ATDEPARTMENT OF HEALTH AND HUMAN SERVICES

> FOOD AND DRUG ADMINISTRATION
>
> CENTER FOR DRUG EVALUATION AND RESEARCH
>
> **PEDIATRIC ADVISORY SUBCOMMITTEE**
>
> **OF THE ANTI-INFECTIVE DRUGS ADVISORY COMMITTEE**
>
> **OPEN SESSION**
>
> Wednesday, June 11, 2003
>
> 8:35 a.m.
>
> Holiday Inn Gaithersburg
>
> The Ballrooms
>
> 2 Montgomery Village Avenue
>
> Gaithersburg, Maryland
>
> PARTICIPANTS
>
> Joan P. Chesney, M.D., Chair
>
> Thomas H. Perez, R.Ph., M.P.H. Executive Secretary
>
> MEMBERS
>
> Steve Ebert, Pharm.D (Consumer Representative)
>
> Mary Glodé, M.D.
>
> SGE CONSULTANTS
>
> Michael Aschner, M.D.
>
> David Danford, M.D.
>
> Norman C. Fost, M.D., M.P.H.
>
> John Freeman, M.D.
>
> Susan Fuchs, M.D.
>
> Richard Gorman, M.D., FAAP
>
> Mark Hudak, M.D.
>
> Stanley Ip, M.D.
>
> Joseph Lau, M.D.
>
> Naomi Luban, M.D.
>
> Robert Nelson, M.D., Ph.D.
>
> Judith O\'Fallon, Ph.D.
>
> William Oh, M.D.
>
> Don Mattison, M.D.
>
> Thomas Newman, M.D., M.P.H.
>
> Rebecca Flynn O\'Brien, M.D.
>
> Kevin Smith, Ph.D.
>
> David Stevenson, M.D.
>
> Benjamin Wilfond, M.D.
>
> GUEST SPEAKERS
>
> Susan Sheridan
>
> Connie Schomann, R.N.
>
> Marshallyn Yeargin-Allsop, M.D.
>
> FDA
>
> Robert Justice, M.D.
>
> Susan Cummins, M.D.
>
> Dianne Murphy, M.D.
>
> [C O N T E N T S]{.underline}
>
> Call to Order/Introductions
>
> Joan P. Chesney, M.D. 4
>
> Meeting Statement
>
> Thomas H. Perez, R.Ph., M.P.H. 9
>
> Opening Comments
>
> Dianne Murphy, M.D. 11
>
> Historical Background and Selected Recent
>
> Research Findings
>
> Tom Newman, M.D., M. 16
>
> Agency for Healthcare Research and Quality Report
>
> Joseph Lau, M.D. 54
>
> Stanley Ip, M.D. 67
>
> Rebecca O\'Brien, M.D. 77
>
> Discussion of Presentations 95
>
> Phototherapy
>
> William Oh, M.D. 122
>
> Outpatient Phototherapy
>
> Connie Schomann 153
>
> A Parent\'s Perspective
>
> Sue Sheridan 171
>
> Kernicterus Surveillance
>
> Marshallyn Yeargin-Allsop, M.D. 195
>
> Metalloporphyrin Heme Oxygenase Inhibitors
>
> David Stevenson, M.D. 195
>
> Open Public Hearing
>
> Attallah Kappas, M.D. 243
>
> Vinod K. Bhutani, M.D. 253
>
> Martin J. Hatlie, JD 258
>
> Duane Alexander, M.D. 273
>
> Andrew Moosa, M.D. 277
>
> Jerold F. Lucey, M.D. 282
>
> Timos Valaes, M.D. 287
>
> Murray Goldstein, D.O. 294
>
> Ethical Issues
>
> Robert Nelson, M.D., Ph.D. 298
>
> Discussion of Questions 2, 3 and 4 316
>
> Committee Final Comments 378
>
> [P]{.underline} [R]{.underline} [O]{.underline} [C]{.underline}
> [E]{.underline} [E]{.underline} [D]{.underline} [I]{.underline}
> [N]{.underline} [G]{.underline} [S]{.underline}
>
> **Call to Order/Introductions**
>
> DR. CHESNEY: Good morning. We are ready to begin what is going to be a
> very full day. I would like to welcome you all to this Pediatric
> Advisory Subcommittee Meeting.
>
> I would like to start with the usual roll call, if we could maybe
> start down at this end with Dr. Murphy.
>
> DR. MURPHY: Dr. Dianne Murphy. I am the Office Director for the Office
> of Counterterrorism and Pediatric Drug Development and also the Office
> Director for the Office of Pediatric Therapeutics. Thank you.
>
> DR. CUMMINS: I am Dr. Susan Cummins. I am a team leader in the
> Division of Pediatric Drug Development with the FDA.
