadler, do you 9 want to address that? 10 DR. SADLER: I don't think there's any 11 question but that back diffusion occurs in dialyzers. 12 And I don't think there's any evidence that it's 13 harmful. And, as I said before, I am still waiting 14 for any evidence that anyone is harmed by water that 15 meets AAMI standards, even the original AAMI 16 standards. 17 CHAIRPERSON TALAMINI: Thank you. 18 Dr. Kalota? 19 DR. KALOTA: Pass. 20 CHAIRPERSON TALAMINI: Dr. Aranoff? 21 DR. ARANOFF: Just a couple of brief 22 things about water. First of all, I agree with my 23 colleagues that there is no evidence that water that 24 meets the AAMI standard would be inadequate in any way
  • 162. 1 for this form of therapy. 2 However, with regards to the increased 3 amount of ultra-pure water that is processed, we need 4 to make sure that the home systems that are used are 5 capable of handling the increased volume for the 6 creation of dialysate that may not be considered. 7 You're running a lot more water through the systems. 8 And so issues of number of hours on the 9 device, issues of preventative maintenance and so 10 forth, those issues need to be considered in the use 11 of the device because they may need to be done more 12 frequently than we are used to than with current home 13 devices. 14 And, again, with regards to procedures to 15 handle water quality from municipal systems, many of 16 our home patients live in very rural areas. If they 17 have city water at all, the people who make that city 18 water may not be as highly trained as in larger 19 cities. And they have a tendency to dump things into 20 the water to make it taste better or clearer. 21 And there needs to be some way of 22 monitoring when alum is dumped in to take out 23 particulates, when chloramines rise and may foul the 24 carbon tanks. And so that needs to be monitored, I
  • 163. 1 think, as Dr. Lockridge pointed out. 2 CHAIRPERSON TALAMINI: Thank you. 3 Dr. Afifi? 4 DR. AFIFI: No comment. 5 CHAIRPERSON TALAMINI: Dr. Sadler, further 6 comments? 7 DR. SADLER: Only two. One, we need to 8 remember that the AAMI standard is a performance 9 standard. It's not a prescriptive standard that says, 10 "Thou shalt use" this device or that but that the 11 water should come out meeting the standard. 12 I agree completely with Dr. Weinger that 13 we haven't thought enough about the displays on water 14 treatment systems for the benefit of patients and that 15 should be considered. 16 And beyond that, nothing except to remind 17 you that a private well doesn't have to worry about a 18 municipal operator fouling it up. 19 CHAIRPERSON TALAMINI: Thank you. 20 Dr. Schulman? 21 DR. SCHULMAN: Most of what I thought of 22 has been said already, but just for completeness, I 23 would add that for the areas that have hard water or 24 water softener should be part of the water treatment.
  • 164. 1 CHAIRPERSON TALAMINI: Okay. Dr. Duffell? 2 DR. DUFFELL: I'll pass. 3 CHAIRPERSON TALAMINI: Ms. Moore? 4 MS. MOORE: Pass. 5 CHAIRPERSON TALAMINI: Dr. Hoy? 6 DR. HOY: As usual, I have a lot to say. 7 We have had a lot of different experiences with 8 different water sources. Several of our patients are 9 in rural areas. And we have discovered that if you 10 are downstream, if your aquifer is downstream, of 11 agricultural lands, there are real issues with 12 increased phosphates when people are fertilizing and 13 when there is a lot of rain. 14 We also have problems with droughts. And 15 so patients have had to come in center for that. We 16 have also had people who were downhill of somebody 17 else's septic system. Their well was downhill with 18 someone else's septic system. These are real 19 problems, but we have managed to settle all of them 20 when we need to. 21 We have urban systems that are old with a 22 lot of particulate matter. You have to have 23 pre-filters. We do water softeners and carbon 24 filters. We use ROs because they are less expensive
  • 165. 1 and they're less cumbersome and bulky. 2 We have had problems with suburban homes 3 with patients getting constantly reinfected. And it 4 turned out that the home itself had E. coli infection 5 and other gram-negative bacteria in the piping of the 6 system. We had to shock the whole house to get rid of 7 the problem. 8 The supply, especially for ROs, needs to 9 be more efficient. You throw away half of the water 10 we use in RO. We want to get up to the industrial 11 efficiencies, where 75 percent is recovered for 12 dialysis. 13 You have a problem with the adequacy of 14 septic systems for effluent. You're dumping a lot of 15 water every day into a septic system. You often need 16 a larger drainage tank. There is an ongoing cost, 17 increased cost, to the patient of water, though in our 18 area, it's not huge. 19 Reverse osmosis machines if they have 20 stagnant loops often get contamination. And they need 21 to be designed so that water is always flowing between 22 the dialysis machine and the RO. 23 Incorrectly collected cultures are the 24 bane of our existence. In our unit in March, five
  • 166. 1 patients had to be treated in center for at least one 2 dialysis and in April, four patients. And half of 3 those were because of incorrect or because of falsely 4 positive cultures. 5 Our patients point out that they cannot 6 collect the cultures if there is an open window, a 7 fan, or a ventilation system going on in the room at 8 the time they collect them. It would be very nice to 9 have what Bob suggested, which is an easy port through 10 which those cultures can be collected safely and 11 cleanly because it a huge inconvenience to the 12 patients to have to go in center while we are waiting 13 for cultures to come back and be proven to be 14 incorrect. 15 The new AAMI standards don't worry me 16 particularly. I think the issue of ultra-pure water 17 is a problem that you should be addressing for all 18 dialysis patients. If you told someone that you were 19 exposing them to two liters of water a day that they 20 drank and then you told them that you were exposing 21 them to 576 liters of dialysis weekly because they go 22 to dialysis 3 times a week for 4 hours and then have a 23 dialysate flow rate of 800 cc, you wouldn't even worry 24 about whether the 1,400 liters that we expose our
  • 167. 1 nocturnal patients to is an issue. 2 I think you need to address the issue of 3 ultra-pure water for all of our dialysis patients. 4 And you don't require it for our in center patients, 5 and we should probably. 6 Maintenance of ROs is incredibly 7 cumbersome. They should be made simpler. They should 8 have timers. They should have automation. They 9 should be online so that we can download preventive 10 maintenance. They're not reliable. They need to be 11 more reliable. 12 DI tanks we find give more efficient water 13 use, but they're more expensive over the long run. 14 They do have lower maintenance. They're bulky, and 15 they have to be replaced every three months. 16 CHAIRPERSON TALAMINI: Thanks. 17 Dr. Weinger, would you be willing to 18 address a human performance way to help the false 19 positive culture problem? 20 DR. WEINGER: I'm not sure I fully 21 understand it, but what I think I heard from one of 22 you was the idea of having this dedicated port. And 23 certainly if this is critical to the success of the 24 overall treatment, then that ought to be part of the
  • 168. 1 waster component, needs to be part of the overall 2 system. And built into that should be a mechanism to 3 take the cultures easily and effectively as necessary. 4 I think that I have a general comment, if 5 I could, at this point -- 6 CHAIRPERSON TALAMINI: Sure. 7 DR. WEINGER: -- about the fact that what 8 we see with other medical devices, whether it's in the 9 home but even in the hospital, is that when the 10 functions that need to be accomplished require 11 multiple components, particularly if they are 12 manufactured by different companies, the risk of use 13 there and injury increases substantially, probably 14 exponentially. 15 And so something to think about is whether 16 home systems need to be a comprehensive integrated 17 system that includes the monitors, the water 18 treatment, et cetera, all as one unit, rather than the 19 ability or the obligation, as happens now, where the 20 practitioners are cobbling together devices and 21 solutions from multiple sources, which I think 22 substantially increases the risk. 23 CHAIRPERSON TALAMINI: Thank you. 24 Let me just try and get again the
  • 169. 1 temperature of the committee with respect to question 2 B here because it sounds like there have been slightly 3 different opinions. And that is whether water quality 4 recommendations should be different for nocturnal home 5 use, as opposed to conventional. 6 I think I heard mostly a no. So I'll ask 7 the opposing question. Is there anybody who thinks 8 that they indeed should be different for nocturnal 9 home use. A show of hands, anybody who thinks they 10 should be different? 11 DR. HOY: Dr. Talamini, do you want the 12 consultants to vote or not? 13 CHAIRPERSON TALAMINI: You know, I don't 14 think it much matters here because we are really just 15 getting the opinion of this committee. It's not an 16 official vote. So don't think -- 17 DR. SADLER: Dr. Talamini? 18 CHAIRPERSON TALAMINI: Yes, sir? 19 DR. SADLER: When we go from normal kidney 20 function to dialysis, we increase water exposure 21 200-fold. 22 CHAIRPERSON TALAMINI: Right. 23 DR. SADLER: When we go from conventional 24 dialysis to frequent nocturnal dialysis, we double it
  • 170. 1 again. So that's not an order of magnitude, and I 2 don't think the difference is significant. 3 CHAIRPERSON TALAMINI: Thank you. 4 I would ask the FDA again if there are 5 other issues you would like the panel to address 6 specifically on this question before we close the 7 question. Yes, sir? 8 DR. MENDELSON: I have a question. This 9 doesn't pertain directly to human factors but just a 10 thought. Does the presence of plastic piping, which 11 is probably more prevalent in the home, place a higher 12 bacterial load on the filtration equipment that is 13 going to be used to treat the water? 14 CHAIRPERSON TALAMINI: Any panel members 15 have insight or response? 16 DR. LOCKRIDGE: You know, you're talking 17 about microfilming that happens in plastic, but I just 18 think that that is probably not an issue for the 19 amount of water that runs. I just can't -- 20 DR. ARANOFF: Functionally in dialysis 21 units, all of the piping is plastic in dialysis units. 22 We have to use PVC piping. Otherwise, ultra-pure 23 water will etch metal pipe. So every fitting, every 24 pipe in a dialysis unit is already plastic.
  • 171. 1 CHAIRPERSON TALAMINI: Okay. Perfect. 2 Any further questions from the FDA? Yes? 3 MS. MOORE: I have a question. I just 4 have a question based on the last comment that was 5 made. 6 CHAIRPERSON TALAMINI: Ms. Moore, if you 7 could just bring the microphone in? Thank you. 8 MS. MOORE: I have a question just on your 9 last comment. Does that mean that the old houses, you 10 know, with still the copper piping and that kind of 11 things, there would have to be a change or something? 12 DR. ARANOFF: No. The difference is that 13 in a dialysis unit, you process the water before the 14 dialysis unit. So, actually, what is delivered to the 15 dialysis unit is essentially ion-free ultra-pure water 16 to be mixed into dialysate at the machine. 17 So from the point that the water is 18 purified in the dialysis unit in the basement or on 19 the ceiling or on the roof, wherever, from that point 20 on, it has to go through plastic piping. 21 In a home, in a home setting, the water is 22 purified closer to the machine. But from the point, 23 that point on, it has to be plastic piping. 24 CHAIRPERSON TALAMINI: Dr. Neuland?
  • 172. 1 DR. NEULAND: Yes. I still need a little 2 bit more clarification on the views on the ultra-pure 3 water because your question, Dr. Talamini, was, do you 4 think that the systems in the homes should be 5 different than the clinic? But I heard a number of 6 people here say, "I think ultra-pure water should be 7 used, and then it should also be used in the clinic." 8 So, I mean, I'm not getting a good picture 9 on whether you really believe ultra-pure water should 10 be used in the nocturnal home hemodialysis. I mean, I 11 feel like we have kind of evaded the exact question. 12 CHAIRPERSON TALAMINI: Well, I think this 13 panel is unwilling to say that there is a difference 14 between the two. But I think it would be fair enough 15 to ask for the temperature of the committee with 16 respect to that question, whether overall ultra-pure 17 water should be used in dialysis, period. 18 Is that fair enough? Can I ask the panel 19 that? Dr. Lockridge, do you have a better suggestion 20 or -- 21 DR. LOCKRIDGE: No. You know, I think 22 that the literature from Europe and some literature 23 now that is coming out here would suggest that 24 ultra-pure water is better, that we're looking at more
  • 173. 1 of an inflammatory marker, but I agree with when 2 you're looking at 1,000 patients versus 300,000 3 patients and trying to make a difference when it's 4 just a twofold difference, I would hope that the 5 designers or the manufacturers would have what we call 6 a dialysate filter before their filter or they're 7 using columns to remove it to make it ultra pure. 8 I would think that would be a goal, but if 9 FDA requires it for home patients to be a goal, then I 10 think that is inappropriate unless they are going to 11 require it for in center. 12 CHAIRPERSON TALAMINI: Dr. Gillespie? 13 DR. GILLESPIE: I think this is still a 14 developing field of research. I mean, intuitively 15 cleaner water sounds better, but we still haven't 16 totally figured out how it plays out clinically. And 17 we also have to consider when we're talking about 18 outcomes that I think most of us would agree that more 19 frequent dialysis has a tremendous effect on outcomes. 20 That's kind of the big picture. 21 And so issues about the water purity are 22 probably just the detail that may not have as much of 23 an effect as just the transition from less frequent to 24 more frequent dialysis.
  • 174. 1 CHAIRPERSON TALAMINI: Other comments 2 regarding ultra-pure water? Dr. Sadler? 3 DR. SADLER: I think I have already made 4 it clear that I believe the increase in the quality of 5 water, the standards reached for have nothing to do 6 with the treat to patients that we can define. It has 7 to do with the fact that we are capable of making a 8 higher quality of water. 9 There is indeed some literature that says 10 perhaps there will be a lesser inflammatory response 11 with ultra-pure water, but I don't think that data is 12 anything like strong enough to change the practices 13 across the field. And I think we have to be cautious 14 about requiring things for which there is no clear 15 need. 16 You know, this is a group that is a 17 mixture of zealots and skeptics. And so we're always 18 going to have differences. 19 CHAIRPERSON TALAMINI: Right. We'll take 20 a one-hour lunch break at this point. I would like to 21 thank the panel for really terrific work and concise 22 comments. And hopefully we'll be able to continue the 23 same. 24 Yes, Dr. Duffell?
