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1 U.S. FOOD AND DRUG ADMINISTRATION
2 CENTER FOR DEVICES AND RADIOLOGICAL HEALTH
3 MEDICAL DEVICES ADVISORY COMMITTEE
5 + + + +
7 GASTROENTEROLOGY AND UROLOGY DEVICES PANEL
9 + + + +
12 JUNE 8, 2005
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.
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
38 NANCY C. BROGDON, Director, Division of
39 Reproductive, Abdominal, and Radiological
41 JEFFREY W. COOPER, DVM, Executive Secretary
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
1 FDA PRESENTERS:
3 SUSAN S. ALTAIE, Ph.D.
4 Scientific Policy Advisor, OIVD/CDRH
6 SUSAN GARDNER, Ph.D.
7 Director, OSB/CDRH
9 CAROLYN Y. NEULAND, Ph.D.
10 Branch Chief, GRDB/DRARD/ODE/CDRH
12 JOSHUA C. NIPPER, M.E.
13 Biomedical Engineer, GRDB/DRARD/ODE/CDRH
15 MICHAEL MENDELSON, D.D.S., M.S.
16 Biomedical Engineer, Director Health Promotion
17 Officer, Human Factors Science and Engineering
20 CLAUDIA C. RUIZ-ZACHAREK, M.D.
21 Medical Officer/Nephrologist, GRDB/DRARD/ODE/CDRH
24 PUBLIC SPEAKERS:
26 ROD KENLEY
27 Aksys, Ltd.
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 AGENDA ITEM: PAGE
5 CALL TO ORDER: 4
7 Introductions 4
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
14 Post Market Study Design 19
15 Susan Gardner, Ph.D., Office of Surveillance
16 and Biometrics
18 OPEN PUBLIC HEARING: 32
20 OPEN COMMITTEE DISCUSSION: 33
22 1. Regulatory Briefing - 34
23 Carolyn Neuland, Ph.D., Branch Chief of
24 the Gastro-Renal Devices Branch
26 2. Overview of Conventional Hemodialysis 47
27 Systems - Josh Nipper, M.E.
29 3. Human Factors - Mike Mendelson, D.D.S., 61
30 M.S., Biomed Eng
32 4. FDA Presentation - Claudia Ruiz. M-D., 80
35 5. Questions for the Panel 103
37 OPEN PUBLIC HEARING: 309
39 7. Final Comments 322
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 (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.
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,
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
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,
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
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
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.
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
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,
1 therefore, that they may participate fully in today's
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
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
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
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
8 Dr. Talamini will now continue.
9 CHAIRPERSON TALAMINI: Thank you, Dr.
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
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
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
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
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
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
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
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
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.
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
7 Any questions?
8 (No response.)
9 DR. ALTAIE: All right. Thank you.
10 CHAIRPERSON TALAMINI: Thank you, Dr.
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.
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
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
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
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
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.
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
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
23 During the post-market period, we're
24 committed to having either FDA or industry come back
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.
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.
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?
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
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
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
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
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
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.)
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
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
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.
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
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
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;
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
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
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
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
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
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
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
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
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
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
1 still reviewed under the 510(k) process. We are
2 looking into the reclassification of these products
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.
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
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
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
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
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
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,
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
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
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.
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
1 arterial side at all. However, all systems are
2 responsible for monitoring the pressures during the
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
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
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
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
12 From these pressures, the systems
13 calculate the transmembrane pressure, which is
14 essentially the difference in the blood and dialysate
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.
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
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
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
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
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
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
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
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
22 Catheters contain alternating luer lock
23 connectors that meet ISO standards for connection to
24 the blood tubing. This is important because catheters
1 are less prone to any type of disconnection and
2 completely remove the possibility of needle
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.
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
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.
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
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"
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.
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.
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
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
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
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
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
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
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.
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
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
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.
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
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
1 for common needs. It's more advisable to rely on
2 on-screen help or laminated cards attached to the
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.
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
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
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
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
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
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
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
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
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
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
23 One of the main features of conventional
24 dialysis that I would like to point out is the
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
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
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
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
1 which 843 have home dialysis, are home dialysis
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
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
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
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
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
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
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
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,
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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.
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
1 center. And the second is the issue of frequency and
2 whether it's better for patients to have more frequent
4 But with that question, do any of the FDA
5 speakers have a response to the issue of the
7 DR. MITCHELL: Hi. My name is Dr. Dianne
8 Mitchell. And I'm the chief medical officer for this
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
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.
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
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
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
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
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
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.
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
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
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
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.
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
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
24 DR. RUIZ-ZACHAREK: Yes. As you said, the
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
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
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
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 --
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
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, --
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
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
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
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
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
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.
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
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)
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
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
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.
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
1 rational force for problem-solving. It's just a
2 matter of admiring our capacity and responding to
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
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
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
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
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
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
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
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
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
18 CHAIRPERSON TALAMINI: A little closer,
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
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
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
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
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.
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
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.
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
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
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
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
1 perhaps less well-trained, but the issue is how
2 trained should they be, going to be using the complex
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.