>
> DR. JUSTICE: Robert Justice, Director of the Division of
> Gastrointestinal and Coagulation Drug Products at FDA.
>
> DR. NELSON: Robert Nelson, pediatric critical care medicine at
> Children\'s Hospital, Philadelphia, and a member of the committee.
>
> DR. GLODE: Mimi Glodé. I am head of the section of Pediatric
> Infectious Disease at the Department of Pediatrics, the University of
> Colorado, School of Medicine, Denver, Colorado, member of the
> committee.
>
> DR. DANFORD: David Danford. I am Professor of Pediatrics in the
> section of Cardiology, University of Nebraska Medical Center,
> Creighton University. I am a member of the committee.
>
> DR. FUCHS: Susan Fuchs, Associate Professor of Pediatrics,
> Northwestern University Medical School, and pediatric emergency
> physician, Children\'s Memorial Hospital, Chicago.
>
> DR. O\'FALLON: Judith O\'Fallon, statistician at the Mayo Clinic
> Cancer Center, Rochester, Minnesota.
>
> DR. HUDAK: Mark Hudak, Professor of Pediatrics and a neonatologist at
> University of Florida, Jacksonville.
>
> DR. FOST: Norman Fost, University of Wisconsin, Professor of
> Pediatrics, Director of the Bioethics program and Chair of the IRB.
>
> DR. CHESNEY: Joan Chesney. I am Professor of Pediatrics in the
> Division of Infectious Diseases at the University of Tennessee Health
> Science Center.
>
> MR. PEREZ: Tom Perez, Executive Secretary to this meeting.
>
> DR. EBERT: Steve Ebert, Professor of Pharmacy at University of
> Wisconsin, Madison, an Infectious Diseases at Meriter Hospital in
> Madison.
>
> DR. GORMAN: Rich Gorman, pediatrician in private practice in Ellicott
> City, Maryland, and a member of the committee.
>
> DR. MATTISON: Don Mattison, staff at NICHD.
>
> DR. IP: Stanley Ip, Assistant Professor of Pediatrics at Tufts
> University Medical School.
>
> DR. FREEMAN: John Freeman, Professor of Pediatrics and Neurology at
> Johns Hopkins.
>
> DR. ASCHNER: Michael Aschner, Professor of Physiology and Pharmacology
> at Wake Forest University School of Medicine.
>
> DR. O\'BRIEN: Rebecca O\'Brien, Assistant Professor at Tufts
> University School of Medicine in the Division of General Pediatrics at
> the Floating Hospital in New England Medical Center.
>
> DR. WILFOND: I am Ben Wilfond, a pediatric pulmonologist at the
> National Human Genome Research Institute and also with the Department
> of Clinical Bioethics at the NIH.
>
> DR. SMITH: Kevin Smith, Vice Chancellor of Research and Dean at the
> Graduate School and Professor of Chemistry at Louisiana State
> University.
>
> DR. OH: I am Bill Oh. I am a neonatologist who is Professor and Chair
> of Pediatrics at Brown Medical School.
>
> DR. NEWMAN: I am Thomas Newman, Professor of Epidemiology and
> Biostatistics and Pediatrics at UCSF and a general pediatrician.
>
> DR. LAU: I am Joseph Lau, Professor of Medicine at New England Medical
> Center, and the Director of Agency for Healthcare Research and Quality
> Evidence-Based Practice Center.
>
> DR. STEVENSON: David Stevenson. I am a neonatologist and Professor of
> Pediatrics at Stanford University, also serving as Senior Associate
> Dean for Academic Affairs at that institution.
>
> DR. CHESNEY: Thank you.
>
> Today\'s session is devoted to the current epidemiology and
> therapeutic interventions relevant to hyperbilirubinemia in the term
> and near-term newborn or, in other language, the current state of
> medical practice with regard to management of neonatal
> hyperbilirubinemia and the potential role for new drug therapies in
> the prevention and management of jaundice in this population.
>
> We have a very, very full and interesting agenda, and we are
> particularly honored to have speakers today, both scheduled and in the
> open public hearing, who have contributed so much to and for some
> their life\'s work to this issue.
>
> I also have to remind myself that Agency doesn\'t bring issues with
> straightforward answers to the Advisory Committees. The complexity of
> today\'s topic is an example of the kind of issue that they do bring
> to advisory committees.
>
> Before asking Dr. Murphy to begin the meeting, I wanted to make two
> comments. The first is because it is a very full agenda, I would
> request that all the speakers adhere as closely as possible to their
> allotted times.
>
> If anyone goes 10 minutes over their allotted time, Tom and I may have
> to intervene, which is very uncomfortable for us, so if we do
> intervene, please know that we are sympathetic to your wanting to
> share everything you have with us.