  • 175. 1 DR. DUFFELL: Just to the audience in my 2 role as industry rep, if there are any members of 3 industries out there that have any matters that are 4 going to be discussed with the panel today that you 5 would want to discuss with me, please approach me 6 during lunch. Thank you. 7 CHAIRPERSON TALAMINI: And I would remind 8 the panel again that this is an open proceeding. So 9 may not discuss any of these issues that are before 10 the panel during lunch. So I would ask you to be 11 disciplined. 12 So we will reconvene at 1:46. Thank you. 13 (Whereupon, at 12:46 p.m., the foregoing 14 matter was recessed for lunch, to reconvene at 1:30 15 p.m. the same day.) 16 17 18 19 20 21 22 23 24
  • 176. 1 2 3 4 5
  • 177. 1 A-F-T-E-R-N-O-O-N S-E-S-S-I-O-N 2 (1:48 p.m.) 3 CHAIRPERSON TALAMINI: I think we will go 4 ahead and reconvene the panel at this time, again in 5 the interest of getting done in a timely manner. So 6 the meeting now reconvenes with the continuing panel 7 discussion portion of the meeting. And we will begin 8 with the third question. So far the processes seem to 9 work well. So we'll stick with it. 10 Question number 3 has to do with risk 11 analysis. FDA has identified the following potential 12 risks associated with NHD, in addition to those 13 related to conventional hemodialysis: a) increased 14 risk of inadvertent disconnections, the increased 15 blood loss from increased frequency of treatments, c) 16 potential increased rate of vascular access infection 17 due to increased use of access, and d) psychological 18 effects; e.g., impact of treatments on patients, such 19 as loss of social interaction, and the impact of 20 increased responsibility on the patient, requiring 21 need for adjustment or discontinuation of therapy. 22 To aid FDA in the development of a 23 guidance document on NHD, please comment on the 24 completeness and appropriateness of this list. I
  • 178. 1 think we left off with Dr. Moran if you're willing to 2 pick a piece of that and comment for a minute and a 3 half. 4 Again, I would applaud the Committee on 5 their clarity and brevity this morning. And if we 6 could continue to push that, we'll make the taxis and 7 so forth, the flights this afternoon. 8 Dr. Moran? 9 DR. MORAN: I think this is a very good 10 list. I agree that the risk of disconnection is the 11 single most serious problem we should be dealing with 12 with nocturnal hemodialysis. And that has to be 13 addressed, whether it's catheters, as Dr. Sadler wants 14 to do, or with fistulas and button holders I want to 15 do with precautions against disconnect. 16 I agree it's a very serious issue. I 17 think technically the best answer to that would be a 18 single needle technique, either a dual/single needle 19 or a machine that is providing a single needle. 20 Increased blood loss, I can see that that 21 occurs. I don't think it is an issue in the age of 22 intravenous iron and erythropoietin. I think the 23 benefits of frequent dialysis far outweigh this risk. 24 And conventionally most people find that
  • 179. 1 erythropoietin usage actually goes down with nocturnal 2 hemodialysis. 3 Vascular access infection, I would make 4 one point. In our home patients using the button hole 5 techniques six times a week, we have had two serious 6 episodes of staph aureus septicemia in young men with 7 fistulas using the button hole technique. And I can't 8 remember the last time I saw staph aureus septicemia 9 with a fistula. 10 We know there was a break in technique 11 from one patient. We know the other patient was doing 12 things like dialyzing himself at 3:00 a.m. and 13 probably, therefore, careless. We have since then 14 very strongly emphasized skin prep and haven't had any 15 more problems. 16 But the button hole technique is 17 wonderful. The patients love it. But I would caution 18 about the increased risk of infection. 19 Psychological effects. I don't see those. 20 The psychological effect I think you have to be 21 careful about is the partner. I think it's like 22 living related donor transplantation. You have to 23 take the partner aside and make sure the partner 24 understands what they are committing to and make sure
  • 180. 1 that they have a real commitment, they're not just 2 saying yes because they don't know how to say no. I 3 think that is a major issue. 4 I think that is the end of my comments. 5 CHAIRPERSON TALAMINI: Okay. Thank you, 6 Dr. Moran. 7 Dr. Blagg? 8 DR. BLAGG: I agree with all that has been 9 said. I think the bit I would add is that our 10 experience at least has been that vascular access 11 problems of all sorts are not increased with more 12 frequent sticks and that this reflects the fact that 13 the patient or one other person is doing all of the 14 sticks, rather than the 20 people that somebody 15 mentioned a little while ago. 16 And in terms of the psychological effect, 17 we still try to persuade the patient to do as much 18 themselves. And in our program, about two-thirds of 19 the home patients, the patient is the prime mover and 20 does most of everything or everything, but 21 psychological problems do occur from time to time 22 obviously. 23 The second patient that we trained in 24 Seattle should have been divorced. Unfortunately, the
  • 181. 1 patient died, but it really destroyed his marriage. 2 And that made us aware of these things very early on. 3 CHAIRPERSON TALAMINI: Thank you. Dr. 4 Gillespie? 5 DR. GILLESPIE: I agree with all the 6 preceding. I would just add that on item C for the 7 potential increased rate of vascular access infection, 8 I would broaden that to just any vascular access 9 complications because if you are worried about 10 potentially thrombosis or other failures resulting 11 from increased use. And, of course, the literature 12 hasn't really borne that out, but if you're looking at 13 risk, that would be what you would want to consider, I 14 think. 15 CHAIRPERSON TALAMINI: Okay. Dr. Weinger? 16 DR. WEINGER: One item that isn't on here 17 that we have mentioned before is acute decreases in 18 water quality, for whatever reason. In terms of 19 useability issues, I would add to the list risks of 20 misconnection, particularly related to disposable 21 components, issues related to family, friends, pets, 22 and other entities in the environment interacting with 23 the device, and then the general issue of response to 24 abnormal conditions and either a failure to respond or
  • 182. 1 an inadequate or inappropriate response to emergency 2 or just atypical condition. 3 CHAIRPERSON TALAMINI: Thank you. 4 Dr. Gibson? 5 DR. GIBSON: Well, I'm glad to see 6 psychological effects on the list at all. In terms of 7 adaptation to chronic illness, there is much more that 8 we don't know than we do know in terms of how people 9 cope with the stress of chronic illness. 10 As I said before, I think that there are 11 some potential benefits to home dialysis that need to 12 be considered along with the risk. And those benefits 13 would be a sense of mastery that increases self-esteem 14 and psychological well-being. And I don't think that 15 is trivial. 16 I think other people have already 17 emphasized another aspect of this that is extremely 18 important. And that is if negative effects are seen, 19 it is more likely to be on the family, rather than on 20 the receiver of the dialysis solely. 21 Now, I think that was shown beyond any 22 question. And what limited data is available from 23 studies of conventional home hemodialysis and 24 peritoneal dialysis is that care-giver burnout, which
  • 183. 1 someone has already mentioned, is one of the more 2 significant negative aspects, negative psychological 3 aspects, of dialysis. 4 And it's not just limited to the 5 care-giving partner, but it involves the whole family 6 in new ways of learning social interaction and new 7 ways of scheduling activities and new limitations on 8 things that they can no longer do that they used to 9 do. 10 Now, I don't think any of these are 11 reasons for the FDA to not approve this as a method. 12 As I've said before, these are things that we don't 13 know the answers to on conventional dialysis. And the 14 purpose, as I understand it, of our meeting here is to 15 determine safety and effectiveness, not to determine 16 long-term effects. 17 So I do not like to see us use 18 psychological exclusions, arbitrary psychological 19 exclusions, as reasons not to put people on nocturnal 20 hemodialysis. I was very impressed with what Dr. Hoy 21 said earlier, which was that the main determinant of 22 who can go on nocturnal dialysis is a person's 23 motivation for doing it. 24 I don't think psychiatrists are able to
  • 184. 1 predict with any degree of accuracy who is smart 2 enough and adept enough and intellectually aware 3 enough to do this successfully over the long term. 4 CHAIRPERSON TALAMINI: Thank you. 5 Perhaps to add a little bit of clarity, it 6 seems -- and anybody can correct me if I am wrong on 7 this -- the key question here is whether any of these 8 four or any that aren't on this list represent 9 incremental or additional risk for nocturnal home 10 dialysis, as opposed to dialysis as it's now 11 practiced. 12 So it sounds like we've got a set of 13 comments from the beginning folks on all of these 14 issues, but as you think about this question, I think 15 that is the real thing we need to get at is whether 16 the FDA has to be concerned about incremental risk 17 with doing this at home, as opposed to the way it is 18 currently practiced. 19 Dr. Kalota? 20 DR. KALOTA: I think Dr. Gibson elaborated 21 my comments much better than I would have. 22 DR. ARANOFF: I think to address that 23 specific question is that the incremental risk is 24 related to the incremental number of treatments and
  • 185. 1 the time that are incrementally increased on dialysis. 2 All of these things could happen in conventional 3 hemodialysis. 4 I would also like to point out that we 5 probably need to give some consideration to risk 6 analysis of the problem of unintended consequences of 7 this therapy. 8 So, for example, we have identified the 9 potential unintended consequence of worsening of 10 anemia because there is a defined amount of blood loss 11 with each treatment. And is that overcome by the 12 better management of uremia per se? And that is a 13 question to be answered. 14 We have also identified the unintended 15 consequence of abnormal electrolyte values because 16 there's increased dialysis exposure, but there may be 17 other unintended consequences. 18 So, for example, although some of the 19 group favor the use of catheters for this procedure, 20 there are others who would passionately argue that 21 catheters are not a good dialysis access for anyone 22 for other reasons, because of plastic and inflammation 23 and the body of evidence for that. So perhaps there 24 ought to be some consideration that ensures that all
  • 186. 1 access devices would be useable for this form of 2 therapy. 3 And, finally, other unintended 4 consequences on things like drug clearance, the dosing 5 of drugs in patients that are getting vastly increased 6 clearances of small molecules, the dosing of the 7 drugs, and those recommendations will need to be 8 considered as well. 9 CHAIRPERSON TALAMINI: Thank you. 10 Dr. Afifi? 11 DR. AFIFI: Yes. There's a close 12 connection between this question and the next one, 13 which is study design. Specifically, risk analysis 14 should be I think, partially at least, aimed at 15 identifying how analyzing the potential risks can help 16 us avoid adverse events. 17 And also in my mind from a statistical 18 point of view, we need to classify the risks and the 19 adverse events later when we get to them as to whether 20 they are life-threatening or not because the kind of 21 thinking I'm sure from the clinical point of view, but 22 what I know more about is from the statistical 23 analysis point of view, the analytical approach would 24 be different for a life-threatening event versus a
  • 187. 1 non-life-threatening event. 2 So these issues I think are ones that need 3 to be clarified. And the connection between this 4 question and the next I advise FDA to think about and 5 spell out more clearly. 6 CHAIRPERSON TALAMINI: Okay. Thank you. 7 Dr. Sadler? 8 DR. SADLER: I have to say that these 9 potential risks are presumptive, rather than 10 demonstrated. And I believe that they are itemized 11 because of the potential for a worse outcome if they 12 happen than if they happen in the presence of a number 13 of other people. 14 And so it would be very important to 15 tabulate these events because I rather doubt that they 16 happen more frequently in this form of dialysis than 17 anywhere else. They might actually happen less often 18 because there will be more consistent procedure by 19 people who have more motivation to do it right. 20 I guess I have to correct George, Dr. 21 Aranoff. I did not say that I supported increased use 22 of central catheters but simply that because there are 23 benefits of them in this environment, we should see if 24 we couldn't improve that device or we should hope that
  • 188. 1 someone would try to improve it because I suspect we 2 will always need some. 3 CHAIRPERSON TALAMINI: Thank you. 4 Dr. Schulman? 5 DR. SCHULMAN: We'll be at the end of the 6 line here. Most of what I thought about has been said 7 already. However, unless and until devices to prevent 8 disconnection occurring at nocturnal dialysis, that is 9 something that probably we have to be concerned about 10 as above the standard dialysis treatment. 11 CHAIRPERSON TALAMINI: Okay. Thank you. 12 Dr. Duffell? 13 DR. DUFFELL: Like Dr. Afifi, I am drawing 14 a connection with this risk analysis to the next 15 question, which is study design. And I guess the 16 cautionary remark I would make is that some of these 17 things, especially when you're talking about infection 18 rate or psychological effects, are probably long-term 19 assessments that have to be made and probably not 20 something that you would want to force on a 21 manufacturer to do in a prospective trial prior to 22 approval of these technologies to go out. 23 So, in other words, I think they are 24 probably more of an issue for post-market
  • 189. 1 surveillance, rather than a prospective study to get 2 to market. 3 CHAIRPERSON TALAMINI: Thank you. 4 Ms. Moore, pass. Dr. Hoy? 5 DR. HOY: I don't think that we're seeing 6 disconnections at the patient's access. However, 7 we've done about 27,000 treatments, and Dr. Lockridge 8 has done 41,000 treatments. And both of us have seen 9 a patient inadvertently either cross--thread or 10 over-exuberantly tighten the blood connection at the 11 dialyzer. 12 And my patient slowly lost blood until he 13 woke up in the middle of the night. And the blood 14 dripped down the tubing and fell away from our 15 moisture protector underneath the machine. 16 So we've both seen the potential for a 17 very strong person in this case to mis-cross-thread 18 the connection at the dialyzer. 19 CHAIRPERSON TALAMINI: Can you bring the 20 microphone in just a little bit? I'm sorry. 21 DR. HOY: I'm sorry. I'm sorry. We have 22 both seen a serious blood loss from a cross-threading 23 where the blood connections are made to the dialyzer. 24 I'm not seeing any disconnections from the arms. I'll
  • 190. 1 be happy to show people what our patients' arms look 2 like. They're a human factor nightmare. 3 But they work. And we have moisture 4 protectors. We have end uresis detectors. And we 5 check them. And they work. And we also put an end 6 uresis detector underneath the machines. And in this 7 particular case, the patient lost two units of blood. 8 And it wasn't picked up until he woke up and 9 discovered this, and we were very lucky in that 10 respect. 11 So I think that there is an issue here. 12 In 68,000 treatments, we have each seen a 13 cross-threading or a misthreading or an over-exuberant 14 threading of the connections at the dialyzer. You 15 know, how often does that happen in center? Probably 16 not as often. And maybe that's something we need to 17 address. 18 I'm not seeing inadvertent disconnections 19 at the arms. I don't think we see increased blood 20 loss from treatments. Actually, our hemoglobins on 21 our patients stay up and are higher than they were 22 when they first come to us. 23 I think there may be a potential increased 24 risk of vascular infection due to button holes. I
  • 191. 1 think we need to collect the data. I certainly think 2 there is an increased risk of infections from 3 catheters, despite Dr. Lockridge's incredible data. 4 CHAIRPERSON TALAMINI: I'm sorry? You 5 said you certainly do think so? 6 DR. HOY: I certainly do think there is an 7 increased risk of infection, no more than we see in 8 the in-center patients, but I think catheters innately 9 have a higher risk of infection. So I don't think 10 it's an additional risk for the nocturnal patients, 11 but it certainly is a risk. 12 And, finally, I think the psychological 13 effects are -- I, frankly, am much more concerned 14 about what happens to my patients in the center than I 15 am about what happens to my nocturnal patients. I 16 think there is some potential adjustment for 17 care-givers. 18 I think that patients who suddenly have a 19 lot of free time do have an adjustment to make, but 20 they don't seem to have much of a problem figuring out 21 what to do with it. 22 I am much more concerned about what the 23 isolation and pacification of 300,000 in-center 24 patients does as they lose control over their lives
  • 192. 1 and their therapies and they're too physically ill to 2 socialize, work, exercise, or make love. The 3 emotional well-being that's engendered by feeling 4 normal in the nocturnal patients, by their free 5 daytime hours, by their greater energy, unlimited 6 diets and fluids, and improved cognition more than 7 compensates most nocturnal patients for the loss of 8 the companionship of their chronically ill and dying 9 in-center fellow inmates. 10 CHAIRPERSON TALAMINI: Thank you. Well 11 said. 12 Dr. Lockridge? 13 DR. LOCKRIDGE: I think it has been 14 well-said. I think the bottom line is this is a risk 15 analysis. And there are risks in doing all of this. 16 And these are outlined very well. But the benefit is 17 so much greater for this with the same experience that 18 Chris and I have that this is about patients doing 19 better, feeling better, living normal lives. 20 I think we have to have industry figure 21 out a way to prevent disconnects. I think that is 22 still an important issue, but it is no greater than 23 what happens in this country. And I don't think it's 24 the risk of putting people at home to do this any
  • 193. 1 greater than in center. 2 The blood loss has been resolved as far as 3 just give them enough iron and enough EPO and their 4 hemoglobins are higher than they were before with less 5 EPO. 6 The psychological issue I think is to 7 think that people -- there are a few people that 8 socialize in center, but we are basically doing it to 9 people. We are making them robots. We're sticking 10 needles in them, and we're saying, "Come to this 11 time." By empowering people to care for themselves, 12 we are making their lives become more normal. They're 13 in control for the first time. 14 CHAIRPERSON TALAMINI: Thank you. 15 So I'm going to push the panel just a 16 little bit. And, again, these are not any sort of 17 official votes, but the question it seems to me the 18 FDA wants to know whether they need to be concerned 19 about the marginal risk of these four things in 20 nocturnal dialysis, as opposed to the way it's 21 practiced. 22 So let me just ask for a show of hands? 23 How many people think for A that there is an increased 24 risk of inadvertent disconnections, a marginally
  • 194. 1 increased risk for NHD, as opposed to normal dialysis? 2 Anybody? 3 (Whereupon, there was a show of hands.) 4 CHAIRPERSON TALAMINI: So we have eight. 5 DR. AFIFI: I'm not voting, by the way, 6 because I'm not an expert in this. 7 CHAIRPERSON TALAMINI: Right. And, again, 8 these aren't official votes. We're just trying to get 9 a temperature here. 10 How about increased blood loss due to the 11 increased frequency of treatments; again, marginal 12 risk for NHD? Anybody feel that that's -- a show of 13 hands? 14 (Whereupon, there was a show of hands.) 15 CHAIRPERSON TALAMINI: Four. 16 DR. ARANOFF: It happens, but does it 17 matter? That's the issue. 18 CHAIRPERSON TALAMINI: Well, the reason 19 I'm not being more specific is that the FDA wants to 20 know, did they need to be concerned about this? Is 21 this something that they need to be additionally 22 concerned about, particularly with the concept that a 23 document is going to be crafted here? So I'm just 24 trying to help crystallize this for the purpose of the
  • 195. 1 day. 2 Comment, Dr. Moran? 3 DR. MORAN: You just rephrased your own 4 question. Your first question was, was there a 5 marginal increased risk of blood loss? The answer to 6 that is yes. 7 And then you rephrased it by saying, 8 should we be concerned about it? And the answer to 9 that is no. 10 DR. ARANOFF: That's correct. That's 11 right. 12 CHAIRPERSON TALAMINI: Okay. Fair enough. 13 Fair enough. 14 How about the third, potential increased 15 rate of vascular access infection due to the increased 16 use of access? How many feel that's a marginally 17 increased risk with home? 18 DR. DUFFELL: Well, but should the 19 question really be again a risk? Is this what we are 20 worrying about? Should not the question, though, be 21 restated as before. Is it clinically relevant? 22 CHAIRPERSON TALAMINI: Sure. We can 23 phrase it as a clinically significant risk. 24 DR. DUFFELL: Yes, exactly.
  • 196. 1 CHAIRPERSON TALAMINI: How many feel it's 2 a clinically significant increased risk? 3 DR. SADLER: Are we just talking about 4 infection or are we talking about all manner of 5 vascular access problems because I think we have all 6 said that we worry about all of them? 7 CHAIRPERSON TALAMINI: I'm just trying to 8 keep it to what it says in C, "potential increased 9 rate of vascular access infection." So no hands? 10 (Whereupon, there was a show of a hand.) 11 CHAIRPERSON TALAMINI: I've got one taker. 12 DR. WEINGER: I think the fact that 13 patients are doing this and they're doing it way more 14 often has the potential for an increased risk of 15 access problems. 16 DR. LOCKRIDGE: I think that is not a 17 truism, so to speak. I think they are better than any 18 person that's in center that's sticking, a nurse or a 19 technician that is sticking. So I think it actually 20 goes the other way. 21 And I think there is clear literature that 22 has looked at using these accesses. It says that 23 there is no difference. So I don't think it's an 24 issue.
  • 197. 1 CHAIRPERSON TALAMINI: And that's probably 2 the predominant opinion, it appears, of the panel. 3 MS. MOORE: May I? 4 CHAIRPERSON TALAMINI: Yes, ma'am. Ms. 5 Moore? 6 MS. MOORE: I recognize the experts, and I 7 know that that is the predominant opinion of the 8 panel. But speaking from a consumer's point of view, 9 even though you may consider the risk minor, I think 10 that it is something that patients ought to be aware 11 of that it is, you know, a risk. And if something 12 should happen to them, then they would recognize that 13 they had already been forewarned that this is a risk. 14 So I guess I would as the non-expert on 15 this panel disagree with the experts. 16 CHAIRPERSON TALAMINI: Okay. Thank you. 17 Dr. Sadler? 18 DR. SADLER: I think that the point that 19 Dr. Lockridge was making is that they do recognize 20 this is a risk. They do recognize how important their 21 technique is. And they do recognize it is their 22 health that hangs in the balance. And that's why they 23 generally do a better job than our staff in the 24 facility does.