22 Dr. Blagg?
23 DR. BLAGG: I would just like to remind
24 you as we talk about these machines, that the first
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
17 CHAIRPERSON TALAMINI: Thank you, Dr.
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
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
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
18 CHAIRPERSON TALAMINI: Thank you, Dr.
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
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
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
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
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
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
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.
1 So, Dr. Hoy, if you could pick a spot in
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.
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
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
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
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.
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.
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
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
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
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
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
14 CHAIRPERSON TALAMINI: Present in the
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
24 (Whereupon, there was a show of hands.)
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
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'
12 CHAIRPERSON TALAMINI: Terrific. Thank
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
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
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.
22 Dr. Kalota?
23 DR. KALOTA: Nothing more to add.
24 CHAIRPERSON TALAMINI: Thanks.
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
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
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
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.
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
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.
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.
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
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.
1 CHAIRPERSON TALAMINI: Thank you, Dr.
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.
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
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
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
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.
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
1 interest, but this is secondary to the more important
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
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,
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
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
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
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.
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
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
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
24 CHAIRPERSON TALAMINI: Yes. Thank you.
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
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
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
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
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
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
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.
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
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
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
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
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
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
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.
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
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
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
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
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
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
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
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
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
22 CHAIRPERSON TALAMINI: Right.
23 DR. SADLER: When we go from conventional
24 dialysis to frequent nocturnal dialysis, we double it
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.
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
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?
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
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.
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
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
24 Yes, Dr. Duffell?
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
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.)
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
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
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
1 erythropoietin usage actually goes down with nocturnal
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
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
23 The second patient that we trained in
24 Seattle should have been divorced. Unfortunately, the
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.
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
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
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
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
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
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
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
1 the time that are incrementally increased on dialysis.
2 All of these things could happen in conventional
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
1 access devices would be useable for this form of
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
1 increased risk for NHD, as opposed to normal dialysis?
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
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
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
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.
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
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.
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.
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
23 (Whereupon, there was a show of a hand.)
24 CHAIRPERSON TALAMINI: Ms. Moore? So we
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,
23 DR. HOY: I think that the dilemma here is
24 that we really don't know what we're doing. We know
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
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
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.
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
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
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
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
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
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.
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
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
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
1 you could expand on why you couldn't do a randomized
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
1 wouldn't be a reasonable design.
2 CHAIRPERSON TALAMINI: Dr. Hoy has a
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
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
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.
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
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
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
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
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
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
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
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
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
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
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
23 DR. ARANOFF: I think you also have to
24 consider, will the specific machine provide the
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.
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
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
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
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.
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
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
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.
1 CHAIRPERSON TALAMINI: Okay. Please do.
2 MS. BROGDON: It was just answered. Thank
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
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
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.
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
16 CHAIRPERSON TALAMINI: Okay. Dr. Duffell?
17 DR. DUFFELL: I agree with Dr. Sadler's
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
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
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
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
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.
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
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.
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
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
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
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?
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
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.
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?
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
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
24 CHAIRPERSON TALAMINI: Thank you.
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
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.
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
18 CHAIRPERSON TALAMINI: Good point.
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.
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.
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
23 CHAIRPERSON TALAMINI: Dr. Gibson?
24 DR. GIBSON: I would like to start by
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
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.
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,
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
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
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
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
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
1 is fundamentally different than routine home
2 hemodialysis with regards to the training
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
24 I do believe that this represents a
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
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
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
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
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
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
5 CHAIRPERSON TALAMINI: So noted.
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
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,
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
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
23 MS. BROGDON: I think we have enough
24 information. Thank you.
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,
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?
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.
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
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
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
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
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
23 CHAIRPERSON TALAMINI: Thank you.
24 Dr. Schulman?
1 DR. SCHULMAN: I have nothing further to
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.
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
1 and what is embedded in the machine altogether as one
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
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
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.
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.
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
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
1 moment we're going to discuss physician labeling? Dr.
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
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
1 from the FDA for the panel with regard to patient
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
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
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
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
22 Dr. Schulman?
23 DR. SCHULMAN: I think some of the issues
24 that are listed here, for instance, of phosphorus down
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
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.
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
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
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.
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
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
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.
1 DR. MITCHELL: This is Dr. Dianne
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
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
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
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
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
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
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
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.
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,
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
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
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
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
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
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
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
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
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.
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
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
1 very clear that I was to bring up four issues that
2 they were concerned about that have to do with these
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
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.
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
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.
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
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
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.
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
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
19 CHAIRPERSON TALAMINI: Thank you, Dr.
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
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
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
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
2 So those are my only comments. Dr.
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,
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
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
1 that if I were a manufacturer of one of these
2 products, I would not come forward and ask for another
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
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
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
1 Thank you for the opportunity to
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.
21 Ms. Brogdon, does FDA have any further
23 MS. BROGDON: Yes. I just wanted to say a
24 couple of things. I wanted to thank all of the panel
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.
1 CHAIRPERSON TALAMINI: Thank you, Ms.
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.)