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  1. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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

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