  • 198. 1 So, you know, there is a much increased 2 awareness of the importance of every step they take. 3 And so they generally take it more carefully, with 4 better habits. And because it's one person doing it 5 every time, I think that there is not really the 6 increased risk. 7 And so, you know, my concern is not so 8 much that the stress gets them down, but the euphoria 9 of freedom may affect their judgment detrimentally. 10 CHAIRPERSON TALAMINI: And I would rush to 11 say that simply because this panel doesn't think it 12 represents incremental clinical risk doesn't mean that 13 the FDA is going to forget about it and not bring it 14 up as an issue with these treatments. But I'm just 15 trying to force the point and crystallize this 16 particular question. 17 So the last one, the psychological 18 effects, how many panel members feel that the 19 psychological effects of being home, as opposed to the 20 standard treatment, represents a clinically 21 significant marginal increased risk? Any panel 22 members? 23 (Whereupon, there was a show of a hand.) 24 CHAIRPERSON TALAMINI: Ms. Moore? So we
  • 199. 1 have one. Do you have a comment? 2 MS. MOORE: No comment. Just -- 3 CHAIRPERSON TALAMINI: No? Okay. So 4 there were two other issues that were brought up. And 5 that is unintended consequences and acute 6 decompensation in the water quality. Do either of 7 those represent significantly increased risks for this 8 that panel members want to comment on further? 9 (No response.) 10 CHAIRPERSON TALAMINI: No? Dr. Lockridge? 11 DR. LOCKRIDGE: Yes. The one thing that 12 was brought up about antibiotics, I think that because 13 nocturnal dialysis, we do dialysis so much longer, two 14 and a half times or three times more than what we're 15 doing now. There are certain clinical issues, like we 16 dose vancomycin every other day instead of every five 17 days or every seven days. 18 So the actual clearance that does occur, 19 the FDA needs to be aware of this, and the companies 20 need to be aware of it in their labeling, I think. 21 CHAIRPERSON TALAMINI: Okay. Dr. Hoy, 22 comment? 23 DR. HOY: I think that the dilemma here is 24 that we really don't know what we're doing. We know
  • 200. 1 that what we do in center doesn't work very well 2 because we haven't changed the mortality rates at all. 3 But we really don't know what the net effects of doing 4 a to of extra dialysis are. 5 And we do see some both potential and 6 detrimental side effects or perhaps they are side 7 effects -- I don't know -- of doing a lot more 8 dialysis, especially with large high flux dialyzers. 9 For example, we have now started to see a 10 lowering of beta-2 microglobulin levels in our 11 patients, which doesn't occur at first very much but 12 then later on seems to be coming much more real. 13 We're also seeing for the first time, both 14 in center and in the nocturnal patients, lower B-12 15 levels, which we have never seen before. And dialysis 16 patients almost never get low B-12 levels because it's 17 excreted by the kidneys normally, and they usually 18 have high B-12 levels. We're starting to see elevated 19 MCVs and lower B-12 levels in these patients because 20 we're using these huge high flux dialyzers. 21 So there's an issue here of the 22 inadvertent consequence, unforeseen consequence, of 23 this good action, namely using bigger dialyzers. It's 24 probably a risk for both sets of patients, not just
  • 201. 1 nocturnal. 2 We also dialyze off a lot more magnesium. 3 We dialyze off a lot of phosphate. What are the net 4 effects of hypomagnesemia chronically? What are the 5 net effects of hypophosphatemia chronically we've 6 never seen before in dialysis patients? I mean, we 7 should be lucky to have this problem. 8 CHAIRPERSON TALAMINI: And I would 9 certainly say that in the absence of a lot of hard 10 data, our job here is to offer opinions, which you are 11 doing well. 12 I would ask the FDA again, being almost 13 out of time for this question, whether there are other 14 issues with respect to the risk analysis that you 15 would like the panel specifically to address. And it 16 would need to be quickly. Any issues? No. 17 MS. BROGDON: No issues. 18 CHAIRPERSON TALAMINI: Okay. Thanks. 19 So we'll move on, then, to the fourth 20 question, which regards clinical study design. "The 21 FDA proposes that manufacturers evaluate NHD devices 22 in clinical trials. The purpose of these studies is 23 to evaluate the incidence of adverse events, the 24 device's ability to deliver prescribed treatments, and
  • 202. 1 the patients' ability to conduct the treatments as 2 prescribed in a home nocturnal hemodialysis setting 3 after appropriate training. 4 "Please consider the following aspects of 5 the clinical study design and provide input on the 6 following elements of the study: a) study design; 7 e.g., retrospective or prospective; b) need for a 8 control group and, if so, appropriate type of control; 9 e.g., prospective, historical, patient at their own 10 control; c) appropriate sample size; d) 11 inclusion/exclusion criteria; e.g., exclusion of 12 patients previously on home dialysis; e) frequency and 13 duration of treatments; f) study duration; g) safety 14 endpoints; h) effectiveness endpoints; and i) length 15 of follow-up." 16 I would turn and ask Dr. Afifi to begin 17 this discussion as our panel expert on these matters. 18 Dr. Afifi? 19 DR. AFIFI: Thank you. 20 I think we should look first at the three 21 items in the second sentence: incidence of adverse 22 events; the device's ability to deliver prescribed 23 treatments; and, the third one, the patients' ability 24 to conduct the treatments as prescribed or described.
  • 203. 1 Item one let me put aside for a moment. 2 And I think the other two items, the device's ability 3 to deliver the treatment and the patient's ability to 4 do it correctly, we can think of those as appropriate 5 to use a pre/post design; in other words, have 6 patients begin who are currently in clinic settings 7 and follow them up for a while and measure those 8 quantities and then do a wash-out, as the FDA person 9 earlier today described -- I think it was Dr. Ruiz -- 10 and then do the same thing for the nocturnal and then 11 compare the performance, both of the machine and the 12 patient. So that would be an appropriate thing. 13 As far as adverse events, we need to look 14 at them by whether they're life-threatening or not, as 15 I mentioned earlier. If they're not life-threatening, 16 then a count of how many adverse events happen for a 17 given period of time. And then there are standard 18 statistical methods, plus one or negative binomial and 19 so on, that gets pretty technical. So I will leave 20 that alone. But there are standard ways of doing 21 that. 22 I think that would need to be a clinical 23 trial with a control group not having the patient as 24 her or his own control. In that case, historical
  • 204. 1 controls could be useful if the data are available in 2 the form that we need them; in other words, how long 3 for a given period of time. If not, then a 4 prospective study comparing home to clinic settings 5 with a two-armed clinical trial would be the 6 appropriate thing to do. 7 For the catastrophic event, 8 life-threatening, and then the event itself would 9 either be death or potential death, the appropriate 10 analysis is what we call survival analysis. In that 11 case, we don't count how many times the patient died 12 obviously. We measure, rather, how long until that 13 catastrophic event has occurred. 14 And then the relationship of that to 15 whether this is a home patient or a clinic patient and 16 a bunch of other co-variates to be adjusted for would 17 be the job of the analysis. 18 So this will take me more than a minute 19 and a half. Is that okay, Dr. Talamini? 20 CHAIRPERSON TALAMINI: Yes, yes, sir. 21 DR. AFIFI: Thank you. 22 So this is as far as the study design on 23 the options and the potential control groups. Sample 24 size computations would depend on the particular
  • 205. 1 outcome. So there is really no recipe as such. 2 Each study would need to be handled 3 differently perhaps. Inclusion and exclusion 4 criteria, I would obviously rely on the clinical 5 people in such studies. 6 The frequency and duration of treatment, 7 it seems already the FDA has proposed a standard. And 8 I think the experts in this area need to review that, 9 whether five to seven days a week. And I think this 10 is what is meant by this point unless it is something 11 else. 12 Study duration and the length of follow-up 13 are closely related. In general, we in designing a 14 clinical trial, especially one that will look at 15 length of time until a catastrophic event occurs, we 16 look at the half-life, if you will, what is the median 17 survival, the median disease-free or survival time, 18 because we want to come close to actually observing 19 half of the patients have the event occur to them. 20 Otherwise there would be too much censoring in the 21 terminology of such studies, so some review of the 22 literature to look at how long does it take until 23 ultimately the patient dies and how long does it for 24 half of the patients to experience that. So that
  • 206. 1 would be my advice on the length of follow-up. 2 Effectiveness endpoints is something I 3 think that is best discussed first by the clinicians 4 but, then, also with input from other experts, such as 5 statisticians, epidemiologists. And, as I mentioned 6 earlier, I'm glad to see the FDA thinking of using 7 epidemiologists more. They can't contribute more than 8 just the clinicians or the statisticians can. 9 So these are my comments. And there are 10 more technical things that I don't think we need to go 11 into now. 12 CHAIRPERSON TALAMINI: Thank you very 13 much. That's very helpful. 14 We'll just start from there and go around. 15 Additional comments on any of those points and perhaps 16 particularly the effectiveness endpoints? Dr. Sadler? 17 DR. SADLER: Since this is a clinical 18 trial to evaluate a device, when the question of 19 retrospective versus prospective comes up, your 20 immediate assumption is, well, it should be done 21 prospectively. But if somebody comes with an existing 22 device that has been used a great deal in this arena, 23 I would imagine retrospective data if it is good and 24 complete and accurate would be very useful.
  • 207. 1 I don't think we can have an ABA switch 2 with these people because in the first place, if you 3 get people in the dialysis center and they get 4 habituated, they don't want to change anything. 5 And if you get somebody dialyzing at home, 6 he doesn't want to come back into the center. So you 7 take one or the other. You put them there. And so 8 you may take historical controls or some sort of 9 additional control group that would be carefully 10 matched. 11 I'll leave the size of the group to the 12 statisticians. And I would think that this could be 13 both people on daily and people on less frequent 14 nocturnal dialysis. 15 It certainly doesn't need to go on for an 16 extended period of time to demonstrate that the device 17 is effective, that it doesn't induce user errors, so I 18 would think something like six months, which would get 19 you close to 100 treatments on alternate days and over 20 100 treatments on every day. And certainly once that 21 had been established, the time would probably shorten 22 for subsequent devices. 23 The safety endpoints certainly should be 24 user errors, should be machine failures, should be
  • 208. 1 false alarms and real alarms, and interruptions of 2 therapy due to device-related or user mishaps. And 3 those would also be much of our endpoints, plus 4 demonstrating that the patient's meter exceeds the 5 DOCI guidelines. 6 CHAIRPERSON TALAMINI: Terrific. Thank 7 you, Dr. Sadler. 8 Dr. Schulman? 9 DR. SCHULMAN: I'll just make two 10 comments. One thing is that the endpoint, one of the 11 endpoints, should be the delivery of adequate therapy. 12 And I would recommend using a GOCHA standard, Kt/V 13 method of kinetics be considered in such a study. 14 That I think is an important way to quantify this. 15 Even though this isn't a survival study, it would show 16 efficacy of the actual treatment. 17 And the other comment is that because this 18 study isn't going to -- you cannot do a really 19 randomized trial in a study such as this. So there is 20 likely to be bias in the way the patients are 21 selected. And you are going to have to rely on your 22 statistician to employ the necessary techniques to 23 account for that bias. 24 CHAIRPERSON TALAMINI: Thank you. Perhaps
  • 209. 1 you could expand on why you couldn't do a randomized 2 trial. 3 DR. SCHULMAN: Well, I mean, you really 4 couldn't take -- a lot of this, the experience of 5 Lindsay is that when he tried to recruit patients for 6 the study, it was really patient-motivated, the ones 7 that would want to actually come out of the unit and 8 go into the home and do this. 9 And so you really couldn't pick a truly 10 equally randomized group. You had social issues and 11 different level motivation in the patients that went 12 into the home, these nocturnal therapies. 13 CHAIRPERSON TALAMINI: It seems to me with 14 the right funding mechanism, you might be able to 15 convince patients, but I don't know. 16 DR. WEINGER: Can I follow up on that? I 17 have heard this from several people, and I am not 18 understanding it. Since this is only going to be for 19 certain patients anyway, if the entry criteria is 20 those patients who are interested and then you promise 21 everybody "Ultimately you'll get it, but we're going 22 to randomize half of you as the control group to stay 23 in clinic and the other half get it" and then use an 24 intent-to-treat approach, I don't understand why that
  • 210. 1 wouldn't be a reasonable design. 2 CHAIRPERSON TALAMINI: Dr. Hoy has a 3 comment. 4 DR. HOY: Can I respond to that? You 5 know, the NIH and CMS are actually trying to do this. 6 The problem is that there has never been a successful 7 dialysis study that has randomized people to two 8 different dialysis modalities. 9 In other words, we have never compared 10 CCPD, continuous cycle peritoneal dialysis, to CAPD. 11 We have never compared home hemo to in-center 12 hemodialysis. We have never compared transplant to 13 hemodialysis. And we are now proposing to talk about 14 doing a randomized controlled trial of in-center 15 hemodialysis against short daily hemo in-center 16 dialysis and nocturnal home hemodialysis. 17 You know, I've got to tell you I'm 18 participating in this because I think it is the gold 19 standard. And I think, actually, if CMS and NIH can 20 get together, probably you ought to think about trying 21 to get information from them as well. But there has 22 never been a successful study that has collected 23 patients for two different modalities. 24 CHAIRPERSON TALAMINI: But if it could be
  • 211. 1 done, it would be a worthy goal, I would assume. 2 DR. SCHULMAN: You could do things like 3 develop propensity scores for the patients and do 4 certain techniques like that, but that's the way you 5 get around. I don't think you'll get a truly 6 randomized trial. 7 CHAIRPERSON TALAMINI: Okay. Well, Dr. 8 Lockridge? Then I need to get us back on track. 9 DR. LOCKRIDGE: Right. I think we really 10 are focusing on the wrong thing here in the sense of a 11 clinical trial that is going to prove efficacy. I 12 think that in the initial definition, we were talking 13 about a trial that looked at a device that delivered 14 the same capability as another device that already 15 existed and whether it was safe. 16 And that doesn't include whether the 17 endpoint is death or not. It includes whether or not 18 the machine is safe and delivers the same form of 19 therapy. 20 So I think we are way out here to think 21 about a six-month trial or a two-year trial 22 randomized. I think we are really looking at a much 23 different trial. 24 CHAIRPERSON TALAMINI: Thanks.