>
> The second issue is that many, if not all of you, in the room know
> that there is a closed meeting tomorrow on a subject related to
> today\'s discussions.
>
> In order to protect the privacy of tomorrow\'s meetings, we ask the
> speakers and particularly the committee members and the invited
> consultants who have had material which they have read in great detail
> for tomorrow\'s meeting not to comment today on the content of
> tomorrow\'s meeting.
>
> Finally, I wanted to thank all the members of the Pediatric Division
> and the Division of Gastrointestinal and Coagulation Drug Products for
> all the work they have put into today\'s meeting and to thank Tom
> Perez, our Executive Secretary.
>
> Our first speaker is\--my apologies\--we have to do conflict of
> interest statements.
>
> Tom.
>
> **Meeting Statement**
>
> MR. PEREZ: Thank you and good morning.
>
> The following announcement addresses the issue of conflict of interest
> with regard to this meeting and is made a part of the record to
> preclude even the appearance of such at this meeting.
>
> The topics to be discussed at this meeting are issues of broad
> applicability. Unlike issues in which a particular firm\'s product is
> discussed, issues of broad applicability may involve many industrial
> companies and academic institutions.
>
> All special government employees participating in this meeting have
> been screened for financial interests as they may apply to the general
> topics at hand. Because Dr. David Stevenson has reported interests
> that could be affected by today\'s discussions, the Food and Drug
> Administration has granted him a waiver under 18 U.S.C. 208(b)(3) that
> permits him to participate. A copy of the waiver statement may be
> obtained by submitting a written request to the Agency\'s Freedom of
> Information Office, Room 12A30, of the Parklawn Building.
>
> Because general topics could involve so many firms and institutions,
> it is not prudent to recite all potential conflicts of interest, but
> because of the general nature of today\'s discussion, these potential
> conflicts are mitigated.
>
> With respect to FDA\'s invited guest speakers, Susan Sheridan would
> like to disclose that she is president of a consumer advocacy and
> educational group called PICK, Parents of Infants and Children with
> Kernicterus. PICK receives charitable contributions from industry,
> however, all members of PICK are volunteers and receive no
> compensation for their activities.
>
> With respect to all other participants, we ask, in the interest of
> fairness, that they disclose any current or previous financial
> involvement with any firm whose product they may wish to comment upon.
>
> Thank you.
>
> DR. CHESNEY: Thank you, Tom.
>
> Dr. Dianne Murphy is going to speak to us to give us a very brief
> overview of the topic for discussion today. As you all know, Dr.
> Murphy is Director of the combined Office of Counterterrorism and
> Pediatric Drug Development, and the Director of the Office of
> Pediatric Therapeutics at the FDA.
>
> **Opening Comments**
>
> DR. MURPHY: I wanted to take a moment and first thank the committee,
> the Pediatric Advisory Subcommittee, who now has built quite a
> formidable experience in pediatric drug development for being so loyal
> and consistent, and being here when we have these meetings. I know
> that we have them fairly regularly scheduled for you all, and it is a
> demand on your time. We want to always express to you how sincerely we
> appreciate your ongoing effort because I think in the arena of
> pediatric drug development, we need to have a very consistent core of
> people who can address the myriad of issues that are going to come
> forward as we continue to develop products for children.
>
> I wish to also thank\--when I looked at the list of invitees and
> speakers, I am always impressed at the commitment of people to put
> time and effort in what I know are extraordinarily busy lives to come
> and advise us. Again, our sincere thanks to everybody who has taken
> that time to do that today.
>
> Also, the people who worked so energetically to put this together -
> Dr. Susan Cummins, Dr. Shirley Murphy, Dr. Debbie Birenbaum, Rosemary
> Addy. They have put together I think a wonderful package that
> articulates for you what the issues are. They made one mistake. They
> asked me to try to provide the overview for you, so that is what my
> job is this morning.
>
> I am supposed to focus you on the fact of what the Agency does and put
> that in perspective as to how to think about the questions we have
> asked you.
>
> \[Slide.\]
>
> This table could be quite extensive with many variations upon the
> theme, but, in general, what the Agency does when it decides to
> approve a product, it must find that it is safe and efficacious for an
> intended population, for an intended use, but that comes in many ways.
>
> The very top line here is a therapy that might be even OTC, a therapy
> which has very low risk, a few side effects, and has tremendous
> benefit for somebody with allergies, let\'s say, so you have an OTC
> product.
>
> That product is going to have a different safety profile than another
> product which would have a high or intermediate risk, but also would
> bring great benefit to the patient.
>
> In this, the number of patients who might be exposed could be anywhere
> depending on the number of options that are available to the patient,
> any other options, and actually the degree of these risks as to how
> many might be involved.