  • 212. 1 Let me go back to going around the room, 2 even though we have sort of gotten ahead of ourselves 3 a little bit. Dr. Duffell? 4 DR. DUFFELL: I don't know if my comment 5 is going to pick up where you left off or not, but my 6 thought behind this is the presumption that a clinical 7 trial is indeed needed in order for a manufacturer to 8 put one of these products on the market. 9 Is that a true assumption? Will the data 10 bring forth a knowledge base that will enlighten us in 11 some way that it is going to really help in the 12 marketability of these products? Because from the 13 conversations I have had with you all around the 14 table, it seems like everybody wants these things. 15 They want them pretty much now. 16 So, you know, the question you need to ask 17 yourself is, is what we're going to get out of this 18 trial really going to enhance our knowledge and change 19 what we are doing because it is going to delay the 20 availability of the technologies to you all as 21 clinicians. 22 So is there a return on this investment, 23 in other words, from a business standpoint, not 24 whether the questions are valid, because the questions
  • 213. 1 maybe could be addressed somewhere else, some other 2 method, such as post-market surveillance registries 3 and things of that sort, where you gather information 4 and revise labeling based on what you learn that way? 5 So do you need it prospectively now in order to put 6 these things out there or can we get it some other 7 way? 8 CHAIRPERSON TALAMINI: Let me just let Dr. 9 Sadler make a comment quickly. 10 DR. SADLER: Very quickly. We already 11 have them. And it may very well be that the 12 manufacturers will not ask. And they can't be refused 13 if they don't ask. And so none of this will come to 14 pass. 15 If somebody wants to get it, they will 16 have to go through the hoops, whatever those hoops 17 happen to be. And, as I said, if it's a machine that 18 has already been out there and has a significant track 19 record, they can probably do it with retrospective 20 data if it's complete and accurate. 21 CHAIRPERSON TALAMINI: Ms. Moore? Pass. 22 Dr. Hoy, further comments? 23 DR. HOY: Just one. I think there's a 24 huge amount of data from Canada. And I know it's a
  • 214. 1 foreign country, but it might be worth thinking about 2 trying to see whether or not the retrospective data 3 that we have in the United States combined with the 4 data from Canada actually gives us some ideas about 5 the safety of this method. I mean, there is a lot of 6 data out there. 7 CHAIRPERSON TALAMINI: Dr. Lockridge, 8 further comments? 9 DR. LOCKRIDGE: Yes. I'm still missing 10 the point here. I think it's not about the safety of 11 the modality as much as the safety of the machine. 12 The safety of the machine and the modality related to 13 nocturnal dialysis, the patient asleep night over 14 night. 15 There are over 500 articles written about 16 more frequent dialysis. Seven years ago, people 17 didn't believe it was better. It's no question that 18 the nephrology community believes that more frequent 19 and longer dialysis is better. The real question is, 20 can a manufacturer make a machine that can safely 21 deliver nocturnal dialysis if they apply for that? 22 So I think we need to answer that question 23 for the FDA. What kind of study does that do? I 24 think it's a prospective. I mean, similar to what
  • 215. 1 Aksys did with their study, it's eight weeks in 2 center, training period, eight weeks at home, see how 3 many alarms there are, how many times the machine is 4 down, is it safe, does it disconnect. I mean, it's a 5 pretty simple thing. 6 To randomize to approve mortality in the 7 NIH study, they're saying we have to do 1,500 people 8 and follow them for 2 years. No business people are 9 going to do that to deliver a machine to the 10 community. We have got to really be realistic here 11 about what we're asking for. 12 CHAIRPERSON TALAMINI: Yes. Those are 13 good comments. 14 Dr. Moran? 15 DR. MORAN: Next time I'm going to sit 16 upstream from Dr. Lockridge. I do have to agree with 17 him. I think the study design should be what was done 18 by both machines that have undergone trials for home 19 use, a period of training in center, and then a period 20 being followed in center, and then a wash-out at home, 21 and then collection of safety data in the home. So 22 each patient is their own control. 23 I entirely agree we will never get a 24 randomized study if we try and do that. I think the
  • 216. 1 only way to design the study is to have each patient 2 in each arm. 3 CHAIRPERSON TALAMINI: Thank you. 4 Dr. Blagg? 5 DR. BLAGG: I agree with both Dr. Moran 6 and Dr. Lockridge, and I also take up John's point 7 that, after all, we have all of these machines out 8 there now that were never designed to do home 9 dialysis, but they're working perfectly well with home 10 dialysis. 11 So if a manufacturer wants to get specific 12 approval for home dialysis, I think the sort of 13 approach that John Moran is talking about and Bob is a 14 way to do this: brief, simple. 15 And the only question I think is, should 16 you use patients who are already home patients to do 17 the study on or should you use patients who are in the 18 center but who are willing to go home? 19 I think that may be very difficult to 20 achieve in terms of patient numbers in a reasonable 21 amount of time. So I think that the minimum study is 22 what we should be looking at. 23 DR. GILLESPIE: And just on a slightly 24 different note, in terms of inclusion and exclusion
  • 217. 1 criteria, I would hope that the age range will be very 2 broad and that the criteria will be very broad. That 3 would help improve the numbers of the study as well, 4 but it's actually young people that have perhaps some 5 of the most to benefit from this modality and might 6 actually be a larger proportion overall using it 7 because of the benefits on nutrition and growth and on 8 reduced school absenteeism. 9 So there is certainly no reason to exclude 10 people under 18 or anything like that from these kinds 11 of studies. 12 CHAIRPERSON TALAMINI: Thank you. 13 Let me just take the prerogative of the 14 chair for a second. So if I hear the majority and 15 what they're seeing, it's that the more frequent 16 dialysis is no longer an unanswered question. That's 17 a question that has been answered in the literature. 18 And, like usual, the key to doing the 19 right study is asking the right question. And the 20 question here is simply, are the machines safe enough 21 to do it at home? Is that what I'm hearing people 22 say? 23 DR. ARANOFF: I think you also have to 24 consider, will the specific machine provide the
  • 218. 1 treatment also? I mean, the modality is proven, but 2 we're talking about individual machines at some time. 3 So the machines are going to have to demonstrate that 4 whatever that machine is also provides a treatment. 5 CHAIRPERSON TALAMINI: Right. Dr. 6 Schulman? 7 DR. SCHULMAN: I don't disagree with the 8 suggestion of Dr. Moran about how this study should be 9 done and what the purpose of the study is, but I don't 10 want the FDA to go away thinking that it's a slam dunk 11 that longer dialysis is better. 12 The whole nephrology community thought 13 that a higher Kt/V was better. And in a real trial, 14 the null hypothesis was fulfilled. So let's not go 15 into that part of things. 16 I think I just want to make that 17 cautionary note. 18 CHAIRPERSON TALAMINI: Okay. It looks 19 like we're going backwards now, but let me get Dr. 20 Kalota, and we'll get back over. 21 DR. KALOTA: Well, I just see it as two 22 separate issues. One, whether daily hemodialysis is 23 better, longer hemodialysis is better, is a medical 24 issue. It's not a device issue. And I thought we
  • 219. 1 were here for the device, which is whether it's safe 2 or not, whether it's comparable or not, not whether to 3 decide whether we should be dialyzing more often, 4 longer, slower, or faster. 5 CHAIRPERSON TALAMINI: Okay. Dr. Gibson, 6 do you have a comment? 7 DR. GIBSON: I just support the idea of 8 the minimal studies about the device. That's all. 9 CHAIRPERSON TALAMINI: Dr. Weinger? 10 DR. WEINGER: Yes. I think we have to 11 separate safety from efficacy. And if you simply are 12 testing the device, it might make sense to have for 13 efficacy a trial of this new home-specific device and 14 an older not home-specific device used in the home. 15 That would test whether it was as good as existing. 16 But safety is a different thing. And I 17 want to reiterate the importance of useability testing 18 before you try and do efficacy testing. That, then, 19 gets at the issue of inclusion and exclusion criteria. 20 The temptation whenever you are doing a clinical trial 21 is to have as narrow a group of patients, the best 22 possible patients so that you can show the best 23 possible result. 24 But if you are trying to look at safety in
  • 220. 1 such a clinical trial, you're going to get a best case 2 scenario of safety. And so you have to pair that with 3 separate useability tests with a broad spectrum of 4 potential users and use environments so that you 5 really understand what the constraints are in terms of 6 safety of the modality. 7 CHAIRPERSON TALAMINI: Thank you. 8 Dr. Moran, further comment? 9 DR. MORAN: I think that is entirely the 10 wrong attitude. What you are suggesting is that we 11 should test these machines in patients who the doctors 12 don't think are safe to go home. People entered into 13 this study need to be the people who are potential 14 users of the machine, not the worst-case scenario. 15 DR. WEINGER: But you misunderstand me. 16 In a useability test, what you want to know is what 17 are the potential failure modes, errors, and such that 18 patients can make? And if you pick the best possible 19 patients and you do a limited clinical trial, you are 20 going to pick up some of those things, but you won't 21 pick up a sufficient number that will reduce the risk 22 of in post-market seeing catastrophic events. 23 And that is why useability testing, where 24 you are looking at worst-case scenarios, what if there
  • 221. 1 is a disconnect, what if there is this and that in 2 simulated environments, mind you. 3 Then you can tell, did my design or 4 warnings or whatever you do really -- is it going to 5 work at preventing a catastrophic outcome. 6 CHAIRPERSON TALAMINI: Well, I don't feel 7 as good about where we came to at the end of that 8 question's discussion because of the complexities 9 involved, but it sounds at least like the panel's 10 opinion is that the prime objective of the study needs 11 to be to test the safety of the machine. 12 It sounds like there is a difference of 13 opinion as to whether these should be naive patients 14 or experienced patients. And is that worth discussing 15 a little bit more for such a study or not? Dr. 16 Sadler? 17 DR. SADLER: Well, one of the key 18 characteristics of a good machine for home is that 19 it's easy to learn. So certainly part of the testing 20 ought to be while the patients are training. And you 21 can't train somebody who is already trained. So I 22 would think yes, it ought to be incident patients, 23 rather than prevalent patients. 24 Again, I think because most of the
  • 222. 1 existing machines are already in use for this purpose 2 and no specific labeling for this purpose has ever 3 existed, I think it is highly unlikely that there is a 4 motivation for the manufacturers to come forward and 5 seek it. And we're probably just having an 6 intellectual exercise here. 7 CHAIRPERSON TALAMINI: Dr. Afifi, summary 8 comments? 9 DR. AFIFI: Yes. I think the concept of 10 substantially equivalent that the FDA uses says that, 11 indeed, what we want to do is find the comparison 12 machine, the currently used one in clinics and the new 13 proposed one. And, therefore, having the patients be 14 their own controls, start there, wash-out period, then 15 do it at home and compare the results. I think that 16 that is an appropriate way of thinking to my mind. 17 The question of long-term effectiveness 18 and long-term safety could I think be thought of as a 19 post-marketing concept. And that is the best that I 20 could offer you. 21 CHAIRPERSON TALAMINI: Terrific. Let me 22 go on to question 5, which is more -- yes? 23 MS. BROGDON: I believe the staff had one 24 question they wanted to ask.
  • 223. 1 CHAIRPERSON TALAMINI: Okay. Please do. 2 MS. BROGDON: It was just answered. Thank 3 you. 4 CHAIRPERSON TALAMINI: Oh, okay. 5 Terrific. So question five is with regard to clinical 6 study design, "Please address these additional issues 7 and discuss whether or not they should be considered 8 in a clinical trial: a) need for dialysate additives, 9 such as phosphate, and monitoring requirements for 10 these levels; b) type of anticoagulant appropriate for 11 home use; e.g., dose, bolus, and monitoring issues; c) 12 type of hemodialyzer membrane and permeability; d) 13 type of monitoring; no partner present, partner awake, 14 no partner but using remote monitoring, or no partner 15 or remote monitoring; e) vascular access choice and 16 location, and risks associated with these; f) practice 17 of hemodialyzer reuse; and g) psychological effects; 18 e.g., impact of treatments on patients, such as loss 19 of social interaction and the effects of the increased 20 responsibility on the patient, and the impact on and 21 the reaction of the family members living in the 22 house). 23 I guess what I might suggest that we do as 24 we go around the room is if you don't feel these need
  • 224. 1 to be studied in the context of what we have already 2 discussed, state that. If so, then state perhaps why 3 it should be part of such a study. 4 Let me start with Dr. Sadler and go around 5 so that Dr. Afifi can summarize after this question. 6 DR. SADLER: Okay. In this particular 7 question, I think that A, B, C, and E are clinical 8 practice and not part of a device investigation. My 9 own feeling with regard to D is that I would be very 10 reluctant to send anybody home without a partner. I 11 just think that to do so is to believe that Murphy was 12 wrong. And I believe that things do go wrong, and 13 that is when the partner is needed. 14 With regard to F, for most patients 15 dialyzing at home, reuse is more trouble than it is 16 worth. And there are effective single use dialyzers 17 these days that they could utilize. 18 And with regard to G, that's not really a 19 factor in the device so much as it is clinical 20 practice again. There are both beneficial and 21 stressful effects on patients at home. And without 22 observation of the individual patient, it would be 23 inappropriate to generalize those. 24 CHAIRPERSON TALAMINI: Thank you.
  • 225. 1 Dr. Schulman? 2 DR. SCHULMAN: With respect to these 3 dialysis additives, I think it's known that the 4 phosphorous levels, for instance, may go down. And 5 they're going to have to be supplemented. That is 6 something the patient is going to have to do. 7 And the device, it should be, that 8 behavior should be, tracked how easy it is for them to 9 do, how often, does it affect the curve, because the 10 phosphorous level went to low and so forth. So I 11 think that that is part of monitoring that should be 12 done in a study design. 13 So I do disagree with Dr. Sadler. With 14 respect to most of the other things he said, I'm in 15 agreement. 16 CHAIRPERSON TALAMINI: Okay. Dr. Duffell? 17 DR. DUFFELL: I agree with Dr. Sadler's 18 remarks. 19 CHAIRPERSON TALAMINI: Thanks. 20 Ms. Moore? 21 MS. MOORE: No additional remarks. 22 CHAIRPERSON TALAMINI: Thank you. 23 Dr. Hoy? 24 DR. HOY: I agree with Dr. Sadler's
  • 226. 1 remarks about A, B, C, and E being clinical decisions 2 that the physicians have to deal with. The monitoring 3 issue, to me the patient has to be monitored in some 4 way, shape, or form, whether it's by a partner at home 5 or by a virtual partner. It doesn't matter to me 6 because I think they're both equally safe or equally 7 risky depending on how you look at it. 8 The practice of dialyzer reuse is 9 unnecessary and inefficient. Ask the largest dialysis 10 company in the world about that one. They don't do it 11 anymore. It would just interfere with the ease of 12 being at home. 13 I do think the issue of the impact of this 14 treatment on other family members needs to be looked 15 at, care-givers, other care-givers, spouses, 16 significant others, and children. It is worth 17 investigating further. 18 CHAIRPERSON TALAMINI: So, Dr. Hoy, let me 19 just pin you down and perhaps Dr. Sadler a little bit 20 more on this. This issue of monitoring and partners, 21 is this an issue worthy of study or no in a trial that 22 the FDA would participate in? 23 DR. HOY: No. 24 DR. SADLER: I think not. It's been
  • 227. 1 demonstrated that both work. There is preference on 2 the part of individual nephrologists who will train 3 patients. And they will practice in conformity with 4 their beliefs, but the evidence is already out there 5 that people can do it both ways. It's just a matter 6 of how much of a margin of safety exists. And I don't 7 think that it's appropriate for this study. 8 CHAIRPERSON TALAMINI: Thank you. 9 DR. HOY: I'm sorry. One last comment I 10 forgot to make about the issue of not reusing 11 dialysis. There is the issue of first use reactions. 12 And we have not run into trouble with that because we 13 recirculate blood for 10 to 15 minutes before we 14 actually hook the patient up. But that is an issue to 15 be looked at if you're not reusing dialyzers. 16 CHAIRPERSON TALAMINI: Dr. Gibson wants to 17 make a comment quickly. 18 DR. GIBSON: Yes, very brief, about the 19 psychological effects. I agree with the industry 20 representative, Dr. Duffell, that it should not be 21 incumbent on the industry to prove that this is 22 psychologically safe. 23 But if I understand Drs. Sadler and Hoy to 24 say that we should not collect data on the
  • 228. 1 psychological effects on the family during the study, 2 I think that would be wrong because, even though it's 3 my opinion, like theirs, that there will not be any 4 psychological effects that are harmful during this 5 period, I think we should collect the data. And there 6 are some fairly simple instruments that at least have 7 a validity among the behavioral health people with 8 regard to outcomes versus the process of coping, which 9 is a different story. 10 But as far as outcomes are concerned, that 11 data could be collected. My hypothesis is that it 12 will not show any adverse effect, but I don't know 13 that. 14 CHAIRPERSON TALAMINI: Yes. I was 15 actually pinning them down on the monitoring issue. I 16 think Dr. Hoy actually was in favor of studying the 17 psychological aspects. 18 DR. SADLER: Well, if I may comment, I 19 didn't say at all we shouldn't study it. I just said 20 that I thought it was not something to be generalized 21 on small populations because people will respond in 22 different ways. It certainly should receive attention 23 because it is always important when we put this kind 24 of a responsibility on a patient.
  • 229. 1 CHAIRPERSON TALAMINI: Dr. Lockridge? 2 DR. LOCKRIDGE: Yes. I probably disagree 3 a little bit about what should be done as far as the 4 dialysate additives. I think nocturnal dialysis is 5 different than daily dialysis, short daily, or in 6 center 3 times a week in the sense that it offers 2 to 7 3 times more dialysis or clearance, clearance of about 8 30 to 40 cc. 9 So in our practical experience, I think 10 that phosphorous is a real issue. And I think new 11 machine designs to the field should address that and 12 figure out how to make the phosphorous at 1.5 to 2. 13 In other words, that should be part of the machine 14 design. 15 The issue of magnesium that Chris brought 16 up, everybody is hypomagnesemic, I think that needs to 17 be looked at in this document that says what you 18 should do to bring this to fruition as far as the 19 manufacturer. Magnesium is an issue. 20 And the third issue is calcium. I think 21 they have clearly shown that when you dialyze this 22 amount of dialysis is actually calcium wasting, there 23 are no phosphate binders or no calcium supplement that 24 patients take.
  • 230. 1 So, actually, with hemo filtration or 2 removal of the fluids, you're removing calcium. And 3 people become calcium-depleted. So I think that we 4 standardly start people on three milliequivalents per 5 liter of calcium. The standard bath in center is 2.5. 6 So I think calcium is another thing that 7 really has to be looked at. You really don't see the 8 changes on the bones for a year, but I think we need 9 to have the manufacturers be able to deliver a 3, a 10 3.25, and a 3.5 calcium bath. And it needs to be 11 proved that they can do that in this trial because 12 that is going to be needed to care for these people. 13 DR. SADLER: Bob, isn't that incumbent on 14 the concentrate manufacturers, not the machine 15 manufacturers? 16 DR. LOCKRIDGE: Well, it depends on what 17 machine and who is -- I agree if you're Fresenius and 18 using the standard proportion machine. If you're 19 Aksys and make your own concentrate or if your renal 20 solutions that are using absorbent cartridge or 21 NxStage you mix the fluid in a bag. They have to 22 bring that to the marketplace. 23 CHAIRPERSON TALAMINI: Dr. Moran, which of 24 these items should or should not be included in a
  • 231. 1 study? 2 DR. MORAN: Reuse should not be included. 3 I don't think anybody is doing reuse in the home 4 patients. I apologize. I agree with Dr. Sadler. 5 It's more complicated than it's worth. I apologize. 6 I'm upstream of you. 7 Water-soluble vitamins is the other thing 8 I think we should be looking at, too, in this 9 long-extended dialysis. 10 CHAIRPERSON TALAMINI: Thank you. 11 Dr. Blagg? 12 DR. BLAGG: I basically agree with Dr. 13 Sadler's comments. The other comment I would like to 14 make, though, is we really need to look or somebody 15 needs to look at what this trial is going to cost the 16 manufacturers to do the more of these things that get 17 put into it because I think that will be one of the 18 reasons why manufacturers may never want to go and 19 have their machines approved for nocturnal 20 hemodialysis. 21 CHAIRPERSON TALAMINI: And that is one of 22 the beauties of being on an FDA panel, that we're not 23 supposed to think about cost. 24 Dr. Gillespie?
  • 232. 1 DR. GILLESPIE: Just to comment on the 2 reuse thing, I think it doesn't make sense in the 3 traditional sense with traditional machines, but it's 4 possible that people are going to come up with 5 different technology. 6 I know there is one machine right now that 7 reuses not only the dialyzer but the entire circuit. 8 And it's self-cleaned each night. So I think we 9 couldn't write off the reuse question entirely if 10 somebody comes up with a novel technology for it. 11 I wouldn't see people like collecting the 12 dialyzers and carrying them back into the center to 13 reprocess, as was done in the past. Like I said, if 14 the machine is something that is categorically 15 different, then we may have to look at it differently. 16 CHAIRPERSON TALAMINI: Thank you. 17 Dr. Lockridge, did you want to make a 18 comment? 19 DR. LOCKRIDGE: Yes. The heparin issue is 20 a real issue, too, because because you dialyze people 21 six or seven or eight hours, the design, you can 22 bolus, but the kidney is going to clot. When my 23 patients forget to cut on the pump, their kidney clots 24 during the night.
  • 233. 1 So I think it's FDA should be having the 2 manufacturers have a machine that has a heparin pump 3 on it that will deal with that anticoagulation. And 4 how that heparin pump works and how it is monitored 5 needs to be monitored in this clinical trial. And 6 that makes this different from nocturnal. I mean, 7 nocturnal is different in that way. 8 CHAIRPERSON TALAMINI: Yes. Right. 9 That's helpful. 10 Dr. Weinger, which issue should be -- 11 DR. WEINGER: I'll pass. 12 CHAIRPERSON TALAMINI: You'll pass? 13 Dr. Gibson, further comments on which of 14 these should be included in a study and which not? 15 DR. GIBSON: Pass. 16 CHAIRPERSON TALAMINI: Pass? 17 Dr. Kalota? 18 DR. KALOTA: I can't comment on the things 19 specific to the hemodialysis, but I would say for the 20 test, we should have some kind of monitoring present 21 to answer the question as to whether or not we need to 22 have monitoring present. 23 CHAIRPERSON TALAMINI: Okay. 24 Great. Dr. Aranoff?
  • 234. 1 DR. ARANOFF: I think it's less important 2 for us to consider which ones of these individually 3 specifically should be studied and more incumbent upon 4 us to comment about whichever ones are studied for a 5 particular device, that that then be covered in the 6 labeling of that device. 7 So, for example, we may have technology 8 where a particular machine would use a dialyzer that 9 has heparin covalently bound to the membrane. And so 10 it wouldn't need bolus or infusion heparin to keep it 11 one. That ought to be covered, then, in the labeling 12 for the device as it is studied. 13 If a device is studied with both remote 14 monitoring and a partner, if that manufacturer chooses 15 to use their machine and study it in that way, then 16 that ought to be included in the labeling, that this 17 was shown to be safe with a remote monitoring and the 18 partner. 19 If, on the other hand, a device 20 manufacturer chooses to study their device without 21 remote monitoring or without a partner and still 22 proves it to be safe, then they ought to have that 23 indication. 24 CHAIRPERSON TALAMINI: Thank you.
  • 235. 1 Dr. Afifi, summary thoughts about these 2 issues and the clinical study question in general? 3 DR. AFIFI: Yes. First, it seems that 4 none of the items A through G under this area need to 5 be thought of as randomization variables. In other 6 words, we don't need to randomize do you have a 7 monitor or not, do you have an in-resident person or 8 not, et cetera? 9 I think it would be wise to collect the 10 data on them. I don't think that will be a burden, an 11 excessive burden. I think the point that if we then 12 collect those variables and look at them as covariates 13 and perhaps do some stratification or subgroup 14 analysis, we will learn about whether some of these 15 items, some choices for these items, are more helpful 16 than others for the success of the whole operation. 17 And, as Dr. Aranoff said, I think these 18 could be helpful conclusions to be included in the 19 labeling later on. 20 CHAIRPERSON TALAMINI: Terrific. Thank 21 you. 22 I would again ask the FDA if there are 23 further issues the panel can address to help with this 24 clinical study design question.
  • 236. 1 MS. BROGDON: I need to confer with the 2 staff for just a moment if you would allow that. 3 CHAIRPERSON TALAMINI: Sure. There was a 4 housekeeping detail that somebody mentioned about the 5 front desk and needing to -- okay. 6 DR. SADLER: Well, while we have a gap, 7 let me put one loose comment into it. 8 CHAIRPERSON TALAMINI: Absolutely. 9 DR. SADLER: It's been a thought that has 10 been rattling around since we started that we talk 11 about training laymen to do dialysis at home and 12 dialysis in center being done by professionals. But 13 those professionals are ordinarily technicians who 14 have a highly varied and relatively short period of 15 training. The difference is not so much the quality 16 of the people doing the dialysis but the presence of 17 oversight. 18 CHAIRPERSON TALAMINI: Good point. 19 Yes? 20 DR. RUIZ-ZACHAREK: Yes. We actually 21 wanted to elaborate on the psychological effects. One 22 of the concerns we had -- again, this might just fall 23 in the practice of medicine and individual 24 prescription by each nephrologist.
  • 237. 1 Our concern was, how stable would a 2 patient need to be to go home with a dialysis machine 3 to perform nocturnal dialysis. And our concern was on 4 patients who have prior suicidal attempts or some 5 psychological instability. 6 CHAIRPERSON TALAMINI: So let me ask 7 perhaps if four of the clinical nephrologists could 8 address that for us. What four clinical nephrologists 9 would like to address that question? Dr. Lockridge 10 obviously would. 11 DR. LOCKRIDGE: I think there are criteria 12 for who should not go home. We treat nocturnal 13 dialysis as a privilege in our facility. And we look 14 at it similar to a transplant. 15 In a transplant, basically if you're a 16 drug user, you have to be drug-free for six months 17 with randomized studies. So that's dealing with the 18 drug user. 19 If you're an alcoholic, you have to be 20 alcohol-free and be tested. And if you smell of 21 alcohol, it's looked within the document, in six 22 months, you don't get a chance to dialyze, to do 23 nocturnal dialysis. And if you have mental health 24 issues, you should not be allowed to go home.
  • 238. 1 We have found that education is not an 2 issue. We have taken cards. We have sent people home 3 with third grade or less education to do it. It is 4 the desire to do it. If the patient wants to do it, 5 they can do it. 6 So I think that teaching, taking the same 7 approach that this is a privilege and treatment it as 8 if it's a transplant patient and having the same 9 requirements for drugs, mental illness, and alcohol is 10 the thing. 11 As far as the issue of stability, we feel 12 that having the social worker makes a social work 13 visit in the home by herself with the family to try to 14 get a feel for the family interaction, which we think 15 makes a difference as far as what kind of input. 16 We have trained people that weeks into 17 training the wife said, "the machine or me in the 18 bedroom." And certainly the person took the wife in 19 the bedroom, instead of the machine. 20 So I think there are limitations of what 21 we can do, but I think that is where I would structure 22 it. 23 CHAIRPERSON TALAMINI: Dr. Gibson? 24 DR. GIBSON: I would like to start by
  • 239. 1 saying what I said before, that I would not like to 2 see arbitrary exclusions based on the psychological 3 data because, frankly, psychiatrists are not all that 4 good at predicting who is going to do what in the 5 future. And nobody is all that good at predicting 6 human behavior with any certainty. 7 With that said, I think Dr. Lockridge is 8 right on target that the evaluation needs to be 9 center-specific, much like transplant programs, where 10 transplant programs do exclude people who are actively 11 using substances and people with unstable mental 12 illnesses. And that is certainly appropriate to do, 13 but I would certainly argue that there are very likely 14 people with stable mental illnesses who do extremely 15 well on home hemodialysis of any modality. So that's 16 really all I would like to do, is just make a plea for 17 not excluding people based on what you think is going 18 to happen. 19 And there is one other point. I mean, the 20 active substance abuse and unstable mental illness I 21 would view as exclusions from entering the program, 22 but when people are in the program, of course, they're 23 going to be trained. And during that period of 24 training, you have an opportunity to evaluate how
  • 240. 1 people are actually doing. 2 And my prediction is that, of course, like 3 everything else, we'll be surprised that some people 4 you will predict will just pick this up in a flash and 5 do well, will flunk, and never go home and people that 6 you will predict are just dumb as dirt will learn how 7 to do this procedure just fine and will stay at home 8 and never come back. 9 CHAIRPERSON TALAMINI: Which leads nicely 10 to the next question. Any other burning comments in 11 response to that? Great. We've got a process 12 comment. We're doing great, but we've got to pick it 13 up just a little bit. So on to question number 6 with 14 regard to training. 15 The training of patients and their 16 partners, if applicable, is crucial in performing NHD 17 treatments. Please comment on the training needs for 18 this modality in terms of the important aspects to be 19 included in the training program, how long the 20 training period should be, and what criteria should be 21 used to determine if a patient has been adequately 22 trained and is ready to begin self-care at home. 23 Please also consider who should do the training and 24 how they should be qualified.
  • 241. 1 Dr. Blagg, let's start with you. 2 DR. BLAGG: Okay. First of all, training 3 needs obviously have to cover various things. The 4 first thing, in our program at least, is to teach the 5 patient to stick themselves or if family members can 6 do it, to teach them because our experience is it is 7 difficult for patients to learn until they feel at 8 least reasonably comfortable with sticking themselves. 9 They need to know about their disease. 10 They need to know about dietary management and so on. 11 They need to know how to do the dialysis. They need 12 to know the complications that are likely to occur and 13 how to handle them, how to contact for support and 14 when to see their physician and so on. 15 How long a training period? In our 16 program, once the patient can stick where we take 17 three to four weeks to train the patient, we train 18 them three days a week. And the other two days, they 19 come in and go to classes and do other things, like 20 work on the equipment and so on. 21 Criteria to be adequately trained. We 22 have a series of tests of various procedures that the 23 patients do that the nurses do with the patients on a 24 regular basis. They have a final exam, if you like,
  • 242. 1 on which they have to reach a certain minimum score 2 before they're allowed to go home. 3 During the last couple of so dialyses that 4 they do in the training program, they're in the room 5 with the door shut, and they're talking to the staff 6 by the telephone, like you would at home. 7 Staff. I think the important thing -- I 8 don't think it really matters whether it's a nurse or 9 in some cases a technician. I think what you need is 10 somebody who has a lot of experience of dialysis and 11 who is capable of being a teacher, not just a treater, 12 and keep their hands off patients if they make 13 mistakes, let patients learn from their mistakes. And 14 I think that covers -- how they should be qualified, 15 well, I guess each individual unit is going to decide 16 how to qualify their staff. 17 Those are my comments. 18 CHAIRPERSON TALAMINI: I guess I would ask 19 the panel also to think about how much of this falls 20 into medical practice and how much of this should 21 really be -- I don't want to use the word "legislated" 22 but should be part of whatever is done in terms of the 23 FDA. As Dr. Weinger pointed out, there are now 24 procedures where training is absolutely essential
  • 243. 1 before you can perform the procedure. So think about 2 that as well in your comments. 3 DR. BLAGG: I would suggest that it's the 4 physician in the dialysis unit's responsibility to 5 take care of these things. 6 CHAIRPERSON TALAMINI: Dr. Gillespie? 7 DR. GILLESPIE: I agree with everything 8 Dr. Blagg said. I don't think I could say anything 9 better. 10 CHAIRPERSON TALAMINI: Dr. Weinger? 11 DR. WEINGER: Yes. I think that the issue 12 of where is the boundary between the manufacturer's 13 responsibility for their specific device and the 14 clinical environment is a very important one. 15 The manufacturer certainly to assure 16 success in the use of their device and, thus, the sale 17 of more of them is going to provide general guidance 18 for the clinical aspects of it, but, really, the focus 19 has to be on the device. And my advice there is that 20 the manufacturer needs to establish clear performance 21 criteria for the key elements and components of their 22 device and perhaps then provide suggestions and some 23 support materials perhaps for helping the clinician 24 attain those performance criteria, helping the
  • 244. 1 clinicians to train the patients to attain those 2 performance criteria. 3 But, really, it's about the patient needs. 4 This would be typically what one would call a 5 useability objective. Patients needs to be able to 6 tend to and respond appropriately to X alarm in Y 7 amount of time correctly. Those are the kinds of 8 performance criteria that a manufacturer needs to 9 identify. 10 And hopefully they will have in parallel 11 with developing the device developed training 12 materials and tested these things themselves so that 13 they know that those are effective materials to attain 14 those performance criteria. 15 CHAIRPERSON TALAMINI: Dr. Gibson? 16 DR. GIBSON: I like the idea of the 17 performance objectives and agree with everything Dr. 18 Blagg said and nothing else to add. 19 CHAIRPERSON TALAMINI: Dr. Kalota? 20 DR. KALOTA: Nothing else to add. 21 CHAIRPERSON TALAMINI: Dr. Aranoff? 22 DR. ARANOFF: I think Dr. Blagg described 23 home training very well. And I don't think that 24 nocturnal home hemodialysis with regards to training
  • 245. 1 is fundamentally different than routine home 2 hemodialysis with regards to the training 3 characteristics. 4 And I think that could even be applied to 5 the psychological issues that we discussed a moment 6 ago. A patient who is appropriate for home 7 hemodialysis or home therapy, whether it's home hemo 8 or PD, should be a candidate for nocturnal as well. 9 So I don't think this is fundamentally 10 different than the guidance the FDA has already given 11 for training. 12 CHAIRPERSON TALAMINI: Terrific. I 13 haven't heard much about who should do the training 14 other than the physician. So perhaps as we go around, 15 we could address that as well. Dr. Afifi? 16 DR. AFIFI: No comment. 17 CHAIRPERSON TALAMINI: Dr. Sadler? 18 DR. SADLER: I agree with Dr. Blagg that 19 the training should be done by somebody who is 20 interested, a good communicator, a teacher, and 21 well-experienced in dialysis. And it doesn't matter 22 what credentials they hold. They can be very 23 effective. 24 I do believe that this represents a
  • 246. 1 function of the dialysis facility. It's the practice 2 of medicine. And while it was perfectly reasonable to 3 ask the facility to certify that the patient has been 4 trained, has demonstrated capability, and been tested 5 on this, you shouldn't get into that box to see what's 6 in it. 7 To quote Mark Twain, "No generalization is 8 worth a damn, including this one. And we ought to be 9 entitled to have a little bit of variation." 10 CHAIRPERSON TALAMINI: Dr. Schulman? 11 DR. SCHULMAN: Well, I agree with what has 12 been said already. I would like the FDA to know that 13 the people who do home training, whether it's CAPP or 14 hemodialysis as it exists now, often among the 15 motivated personnel. And they generally tend to do a 16 good job and are given the latitude by most units to 17 spend as much time as they need with the patient. 18 So I don't think that should be a major 19 concern of the FDA. 20 CHAIRPERSON TALAMINI: Okay. Terrific. 21 Dr. Duffell? 22 DR. DUFFELL: I agree with Dr. Sadler. 23 CHAIRPERSON TALAMINI: Ms. Moore? 24 MS. MOORE: Yes. I agree with Dr. Blagg
  • 247. 1 and the others who spoke about the training for home 2 care, but I think that the manufacturer should take 3 some kind of responsibility for guidelines for 4 training the medical staff, who will then be 5 responsible for training the persons who are going to 6 be doing this at home. 7 CHAIRPERSON TALAMINI: Okay. Great. 8 Dr. Hoy? 9 DR. HOY: I don't think that the 10 manufacturers do very much to help us train our 11 technicians. There may be some very broad stuff they 12 give us, training materials, but basically we train 13 our technicians to do dialysis. And those technicians 14 are actually no different in education or background 15 usually than many of the patients who come to us. 16 Several comments about the training 17 process that we use, one, we find that we can't train 18 the first week. We dialyze them four times a week for 19 the weeks that we do the dialysis. And we do it very 20 aggressively because by the end of the first week, 21 they're less anxious. 22 We're sort of describing what we're doing. 23 We've also gotten to know them a little better. We've 24 decided which one of our three trainers is going to be
  • 248. 1 a personality fit with those patients. And we've got 2 them cognitively improved by the end of the week so 3 they remember what we're saying. 4 Secondly, we also do everything we can to 5 chart self-care in the dialysis unit in center before 6 they come to us. And we start cannulation training 7 before they come to us. 8 CHAIRPERSON TALAMINI: Great. Thank you, 9 Dr. Hoy. 10 MS. MOORE: Excuse me. 11 CHAIRPERSON TALAMINI: Yes, Ms. Moore? 12 MS. MOORE: I think I mentioned the 13 responsibility of the manufacturer because I remember 14 being on a prior panel where there were machines and 15 the manufacturer had some very clear training packages 16 for the physicians because each machine then I think 17 is designed in a special way, maybe very simple 18 training, but it seems to me that a physician might 19 need some kind of guidelines when there is something 20 new introduced in his office, such as a new machine. 21 CHAIRPERSON TALAMINI: Thank you. 22 I think probably what we're caught up in a 23 little bit again is the difference between nocturnal 24 home dialysis and standard in-hospital dialysis, where
  • 249. 1 the practices are already pretty well-established with 2 regard to physicians and others using the machine. 3 But that is an excellent comment. 4 DR. WEINGER: Can I follow up on that just 5 briefly? Based on other devices that have been put in 6 the home and certainly drugs that are being used at 7 home, the manufacturer would probably have substantial 8 -- it's a two-way sword but probably have substantial 9 liability if they left all of the training of the 10 patient to the clinician. 11 So any manufacturer who didn't have a 12 comprehensive patient training program would be in 13 trouble. So you can anticipate they're going to have 14 that. And, therefore, we want to make sure that it's 15 effective. 16 DR. DUFFELL: One other comment. All 17 manufacturers have an FDA responsibility to them to 18 provide adequate instructions for use. That's just an 19 absolute given. So they have to be there. 20 CHAIRPERSON TALAMINI: Right. 21 DR. SADLER: But one quick comment. Now, 22 we get surveyed all the time by several different 23 agencies that come and tell us that we have to follow 24 the manufacturer's recommendation. I'm sorry, but I
  • 250. 1 was doing home dialysis training before these people 2 started manufacturing machines. And I really don't 3 want them telling me how to train people for home 4 dialysis. 5 CHAIRPERSON TALAMINI: So noted. 6 (Laughter.) 7 CHAIRPERSON TALAMINI: Dr. Lockridge? 8 DR. LOCKRIDGE: Well, Dr. Sadler, I may 9 have to disagree with you here, but there are less 10 than 1,000 people doing home dialysis in this country 11 right now. There are 300,000 people doing it. We are 12 rigging new devices to the community that have new 13 ways of doing things. The Aksys machine is totally 14 different. The renal solution is the next stage. 15 I think it's FDA's responsibility to 16 clearly have the manufacturers produce training 17 manuals that are very detailed and complete. The CMS 18 as far as who can train or who cannot train, it's 19 clearly stated that an R.N. has to oversee, that 20 L.P.N.'s can train but an R.N. has to oversee a home 21 training program. That's the standard of care. 22 Now, you can certainly use technicians. 23 You can use L.P.N.'s. Two of the ladies that train in 24 my unit are L.P.N.'s. They're very good, but they're
  • 251. 1 overseen by an R.N. CMS has already covered that. 2 But I think that either we are going to 3 get to in this country with just 1,000 people centers 4 that are specialized in home training, like Wellbound, 5 or we're going to have to have standardization of care 6 if we're going to make a dent in this care. 7 CHAIRPERSON TALAMINI: Thank you. 8 Dr. Moran? 9 DR. MORAN: I agree with what has been 10 said. We have full independent home training centers. 11 And our first criterion when we hire a new nurse is, 12 are they going to be good trainers. Experience with a 13 particular machine comes second to that. We have all 14 three of the new machines in our centers. And we 15 expect the nurses to be able to teach any patient on 16 any of those machines is a strict policy. I think 17 that is something else we have to do. 18 We don't want to get into the old system, 19 where we had PD nurses and hemo nurses and never the 20 twain shall meet. We want the nurse to be able to 21 train a patient on PD in the morning and the Aksys 22 machine or the NxStage machine or the Fresenius 23 machine in the afternoon in a different patient. 24 CHAIRPERSON TALAMINI: Okay. Dr. Blagg,
  • 252. 1 further comment quickly? 2 DR. BLAGG: I would like to disagree with 3 you. I think if you have enough patients, you have a 4 separate program for PD and home hemodialysis. 5 I also think that the physician who cares 6 for the patient probably will have very little to do 7 with the trainings, maybe the medical director of the 8 facility, but we have 45 physicians in Seattle. And 9 most of them don't know anything about training. We 10 just hope they will refer their patients to be 11 trained. 12 And a final comment that we haven't 13 mentioned is that we believe that, at least every year 14 and preferably every six months, one of the training 15 nurses should go out and see the patient do a dialysis 16 in the home to make sure they haven't acquired too 17 many bad habits. 18 CHAIRPERSON TALAMINI: Excellent point. 19 Other questions regarding training? Let 20 me just ask specifically the FDA whether they would 21 like the panel to address other issues regarding 22 training. 23 MS. BROGDON: I think we have enough 24 information. Thank you.
  • 253. 1 CHAIRPERSON TALAMINI: Terrific. Thanks. 2 So the last two questions the panel is 3 asked to address are with regard to labeling. 4 Question number 7, device labeling directed towards 5 the patient should include information on NHD and on 6 the device, including instructions for the use and 7 care of the device, how to deal with alarms and how to 8 run treatments. Please discuss other important 9 aspects of NHD and the value of including them in the 10 lay user's manual; e.g., treatment, not device risks, 11 psychological effects of the treatments, vascular 12 access, information. 13 Dr. Gillespie, would you be willing to 14 start the round? 15 DR. GILLESPIE: That's kind of a tough 16 question to answer right off the top of my head. 17 CHAIRPERSON TALAMINI: We can pass if 18 you'd like. No problem. 19 DR. GILLESPIE: Okay. Appreciate that. 20 CHAIRPERSON TALAMINI: Dr. Weinger? 21 DR. WEINGER: First, labeling, just so 22 everybody is on the same page, is not just a physical 23 manual for use. It includes all aspects, written and 24 electronic, related to the use of the device,
  • 254. 1 including, to some extent, warning and instructions 2 physically attached to or displayed by the device. 3 And so the bottom line with regard to the 4 patient, which is the focus of this question, is again 5 that one needs to test that whatever the piece of 6 information is, that it effectively transmits that 7 information to the patient in the condition and 8 situation where that information needs to be used. 9 And, as well, I want to make sure and 10 appreciate that there are lots of modalities and for 11 lay people, often instruction manuals in the 12 traditional sense are the least effective way of 13 transmitting that information. 14 Again, the drug companies I think have a 15 fair history now of various programs from videotapes 16 and DVDs and Web sites and telephone hotlines, et 17 cetera, that need to be considered in the design of 18 these kinds of instructions, labels, and such. 19 DR. GIBSON: I don't see any value of 20 putting anything on the label about possible 21 psychological effects. 22 CHAIRPERSON TALAMINI: Thank you. 23 DR. KALOTA: Pass. 24 CHAIRPERSON TALAMINI: Dr. Aranoff?
  • 255. 1 DR. ARANOFF: I think in 25 years, I've 2 only had one patient, one home patient, ever quote 3 anything out of an instruction manual to me. 4 (Laughter.) 5 DR. ARANOFF: The patients ignore them. 6 They learn from the training what to do. And they 7 don't read the instruction manuals. 8 However, with the ability now to have 9 instructions embedded into the useability of the 10 machinery, that is where our attention should be 11 focused. 12 And the instructions should be simple. 13 They should be sequential so that patients are not 14 given information that they don't need at the very 15 moment that they are doing something. That is, if 16 they are setting up the machine, the instructions 17 should lead them through it, "Push the green button. 18 Now push the red button. Now push the yellow one. 19 Now you're ready to start." 20 And then once they start their treatment, 21 so on and so forth, and then when they finish their 22 treatment, then come off the machine and clean it out 23 or whatever, that should be sequential. And 24 fundamentally the machine should diagnose what is
  • 256. 1 going on and tell them what to do about it. 2 CHAIRPERSON TALAMINI: So that is an 3 excellent point. With that point in mind, let me just 4 ask the FDA or any panel member who knows to what 5 degree embedded software that is actually part of the 6 patient interface can be considered labeling or is it 7 never to be considered labeling? 8 MS. BROGDON: We would consider it 9 labeling, but that's the extent of my knowledge on 10 this. I can confer with the staff if you want to give 11 me a couple of moments. 12 CHAIRPERSON TALAMINI: No. I only ask it 13 for the benefit of this discussion because certainly 14 as these machines become more sophisticated, indeed 15 much more of the information that is needed is in the 16 software and not a piece of paper. 17 MS. BROGDON: It is certainly a developing 18 area for FDA. 19 DR. WEINGER: It is part of the user 20 interface and, therefore, subjected to all of the good 21 manufacturing practices and other design controls. 22 CHAIRPERSON TALAMINI: Let's keep going 23 around the room. Dr. Afifi? 24 DR. AFIFI: I was just looking at the list
  • 257. 1 of things here. I didn't see water purification. I'm 2 wondering if that could be added to it. 3 CHAIRPERSON TALAMINI: Dr. Sadler? 4 DR. SADLER: I would like to reinforce 5 what Dr. Aranoff said about having the machine's 6 software lead you through this. I think that question 7 seven is inevitably tied to question eight. And the 8 question eight is going to produce a manual for 9 professionals. And then you turn that over to some 10 experts, who translate it down to a fifth grade 11 reading level. And that will satisfy the 12 requirements. 13 But, as he says, it's not very important 14 to patients because they may keep it as a reference to 15 look something up sometime. And so it ought to be 16 laid out so that you can find things in it. 17 The most important part of the training is 18 the materials that are provided by the person who does 19 the training and by how the machine gives them 20 feedback as they operate it. So that I believe that 21 doing it as a software function is much more 22 desirable. 23 CHAIRPERSON TALAMINI: Thank you. 24 Dr. Schulman?
  • 258. 1 DR. SCHULMAN: I have nothing further to 2 add. 3 CHAIRPERSON TALAMINI: Dr. Duffell? 4 DR. DUFFELL: I agree with Dr. Aranoff, 5 but I would also add that our professional staff 6 doesn't read manuals either. 7 (Laughter.) 8 DR. DUFFELL: I mean, I think we fool 9 ourselves. It makes us sleep better at night to have 10 things covered there, but the realization needs to be 11 back to the design of the product to make it 12 intuitively obvious. 13 CHAIRPERSON TALAMINI: As soon as the 14 manual becomes complicated, the first thing you do is 15 make a phone call anyway, rather than thumb through 16 the manual. 17 Ms. Moore? 18 MS. MOORE: Pass. 19 CHAIRPERSON TALAMINI: Dr. Hoy? 20 DR. HOY: I have nothing to add. 21 CHAIRPERSON TALAMINI: Dr. Lockridge? 22 DR. LOCKRIDGE: Yes. I think FDA needs to 23 think about this entirely differently. I think that 24 we need to tie the labeling and the training manual
  • 259. 1 and what is embedded in the machine altogether as one 2 thing. 3 I think that we have rewritten our 4 training manual six times now over the last seven 5 years. We have little cards that we use now. And 6 when we call the patient, they do refer to the manual 7 if it's used in a training manual. So to have a label 8 like what the FDA requires on a drug is worthless for 9 the patient. The patient doesn't use it. 10 But if you have a labeling that ties in 11 the training, the machine, and the embedding of the 12 ideas in there, that is very useable to the patient. 13 And I think that is what we should be moving toward. 14 So I would favor the combining of 15 labeling, training manual, and software in the 16 machine. 17 CHAIRPERSON TALAMINI: Excellent point. 18 Dr. Moran? 19 DR. MORAN: I think our experience says 20 that having a graphical user interface and a touch 21 screen are absolutely wonderful for training, 22 establishing confidence in the patient. And in a 23 situation where an alarm occurs, if the machine tells 24 them, as Dr. Aranoff said, what the problem is and
  • 260. 1 what the steps to follow should be, one, two, three, 2 and they don't even have to think, I would point out 3 that if they are in bed at night and they are awakened 4 by an alarm and you've got a graphical unit user 5 interface that automatically lights up -- I beg your 6 pardon. I was saying if they are in bed at night, if 7 they are awakened by an alarm, if you have a graphical 8 user interface that automatically lights up, and 9 they're not fumbling for the light switch and 10 everything like that, they can just reach out and do 11 the appropriate -- 12 CHAIRPERSON TALAMINI: Great. Thank you. 13 Yes? 14 MS. BROGDON: I just wanted to say to Dr. 15 Lockridge we support the evolution of user and patient 16 labeling. We do review all of that information. And 17 we try not just to require paper labeling just because 18 FDA has always gotten that. We're open to more 19 innovative types of labeling and also then training. 20 CHAIRPERSON TALAMINI: Dr. Blagg? 21 DR. BLAGG: I agree very strongly with Dr. 22 Moran about the touch screen, and I have nothing else 23 to add. I agree with particularly Dr. Aranoff. 24 CHAIRPERSON TALAMINI: Great.
  • 261. 1 Dr. Gillespie, further comments? 2 DR. GILLESPIE: I agree with what people 3 have said, that the importance of printed manuals is 4 dwindling in a world where more interactive types of 5 things are becoming commonplace. 6 I think also part of the problem with 7 printed manuals is that a lot of them are really not 8 readable and not very useable, even by professionals. 9 And that's why people don't use them. So certainly we 10 support any progress in making things that are more 11 user-friendly. 12 The question also asks about other aspects 13 of nocturnal hemo and whether those should be included 14 in the user manual like just general treatment risks 15 and psychological effects and vascular access. And I 16 don't think so. 17 I think the manual should stick to just 18 the machine and try to keep it concise. And those 19 other areas, like things about access are a separate 20 issue that people should discuss with their health 21 care professionals or with other materials made for 22 that purpose. 23 CHAIRPERSON TALAMINI: Okay. Summary 24 comments about the patient labeling because in a
  • 262. 1 moment we're going to discuss physician labeling? Dr. 2 Weinger? 3 DR. WEINGER: Yes. I just want to follow 4 up. Some of my colleagues provided a reasonably 5 effective design solution to a specific user need with 6 regard to specifying a touch screen and such. I think 7 we need to step back from that because especially the 8 FDA's job isn't to design devices for manufacturers 9 but, rather, to see if manufacturers designed devices 10 effectively for use. 11 And so the important thing is for the 12 manufacturers to have an effective human factors 13 engineering process where up front they identify what 14 are the key issues with regard to labeling and 15 instructions and the ability of the patients to 16 respond to alarms, for example, and then to establish 17 performance criteria and then, whatever their design 18 solutions are, to demonstrate those solutions meet the 19 performance criteria. 20 One can be misled. I'll give you an 21 example. AEDs we all know. And the human factors 22 folks put them forward as examples of here are devices 23 that were designed with human factors engineering 24 involved so that eight-year-olds can do defibrillation
  • 263. 1 of strangers in airports. 2 But we have some data that shows that the 3 voice, which is a very powerful guide to getting the 4 end user of that device to do what needs to be done, 5 is, in fact, too powerful sometimes. And we have 6 videotapes of providers who are shocking people over 7 and over and never getting around to pushing on the 8 chest and actually getting some circulation going. 9 So, again, you have to really evaluate 10 your solutions with the end goals in mind. 11 CHAIRPERSON TALAMINI: Thank you. 12 Dr. Lockridge, did you have a comment? 13 DR. LOCKRIDGE: Yes. I think that I have 14 a mixed feeling about this. We talked about how much 15 information should be in the manual, the patient's 16 manual, about NHD and how much should not be. And I 17 feel strongly that the physician and the patient 18 should be making that decision. 19 And I think that that is what you were 20 saying, Dr. Gillespie, that this is a clinical 21 decision. But I think we need -- you know, how much 22 do we do? How do we do that? And I don't totally 23 know how to do that at this time. So I'm mixed. 24 CHAIRPERSON TALAMINI: Okay. Questions
  • 264. 1 from the FDA for the panel with regard to patient 2 labeling? 3 MS. BROGDON: Dr. Mendelson had a comment 4 he would like to make on human factors. 5 CHAIRPERSON TALAMINI: Okay. 6 DR. MENDELSON: My comments will be 7 concerning labeling and human factors in general, what 8 our activities are at FDA. I guess I want to 9 reinforce what Dr. Weinger said. 10 I talked about a process when I did my 11 talk. And I want to emphasize that we try not to be 12 burdensome and prescriptive. We never tell a 13 manufacturer what shape knob to use, what type of 14 sound a user should hear. What we like to do is look 15 at the manufacturer's process. So if they're 16 labeling, if their design works according to their 17 human factors evaluations, that is satisfactory to us. 18 We don't tell them what to do. 19 CHAIRPERSON TALAMINI: Great. Thank you. 20 Appreciate that. 21 Okay. Final question, number eight, with 22 regard to physician labeling, the physician labeling, 23 prescribing information, typically includes the 24 indications for use, contraindications, warnings and
  • 265. 1 precautions, instructions for use, and clinical data 2 on the use of the device. 3 For NHD, there is other important 4 information that clinicians need to know, such as the 5 need for alarms that may not be part of the NHD 6 device; e.g., circuit disconnect alarms, fluid leak or 7 moisture detection alarms, the need for a partner or 8 for remote monitoring, vascular access requirements, 9 and the need for dialysate additives; for example, 10 phosphorus. Please discuss whether or not this and 11 other treatment information should be part of the 12 physician labeling. A lot of these are issues we have 13 already discussed, but this is with respect 14 specifically for the physician labeling. 15 Dr. Weinger, would you like to begin? 16 DR. WEINGER: Sure. I have two points I 17 wanted to make. One is that one of the things it 18 seems to me ought to be part of this is guidance to 19 the clinician on patient selection and evaluation. My 20 colleagues on this side of the table have vast 21 experience, but that needs to be transmitted 22 efficiently to those who are trying to do this for the 23 first time. 24 The second thing that I haven't heard
  • 266. 1 about and I think needs to be in this area is a proper 2 way of evaluating the home environment, which includes 3 a variety of issues that have been mentioned in our 4 early presentation beyond water quality, which I heard 5 about, but lighting, noise, distractions, clutter, 6 other stressors, and issues of when and who and how 7 that home environment evaluation would occur. 8 And then, finally, I just want to put on 9 the record because I didn't hear it mentioned and I 10 think it may be important in terms of the design of 11 the device for the patient to respond to a crisis 12 situation, and that is fatigue and circadian effects. 13 And I heard somebody early on having sleep people 14 involved in the conversations, but that may actually 15 be a real design issue. 16 CHAIRPERSON TALAMINI: Great. Thank you. 17 Dr. Gibson? 18 DR. GIBSON: Actually, I find this 19 question difficult and don't quite know how to respond 20 to all of this. So I think I'll pass for that. 21 CHAIRPERSON TALAMINI: All right, sir. 22 Dr. Aranoff? 23 DR. ARANOFF: Well, I'm not sure exactly 24 how much comes under physician labeling and would fit
  • 267. 1 into a technical manual, for example, of the issues 2 that would be very device-specific. For example, the 3 home environment was mentioned. 4 Different devices will require different 5 water pressure. For example, whether that goes in the 6 physician labeling, or whether that is a technical 7 specification in an owner's manual of some sort, I 8 don't know but that sort of information. 9 I think in this, the one comment I would 10 like to make about physician labeling is that it ought 11 to reflect how the device was proven to be safe and 12 effective. That is, it should describe the situation 13 in which it has been safe and effective. And I made 14 that comment about monitoring and so forth earlier. 15 CHAIRPERSON TALAMINI: Dr. Afifi? 16 DR. AFIFI: Nothing to add. 17 CHAIRPERSON TALAMINI: Dr. Sadler? 18 DR. SADLER: With regard to the additional 19 points made in this question, my answer is no. 20 CHAIRPERSON TALAMINI: Thank you. That's 21 clear. 22 Dr. Schulman? 23 DR. SCHULMAN: I think some of the issues 24 that are listed here, for instance, of phosphorus down
  • 268. 1 in this case, don't necessarily have to be part of the 2 labeling for the physicians. Just some of these 3 functions should take place as a CME type of a thing, 4 you know, where we learn the procedures from 5 experienced people, like Drs. Lockridge, Hoy, and 6 Blagg. But I think these things don't have to be 7 labeled for the physician. 8 CHAIRPERSON TALAMINI: Okay. 9 DR. DUFFELL: I agree with Dr. Aranoff. 10 MS. MOORE: I pass. 11 CHAIRPERSON TALAMINI: Dr. Hoy, what 12 should be in the physician labeling? 13 DR. HOY: I have to tell you I have never 14 read a physician label on a machine or a dialyzer, for 15 that matter. 16 CHAIRPERSON TALAMINI: Don't say that, for 17 goodness sakes. 18 DR. HOY: I know. I know. I know. 19 Shocking. But I think that tells you something. 20 Secondly, anything that you would put in 21 there that has to do with the actual practice of 22 nocturnal dialysis will probably be out of date by the 23 time it's bought off the shelf. So I think it's not 24 worth anything more than just doing what you would
  • 269. 1 normally do for the device. 2 CHAIRPERSON TALAMINI: Okay. The fact 3 that it goes out of there quickly might not mean it 4 shouldn't be done in a manner that could be updated in 5 a timely fashion. So I wouldn't necessarily -- you 6 know, the one doesn't preclude the other is what I 7 suggest. It could be on a Web site or something. 8 Dr. Lockridge? 9 DR. LOCKRIDGE: I have mixed emotions 10 about this. I still go back to 1,000 people in this 11 country doing some type of home hemodialysis. I go 12 back to the fact that there are only two training 13 centers in this country that train people to do 14 nocturnal dialysis. And I think there are some 15 differences. Three. Excuse me. There are some 16 differences in nocturnal dialysis as far as the 17 calcium, the phosphorus, and stuff. 18 Maybe it's not in physician labeling, but 19 I think the companies need to be responsible. If 20 they're getting approval for a nocturnal machine, I 21 think that somebody has got to be responsible to know 22 that the people who are using those machines 23 understand the differences. 24 CHAIRPERSON TALAMINI: Thank you.
  • 270. 1 Dr. Moran? 2 DR. MORAN: I have a mixed response. 3 Looking at the list there of the examples, I think 4 physicians do need to know that they do need to know 5 some sort of full legal motion detection if that's not 6 part of the machine. I think they do need to know the 7 need for a partner for remote monitoring. The 8 vascular access requirements I don't think are 9 necessary. 10 And I think the need for dialysate 11 additives, as has been suggested, there are a lot of 12 people who don't know a lot about nocturnal 13 hemodialysis. 14 CHAIRPERSON TALAMINI: Okay. Thank you. 15 Dr. Blagg? 16 DR. BLAGG: I agree. Nothing else to add. 17 DR. GILLESPIE: And I agree with what has 18 previously been said, too. I think you have to base 19 the label on whether it has been proven to be safe. 20 And if that involved adding a third party item to the 21 setup, then you have to let people know that you are 22 doing that. 23 With regard to -- what was the other 24 thing? I'm sorry. That's all I have to say.
  • 271. 1 CHAIRPERSON TALAMINI: So it sounds like 2 the predominant view on the panel is that these 3 details should not be part of the physician labeling. 4 Is that what I'm hearing? Dr. Lockridge, you had a 5 comment? 6 DR. LOCKRIDGE: I was going to comment 7 about the sleeping issue that was brought up. 8 Actually, there are studies now that show that the 9 rotational sleep pattern that occurs in normal people 10 will go away with in-center hemodialysis three times a 11 week. And it actually comes back to normal terms with 12 nocturnal. So the sleep disorders actually improve. 13 So it's an enhancement or help for people to respond 14 appropriately when they deal with it at night. 15 DR. WEINGER: Though if they're like me, 16 if they get paged at 3:00 in the morning, their 17 response is not going to be as sharp as if they're 18 awake in the middle of the day. That was the point I 19 was making. They may be normal, but that's still an 20 issue because it's happening in the middle of the 21 night. 22 CHAIRPERSON TALAMINI: Any further issues 23 regarding labeling that the FDA would like the panel 24 to address? It has to be fairly brief.
  • 272. 1 DR. MITCHELL: This is Dr. Dianne 2 Mitchell. 3 I just want to clarify. I think what I 4 heard was a comment to the effect that it would be, 5 somehow or another, helpful to make a statement about 6 that the physicians need to have an appropriate 7 understanding of what nocturnal home hemodialysis is 8 in comparison to conventional hemodialysis because the 9 concerns are a little bit different between the two. 10 And that is actually something that we can on some 11 level put in the labeling. 12 Now, my interpretation of the conversation 13 was that that would be a reasonable thing to do, but I 14 didn't hear that directly. 15 CHAIRPERSON TALAMINI: Thank you. 16 So let's put that quickly to the panel, 17 whether physician labeling for a device for NHD should 18 contain information on the differences between 19 standard dialysis and NHD. Is that -- no? Help me. 20 I want to make it as clear as I can. 21 DR. MITCHELL: No. We can't say, "You 22 must be a board-certified nephrologist in order to use 23 this machine," but we can say things like "You must 24 have experience or training in nocturnal hemodialysis
  • 273. 1 in order to prescribe this." 2 CHAIRPERSON TALAMINI: Okay. So should 3 physician labeling contain that sort of a statement? 4 Dr. Lockridge, what is your opinion? 5 DR. LOCKRIDGE: No. I think FDA is going 6 too far the other way now. I would not have them say 7 that unless you had some type of training because what 8 is determined is training. Is it going to a CME class 9 about this? 10 I think that the responsibility is to let 11 the physician known in some manner, the manufacturer 12 know where it's different. And the difference is 13 related to the base. The difference is related to the 14 monitoring and those issues. 15 So there is a difference that needs to be 16 spelled out somewhere. I'm not sure it needs to be in 17 the labeling, but it needs to get across to the 18 physician. But to say that you can't have somebody on 19 home dialysis because -- I just don't think we want to 20 get into that. 21 CHAIRPERSON TALAMINI: Is there a panel 22 member who thinks physician labeling should contain 23 such a statement? 24 DR. SCHULMAN: I think that a general
  • 274. 1 statement like when we use cyclosporin or agents like 2 that, that the person prescribing should have some 3 experience with immunosuppressant agents, I mean, that 4 said and not more than that. 5 CHAIRPERSON TALAMINI: Other opinions from 6 the panel regarding whether some sort of a statement 7 -- now, obviously, we're not going to wordcraft the 8 statement, but should labeling address this issue? 9 Dr. Weinger? 10 DR. WEINGER: I mean, I suspect that there 11 is some kind of statement like that on a regular 12 hemodialysis labeling. We're really talking about how 13 is this different from conventional. And I have to 14 agree fully with Dr. Lockridge that outlining what are 15 some of the differences or at least providing 16 references to documents that outline those differences 17 would be reasonable. 18 CHAIRPERSON TALAMINI: Okay. Terrific. 19 That is great work on the panel's part. I 20 would like you to be thinking about the summary 21 statement. After our public comment, I want to get 22 each panel member to make a brief summary statement. 23 OPEN PUBLIC HEARING 24 CHAIRPERSON TALAMINI: But we do need to
  • 275. 1 go to the open public hearing portion. Now that the 2 panel has responded to the FDA questions, we will 3 proceed with the second open public hearing of this 4 meeting. 5 Prior to the meeting, we received one 6 request from Rod Kenley of Aksys, Limited to speak 7 during the afternoon open public hearing. And I need 8 to read the disclosure statement before having that 9 comment. Is Mr. Kenley here? Yes. Okay. Great. 10 So let me read this statement, "Both the 11 Food and Drug Administration and the public believe in 12 a transparent process for information gathering and 13 decision-making. To ensure such transparency at the 14 open public hearing session of the advisory committee 15 meeting, FDA believes that it is important to 16 understand the context of an individual's 17 presentation. 18 "For this reason, FDA encourages you, the 19 open public hearing speaker, at the beginning of your 20 written or oral statement to advise the committee of 21 any financial relationship that you may have with any 22 company or group that may be affected by the topic of 23 this meeting. 24 "For example, this financial information
  • 276. 1 may include a company's or group's payment of your 2 travel, lodging, or other expenses in connection with 3 your attendance at this meeting. 4 "Likewise, FDA encourages you at the 5 beginning of your statement to advise the committee if 6 you do not have any such financial relationships. If 7 you choose not to address this issue of financial 8 relationships at the beginning of your statement, it 9 will not preclude you from speaking." 10 So with that having been said, I will 11 invite Mr. Kenley to make his public comment. 12 MR. KENLEY: Thank you. 13 Yes. My name is Rod Kenley. My 14 credentials are that I have been on the manufacturing 15 side of the business now for about 28 years, about 16 half that time with Baxter and the second half with 17 Aksys Limited, the company that I founded back in 18 1991, with the specific intent to manufacture and 19 design a machine for daily hemodialysis, daily home 20 hemodialysis. 21 I would like to first start off with 22 advising both the panel and the participants from the 23 FDA to think about the broad picture effects on the 24 industry in general and innovation, in particular.
  • 277. 1 When I started Aksys Limited, that was the 2 first occasion in the business of kidney dialysis that 3 there was a start-up company funded by private money. 4 It wasn't a corporation that was preexisting in other 5 areas that got into the dialysis business. 6 When I was out trying to raise the capital 7 to start this company, I met with a lot of potential 8 investors. And I got one question from every single 9 one of them. Will this require a clinical trial? 10 What will be the length of the FDA review process? 11 Because they always translate that back to a return on 12 their investment. 13 My answer was always the same. There has 14 never been a clinical trial required in the history of 15 mankind for a hemodialysis machine. Unfortunately, I 16 was proved wrong. We became the first machine that 17 was required to do a clinical trial. 18 We figured it cost us about $70 million. 19 It kept us off the market for an additional two years, 20 in addition to the cost of the actual clinical trial. 21 If you require clinical trials for each 22 small step forward in a modality change, you've got to 23 think about the effects on what we're all supposed to 24 be here trying to do, treat these patients better,
  • 278. 1 because it's only through these kinds of innovations 2 that these patients get treated better. 3 Dr. Lockridge made a comment that before 4 1996, almost nobody was talking about daily dialysis. 5 And when we did start talking about it in '95 and '96 6 at the annual meetings, there was universal skepticism 7 except for a few early adopters, like the doctors who 8 are present here. 9 Now it's basically universally accepted 10 that that is a better form of therapy. So we've got 11 to ask ourselves, is what we're doing creating a 12 higher risk of keeping patients off a more beneficial 13 therapy than it is in reducing risks that if they go 14 on that therapy, they're going to be injured? 15 Now, to that point in specific, I would 16 like to talk about hemodialysis machines that have 17 been around now for four years. They are some of the 18 safest medical devices that you can possibly imagine. 19 We do 45 million treatments in this 20 country alone every year with an extraordinarily low 21 incidence of patient injuries related to the machine. 22 Every hemodialysis machine that is on this market 23 fails safely. Absolutely it fails safely. There is 24 almost no way a patient can interact with a machine
  • 279. 1 that will cause injury to themselves. 2 I can challenge people to describe how 3 that can happen. We can debate that. But next I 4 would like to take on some of the specific issues that 5 have been talked about here in this afternoon's 6 session. 7 With regard to requiring a clinical trial 8 to prove the safety -- and I think we establish that 9 efficacy is not at issue here. If you use a dialysis 10 machine to treat a patient that has no kidney 11 function, it's efficacious. The question is, is it 12 safe when it's used? So any clinical trial would 13 really be looking at whether a particular device 14 according to its indications for use is safe. 15 Blood access, the first item here is 16 additional safeguards to prevent blood access 17 disconnections, completely unrelated to a hemodialysis 18 machine. 19 There is no way that my machine nor any 20 other ever built or designed can detect a venous 21 needle disconnection. If it could have been done, it 22 would have been done a long time ago because you could 23 sell a lot more machines. The simple fact of the 24 matter is you cannot detect the change in venous
  • 280. 1 pressure if the needle comes out of the access site. 2 You have a window of venous pressure in 3 which the machine is allowed to operate in order to 4 prevent these nuisance alarms. By the way, there's no 5 such thing as a false alarm. If there's an alarm, 6 it's because it hit a preset limit of some kind. 7 There are nuisance alarms. 8 If you set those pressure alarm limits too 9 tightly, you'll get them going off all the time. 10 You've got to operate within this range of pressure. 11 And it's within that same range that you could get any 12 kind of a change in the venous pressure. 13 If you expect the dialysis machine 14 manufacturer to develop a device that identifies that 15 blood is now dripping off the patient's arm, like 16 these enuresis pads, I think you'll be waiting a long 17 time. Consider the product liability issues there. 18 Those things are not 100 percent effective. What if a 19 patient bleeds out and we manufactured that device and 20 it didn't alarm soon enough or at all? 21 Also, it's not really related to the 22 practice of hemodialysis. When you build a 23 hemodialysis device, you build a device that sends 24 blood through an artificial kidney and dialysate
  • 281. 1 through an artificial kidney and assures that it's 2 done safely. The pressures are safe. The 3 temperatures are safe. The conductivity is safe. 4 There is no air going to the patient. There is no 5 blood coming out of the dialyzer. 6 That's all we can do for you. To ask us 7 to assure that the venous needle stays in the patient 8 arm is not part of our deal. I wish it were. If it 9 could be done, I would have done it before. 10 Software incorporated in the device, 11 allowing connection to the internet, nice to have. It 12 might help me sell more devices. It's not a minimum 13 requirement to treat a patient safely on nightly 14 dialysis, same with central monitoring, as we have 15 heard, I think, multiple occasions. 16 User-friendly design. Who will design a 17 study that quantitatively determines that your machine 18 is now safe because its user-friendliness is above a 19 certain hurdle or it's not safe because it's below a 20 certain user-friendly hurdle? As I said before, 21 there's almost no way a patient can interact with one 22 of these machines and hurt themselves, fortunately. 23 The quality of water. To the degree that 24 that is integrated with a machine -- and it's rarely
  • 282. 1 integrated. It happens to be in our machine. I think 2 the issue is valid in terms of how much extra water 3 they see. 4 I agree with most of what was said around 5 here. The current standards are adequate. What you 6 should be more concerned with is the quality of the 7 dialysate. That is, after the water is mixed with the 8 dialysate concentrates and what is the inflammatory 9 stimulating quality of that solution? 10 Yes, Dr. Sadler, there's not conclusive 11 proof, a whole lot of suggestive indications, that the 12 lower the inflammation stimulation on these patients, 13 the longer they'll live without amyloidosis, the 14 longer they'll live without atherosclerosis and 15 malnutrition. 16 As far as a clinical study design, we have 17 to, as was said here, prove that we are substantially 18 equivalent to another device. Let's take my example. 19 I have now made a device that has gone through a 20 clinical study and has been on the market for two 21 years with essentially no patient adverse events that 22 is cleared with an indication for daily home 23 hemodialysis. It's used any number of hours. 24 Most people have told us that our graphic
  • 283. 1 user interface represents the gold standard in terms 2 of communicating with the patient clearly and 3 directly, as you have all suggested you would like to 4 see with a big flat panel display and a touch screen. 5 That is all well and good, but when it 6 comes to now going through a clinical study to prove 7 that my same device is used safely for nocturnal use, 8 what more do I need to prove? Currently my device can 9 be used for one hour, two hours, three hours, four 10 hours, five hours, six, seven, or eight hours. In 11 fact, it is already. 12 What is it about a hemodialysis machine 13 that is less safe in the fifth, sixth, seventh, or 14 eighth hour than it is in the second, third, or fourth 15 hour? The answer is nothing. It cannot get less 16 safe. It already is as safe as it can possibly be. 17 And with regard to the dialysate 18 prescription, that has to be individualized according 19 to the device. Our device happens to use a batch. 20 All 50 liters of dialysate that you're ever going to 21 get are there at the beginning. That means -- 22 CHAIRPERSON TALAMINI: Excuse me. I'm 23 sorry. About one more minute. One more minute. So I 24 just want you to have an opportunity to summarize.
  • 284. 1 MR. KENLEY: Thanks. That means that the 2 phosphate removal will not be as large as if you used 3 a single-pass device. So, in fact, what we found in 4 our nocturnal treatments is that the phosphate removal 5 is almost optimal. So there may not be a need for 6 phosphate. And that is a different device. 7 The dialysate are regulated under their 8 own 510(k)'s as their own devices. And those are 9 stand-alone from the machines for the most part. 10 Psychological effects are clearly not 11 related to the machine. Increased rate of vascular 12 effect infection, not related to the machine. 13 Increased blood loss, not related to the machine. 14 Training, who is going to design the 15 experiment that says what is the cutoff for good 16 training material for us to train the clinicians 17 versus inadequate training material? It's completely 18 subjective. And I have run into many occasions where 19 physicians have told me, "Don't tell me how to train 20 patients. I know." Clearly they do know. What we 21 have got to do is send our clinical nurse educators in 22 there to train their trainers on how our machine is 23 used, not how to do dialysis. 24 So, in summary, I appreciate the
  • 285. 1 opportunity to address the panel. And I hope you 2 would consider the suppressing effects that any form 3 of regulation can have on the expansion of new 4 technology and innovation in any industry but 5 particularly in this one. 6 Thank you very much. 7 CHAIRPERSON TALAMINI: Thank you, Mr. 8 Kenley. Is there anyone else here who would like to 9 address the panel now? Please raise your hand if so. 10 (No response.) 11 CHAIRPERSON TALAMINI: It looks like we 12 have nobody else who wants to make comments. Since 13 there are no other requests to speak in the open 14 public hearing, I'd now like to ask for final comments 15 from the panel and from the FDA. 16 So if each panel member could give a 17 minute or two summary on today's proceedings and the 18 issues that we have discussed, we would be deeply 19 appreciative. Dr. Hoy, perhaps you would be willing 20 to begin. 21 7. FINAL COMMENTS 22 DR. HOY: I'm actually going to be much 23 more specific. Oddly enough, we haven't talked about 24 the machine issues. And my staff and my patients were
  • 286. 1 very clear that I was to bring up four issues that 2 they were concerned about that have to do with these 3 machines. 4 One is the transducer protectors tend to 5 leak. They're designed for four-hour treatments. 6 They tend to leak. You have to put a second 7 transducer protector on to get through the night. So 8 please design them so they fit more tightly and don't 9 leak. 10 Secondly, the machines are a little noisy, 11 especially mixing water. They'd like them less noisy. 12 They'd also like the ROs less noisy. 13 Thirdly, pH and conductivity need to be 14 able to be checked independently by external meters 15 preferably. We're also concerned about redundancy 16 because in the Fresenius 2008H, there is only one 17 conductivity meter. In our code machines in our 18 dialysis center, there are four in-series conductivity 19 machines. So it's much more fail-safe. We'd like 20 more redundancy. 21 And, finally, our patients are tired of 22 mixing bicarbonate in containers. They would like to 23 develop machines that use the bicart, cartridges that 24 are designed to last for eight hours.
  • 287. 1 I have nothing more to say. Thank you. 2 CHAIRPERSON TALAMINI: Again, the 3 privilege of the chair. If I could just ask for the 4 opinion, particularly of those of you with the most 5 experience in this. If you were to look down the road 6 five years, what you might see in terms of numbers of 7 patients with this sort of a therapy. 8 DR. HOY: I think there are two questions 9 there. One is how many patients can do it. I believe 10 that about 20 percent of our patients in our unit 11 could do that. 12 Now, I think the issue of how many are 13 going to be doing it five years from now really 14 depends on how realistic physicians get on how to run 15 a business because physicians think that if you're not 16 being reimbursed at a profitable rate for one unit, 17 then it's not worth doing it. In fact, you have to 18 make a bunch of widgets before you actually start to 19 make profits. And although we're a not-for-profit, 20 our operating margin is real. So I think there are 21 issues there about the way that physicians look at how 22 one does this. 23 This modality is perfect for the insane 24 health care system we work in, which is so
  • 288. 1 labor-intensive and capital-intensive because our 2 staff costs are half or less of what they are in 3 center. And the supply costs are the one area of 4 price elasticity that is available in the future. 5 CHAIRPERSON TALAMINI: Thank you. 6 Dr. Lockridge? 7 DR. LOCKRIDGE: First of all, I would like 8 to thank the FDA to have me here to make comments. 9 Second of all, I do think that more 10 frequent daily nocturnal dialysis is the future. If 11 you had a disease that the incident year that you had 12 that disease, 23 percent of people would die and 13 thereafter every year 17 percent would die and that, 14 in fact, is still increasing and has not improved over 15 the last 15 years and that we were spending 8 percent 16 of the monies that were spent on Medicare for less 17 than .5 percent of the patients, I feel that we as 18 nephrologists, we as the FDA, we as the government 19 have a responsibility to reach out and to seek new 20 ways of doing things. 21 This is here. It's acceptable. It is a 22 better way. We need more, better technology. 23 Training people how to use machines that are in-center 24 machines is not acceptable.
  • 289. 1 I think the FDA needs to be wise in trying 2 to figure out how to approve quality of one machine 3 versus the other and safety, but we need to get on 4 with trying to have new technology come to the market. 5 If we had new technology come to the 6 market, I'm planning on -- about 11 or 12 percent of 7 my population now are doing nocturnal dialysis. My 8 goal is to have 25 percent in 2 to 3 years. If I have 9 new technology, I feel that I can easily reach that. 10 Can you imagine being 35 or 40 years of 11 age, have a high school or less education, working a 12 factory, where you're making reasonably good money and 13 have hope you get end stage renal disease and your 14 disability check is $600 and you are trapped to come 15 to an in-center unit 3 times a week to feel lousy? 16 That is going on across this country on a routine 17 basis, 300,000 people. We have got to make a 18 difference in what our people are seeing and spend 19 their money wisely. It is my money. 20 Thank you. 21 CHAIRPERSON TALAMINI: Thank you, Dr. 22 Lockridge. It's well-said. 23 Dr. Moran? 24 DR. MORAN: I agree with a number of at
  • 290. 1 least 20 percent of people should be going home. 2 Whether they will be going home in five years is 3 another issue. 4 I constantly hear people say that in this 5 country to so many people that couldn't go home. And 6 that's absurd to say that. There are so many people 7 who couldn't have a transplant, but that doesn't mean 8 we shouldn't be doing the maximum number of 9 transplants we could do. The more people we get home, 10 the better for the system and especially for the 11 patients and the taxpayer. 12 CHAIRPERSON TALAMINI: Thank you. 13 Dr. Blagg? 14 DR. BLAGG: Again, thank you for asking me 15 to come. Just a couple of brief comments. One 16 comment that I think has some bearing on everything we 17 have talked about today is a comment that Dr. Scribner 18 made in about 1965, which was basically that with any 19 chronic disease, the more the patient knows about the 20 disease and its treatment and the more responsibility 21 he's able to take for that, the better rehabilitated 22 he will be at every sense of the word. And I think 23 that is what we are trying to do. 24 I would hope that as a result of what we
  • 291. 1 have said and done today, that the FDA in its wisdom, 2 whatever it decides to do bears in mind that we have 3 to change the numbers of patients. 4 Bob may get to 25 percent. I agree. I 5 think 20 percent of more of patients could do it with 6 the right equipment and everything else. The problem 7 is, though, besides providing the right equipment, 8 we've got to make the large dialysis corporations much 9 more enthusiastic towards this system. 10 We've got to educate physicians, most of 11 whom have never seen home dialysis. They just think 12 it's a strange thing that goes on in Lynchburg or in 13 Seattle or somewhere. And we have to educate patients 14 that this is one of the best things for them. And I 15 just hope that whatever the FDA comes up with will not 16 serve as any sort of deterrent to increasing the 17 numbers of patients. 18 Thank you very much. 19 CHAIRPERSON TALAMINI: Thank you, Dr. 20 Blagg. 21 Dr. Gillespie? 22 DR. GILLESPIE: Yes. I think we have 23 covered a lot of ground today. And I think certainly 24 I feel like there is a lot of potential for this as
  • 292. 1 being one modality among several that we really need 2 to move forward beyond the thrice weekly paradigm, 3 which is really more of a 1970s standard of care. 4 And so whether it's nocturnal or short 5 daily or peritoneal, there are a lot of options. And 6 this is one that we need to look at. I think we 7 certainly have the technological ability to do it with 8 the state of our technology today. 9 What we really need now is the will to 10 transform what our patients think, the doctors, the 11 dialysis companies, the manufacturers, everybody. 12 There are a lot of different pieces to that puzzle, 13 but we certainly need to keep pressing on for that, 14 anything we can do to try to encourage more innovation 15 in this, whether it's adapting existing equipment to 16 work more optimally for this or whether coming up with 17 completely new equipment is a goal we need to strive 18 for. 19 CHAIRPERSON TALAMINI: Thank you, Dr. 20 Gillespie. 21 Dr. Weinger? 22 DR. WEINGER: Thank you. This is a very 23 exciting opportunity for society to really improve 24 quality of life and potentially outcomes for patients
  • 293. 1 with a serious disease, but because we're talking 2 about lay persons using a potentially lethal device 3 and process in their homes with limited or more 4 limited support, it really kicks it up a notch. 5 And I feel that the FDA and the 6 manufacturers, if for no other reason than for their 7 own self-protection but regardless, need to look at 8 these devices a little more rigorously than existing 9 in-center devices. 10 That doesn't mean that the FDA should 11 stipulate how these things should be designed but, 12 rather, to ensure that the manufacturer has a rigorous 13 design process, which in this case particularly 14 focuses on the human factors engineering principles 15 and includes, as specified in existing national and 16 international standards, key aspects of the design 17 process, including a user-centered process; that is, 18 patients and nephrologists are actively involved in 19 the design of the devices, that there is iterative 20 design and evaluation, and that there is functional; 21 that is, performance-based testing of the user 22 interface to assure that use errors are minimized. 23 In addition, I think it's critical that 24 both representative users and the use environment be
  • 294. 1 included in the evaluation, the design considerations 2 and evaluation, of these devices. And it includes not 3 just the design of the device but the training and 4 labeling as well. 5 CHAIRPERSON TALAMINI: Thank you. 6 Dr. Gibson? 7 DR. GIBSON: As I have said before, I just 8 wanted to make a plea that there be no arbitrary 9 exclusions based on psychological criteria that 10 centers, of course, have specific exclusions, much 11 like transplant programs do with regard to active 12 substance abuse and unstable mental illness. 13 And even though I agree with the 14 proposition that industry should not be charged with 15 proving this treatment is psychologically safe, I do 16 think that if there is a study, that it should be 17 collected with regard to psychological effects that 18 occur, particularly on the family. 19 Whatever labeling is decided upon, again, 20 I just want to remind people that it should take into 21 account the cultural and ethnic diversity of the 22 country that we live in. 23 It's my unfortunate duty to say that when 24 I read through this, I noticed that we were to talk
  • 295. 1 about single needle devices, and I didn't hear that 2 mentioned. I suspect that could fall under physician 3 practice and using a single needle device with this, 4 but I'll just remind people that that was not 5 mentioned in the discussion, even though it was 6 mentioned in the material. 7 CHAIRPERSON TALAMINI: I would take the 8 privilege of the chair just for a moment. I run the 9 home TPN service at Hopkins. We had a young woman who 10 lost all of her bowels dependent on home TPN and had 11 been quite an outdoors woman. 12 She called my office and asked if she 13 could go camping on Assateague Island, wasn't sure how 14 that was going to happen. But, in fact, she managed 15 to do that. 16 She took her cooler with her TPN and had 17 it in the park ranger's tent. And every night, she 18 would walk to the tent and get her cold bag of TPN and 19 infuse in her tent with her husband so that she could 20 have her camping experience. 21 So I know that dialysis patients can't do 22 that right now, but it certainly was exciting for me 23 to study these materials and to see the possibilities 24 of increased patient freedoms for this group of
  • 296. 1 patients. 2 So those are my only comments. Dr. 3 Aranoff? 4 DR. ARANOFF: I agree with my colleagues 5 that dialysis is good and uremia is bad. And although 6 nocturnal hemodialysis shares many aspects with 7 current in-center and home dialysis therapies, it is 8 fundamentally different in one way, and that is that 9 the treatment is provided by the patient while they 10 are unconscious. 11 So I think it is incumbent on this process 12 through the FDA to assure that the devices that are 13 involved in this unique form of therapy have unique 14 safety precautions to provide these treatments in a 15 safe and effective way. 16 CHAIRPERSON TALAMINI: Thank you. 17 Dr. Afifi? 18 DR. AFIFI: I would like to make a comment 19 about the use of retrospective data to demonstrate 20 substantial equivalence. In principle, there is 21 nothing to prevent us from doing that. And if, 22 indeed, someone comes in with a 510(k) application and 23 can demonstrate that there are existing data that 24 could be used to show the substantial equivalence,
  • 297. 1 then all they have to do is demonstrate that, indeed, 2 they have the power in those data to be able to reject 3 the null hypothesis of equivalence against a specified 4 alternative that the new device is so much worse than 5 the original device. So in principle, I think we 6 should not rule out historical data or retrospective 7 data analysis. 8 CHAIRPERSON TALAMINI: Thank you. 9 Dr. Sadler? 10 DR. SADLER: I did not come here as an 11 advocate for nocturnal dialysis nor for in-center 12 dialysis nor for daily dialysis or peritoneal 13 dialysis. I come as an advocate for patients. 14 I think that all of these therapies are 15 beneficial. We know that if we don't do any of them, 16 the patients die. If we do one of them, the patients 17 live. Depending on what we do and how we do it -- and 18 it varies from one facility and one physician to the 19 next -- the quality of the outcomes is different. 20 It is very important that we focus on the 21 patients and we try to do the best job. I have 22 serious concerns about the nuisance value of dialyzing 23 every day or five days a week. And I think that the 24 optimal dialysis is probably not the same for every
  • 298. 1 patient and that we have not yet defined what really 2 should be considered optimal dialysis. 3 We have certainly defined adequate 4 dialysis in terms of something that avoids many 5 complications and keeps patients reasonably well but 6 not really well. And we have enthusiasts who say that 7 more is better, and presumably there is no ceiling on 8 that. I don't believe that either. 9 So I think we have much to learn. And I 10 think that support of these efforts to use every 11 modality that we can get to is beneficial because it 12 will give us more knowledge and we will learn where 13 the golden mean among these therapies is. 14 Having said that, I'd like to say that I 15 would agree with Rod Kenley that our manufacturers 16 have done a remarkable job. We have very good 17 machines. They may not be quite as elegant as Charlie 18 Willock's first product in terms of the ideas in it 19 and the conservation of materials and energy, but they 20 are remarkably reliable, safe, much quieter, much more 21 accurate, and they perform a good service. 22 I don't think that their performance is in 23 question. And because of that, I don't think that we 24 have a lot to recommend to the FDA. And I believe
  • 299. 1 that if I were a manufacturer of one of these 2 products, I would not come forward and ask for another 3 certification. 4 And I'd be careful how I use my 5 advertising, but I would point out to people what my 6 machine could do because I think all of them can do a 7 lot. And I think that we need to be appreciative of 8 the information coming out of these trials so that we 9 know what is best for patients. 10 I hope that Bob and Chris are correct that 11 20 percent of patients can do this, but I'm skeptical. 12 I think the number may be closer to half that. But I 13 think that more people should do it. 14 I do like home dialysis because of the 15 convenience and flexibility it gives patients, 16 whatever kind of home dialysis they do. I don't 17 believe that home dialysis just because it's at home 18 is better than because it's not at home, but the 19 convenience and flexibility are a great advantage. 20 I think we have made some progress. We 21 have done a lot of conversation. And we have reached 22 a lot of agreement. I think we have managed to 23 demonstrate that whatever differences we had were far 24 smaller than our agreements. And I feel pretty well
  • 300. 1 fulfilled by what we accomplished today. 2 CHAIRPERSON TALAMINI: Terrific. Thank 3 you, Dr. Sadler. 4 Dr. Duffell? 5 DR. DUFFELL: Well, my compliments to the 6 chair. You ran a tight ship today, and we kept 7 moving. 8 CHAIRPERSON TALAMINI: Thank you. 9 DR. DUFFELL: So thank you for that. 10 My closing comments are really more 11 directed at FDA. Thank you for bringing this 12 together. I think what I would like to ask of FDA is 13 just that you all quickly and efficiently pull this 14 information together in industry. The toughest thing 15 is not knowing, rather than knowing, quite honestly. 16 So even if we don't like what comes out of 17 some of this today, I think at least having it in a 18 written format to start dealing with or to prepare 19 cogent arguments for another viewpoint is really what 20 is important. 21 So as quickly as you can summarize this 22 and get out a guidance document, even in the draft 23 form, I think is going to be really helpful to 24 everyone.
  • 301. 1 Thank you for the opportunity to 2 participate. 3 CHAIRPERSON TALAMINI: Ms. Moore? 4 MS. MOORE: I would like to thank you 5 professionals for tolerating and listening to a lay 6 person. This has been a learning experience for me. 7 I believe that the nocturnal home dialysis 8 system is a positive and that if it increases the 9 quality of life for patients, if it increases their 10 state of a well-being, I think then it is worthwhile. 11 And I think that if we could get the technology to the 12 point that there won't be too many questions about it 13 and that the users will be able to handle it, then 14 this will be a gift to society. 15 So, therefore, I feel that with all that 16 we have said here today and with FDA, in a few years 17 perhaps there will a few more lives saved. And that 18 will be good. 19 CHAIRPERSON TALAMINI: Thank you, Ms. 20 Moore. 21 Ms. Brogdon, does FDA have any further 22 comments? 23 MS. BROGDON: Yes. I just wanted to say a 24 couple of things. I wanted to thank all of the panel
  • 302. 1 members for your preparation time and for your 2 experience and the energy that you have expended in 3 this discussion today. 4 This type of preliminary discussion for 5 guidance development is typically very difficult for 6 panels to handle. And sometimes we come away with not 7 much to work with. I have to say in my many years at 8 FDA, this is one of the best preliminary discussions 9 that I have heard. 10 So our plan is to put together a draft in 11 the next few months and send it out to the public and 12 to the panel members. It would come up for further 13 discussion at a panel meeting. 14 Also, I just wanted to allay the fears as 15 expressed earlier. This is not just an intellectual 16 exercise. We are getting these sorts of requests from 17 companies. And we do need a guidance document, and 18 this will help us develop that. 19 I also wanted to say that we never forget 20 that we have an obligation to regulate in a least 21 burdensome manner. And it's least burdensome to all 22 parties. And we will try to keep that in mind as we 23 draft the guidance document. 24 So thank you all for your time.
  • 303. 1 CHAIRPERSON TALAMINI: Thank you, Ms. 2 Brogdon. 3 I would, as the chair, like to also thank 4 the panel. It's really pretty incredible to me the 5 degree of expertise, the set of pioneers that we have 6 here, your ability to speak clearly and succinctly, 7 your obvious preparation before the meeting to be able 8 to come and crystalize these things quickly. So I 9 thank you very, very much. It's what has made this 10 really I think an excellent panel. 11 So having said that, this concludes the 12 report and recommendations of the Gastroenterology and 13 Urology Devices Panel on nocturnal home hemodialysis. 14 And, again, on behalf of the FDA, I would like to 15 thank the entire panel. The meeting is adjourned. 16 (Whereupon, at 4:18 p.m., the foregoing 17 matter was adjourned.) 18 19 20 21 22 23 24
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