>
> I think today, we really are going to be talking about drug
> development where the risks are in this arena, where the benefits are,
> and can we define a population that would fit in this category or not,
> or are we not in this category.
>
> We are asking you to think about what is the population that would
> warrant therapy, how do we identify it, and what are the things that
> we should be asking for if we are going to develop a product as to its
> safety profile and its benefit.
>
> To do that, we have to first go through many of the areas that are
> being brought up for discussion today, which is what is the status of
> the therapeutic interventions that we have available and what is our
> status of knowledge in this area.
>
> I have put on these other things just because, yes, there are products
> that have lots of known high risk, not a lot of benefit, but if there
> are absolutely no other options, they are actually products that may
> get approved in this area, too.
>
> So, there is a complete spectrum and what we are simply asking you
> today is not simple, it is very difficult to consider drug development
> for therapy of hyperbilirubinemia, what are the kinds of risks, and
> for what kind of population.
>
> \[Slide.\]
>
> Right now, these few slides summarize where we think, I will try to
> define that table in graphic form. We have a very high risk
> intervention for very few patients that are involved usually, and were
> willing to take it because there aren\'t any other options when we
> reach this point.
>
> \[Slide.\]
>
> We have another intervention earlier on, more patients involved, less
> risk, and where are we, is this where we want to go with drug, or is
> it really here, where is it, what is the population, and what is the
> safety profile for that population.
>
> Those are the sort of things we want you to be thinking about as you
> go through the broader issue of where are we today in this field in
> our knowledge of hyperbilirubinemia and how it occurs, what the
> prevalence is, what the incidence is, and what the interventions are
> and should be.
>
> \[Slide.\]
>
> That is again summarizing in a very simplified way, we need to be able
> to put these therapies where you decide the population would be would
> really define what the risks might be, because you are going to be
> really defining whether you are going to expose a lot of patients or a
> few patients.
>
> I hope that hasn\'t muddied the water, but again, summary from a drug
> development point of view, you are going to develop a drug, you want
> to know what is the population that is going to receive this intended
> therapy and how do we define the efficacy and the benefits and the
> risks of that product.
>
> Thank you very much.
>
> DR. CHESNEY: Thank you, Dr. Murphy.
>
> Our next speaker is going to be Dr. Tom Newman, who will give us a
> historical background and selected recent research findings relative
> to this issue.
>
> He is a professor in the Departments of Epidemiology and
> Biostatistics, Pediatrics, and Laboratory Medicine at UCSF. We thank
> him for coming to speak with us today.
>
> **Historical Background and Selected Recent**
>
> **Research Findings**
>
> DR. NEWMAN: Thank you.
>
> I think the slides for my presentation are on the lefthand side of
> your little packet there. This is what I was asked to talk about. I
> guess maybe I am getting old if I am talking about history. It is
> usually people who have been around a while.
>
> You will see that a lot of this presentation is kind of focused on my
> perspective. You will see sort of an overemphasis on research that I
> have done and on the history that I have experienced myself. I am sure
> that as others speak, we will be able to even that out a bit.
>
> \[Slide.\]
>
> But I will be talking about the history leading up to the 1994 AAP
> guideline which I participated in writing, the content of the
> guideline, what has happened since then, and some research findings
> focusing on research we have done at Kaiser Permanente, and close with
> some unanswered questions if I have time.
>
> \[Slide.\]
>
> Starting in the 1950s, and, of course, I was not around much in the
> \'50s, so this is based on reading the literature and talking to
> people.
>
> Before the \'50s, there was a lot of Rh disease and kernicterus that
> was mostly from Rh disease, and in the 1950s was the first randomized
> trial that showed that exchange transfusion could prevent kernicterus
> in children with Rh disease, but it is interesting that in that trial,
> the benefit was restricted to babies who had a cord hemoglobin of less
> than 11, and bilirubin was not even measured in that trial, so the
> index of severity for the Rh disease was how anemic the baby was at
> birth.
>
> But, in fact, by doing exchange transfusions and treating these very
> anemic and sick babies, it was found that kernicterus could be
> prevented because, of course, when the red cells were made compatible
> with the mothers, the hemolysis was reduced.
>
> The data relating kernicterus to bilirubin were observational data
> sort of added parenthetically at the end of an article in the New
> England Journal by Shaw, et al., where they said that since they had
> started keeping the bilirubin level below 20, they had not seen any
> cases of kernicterus, and that 20 mg/dl sort of stuck for many years
> as the level to try and keep the bilirubin below.
>
> The other thing that happened in the \'50s was a randomized trial, the
> only other randomized trial I know of where kernicterus ended up being
> an endpoint, but this was a randomized trial of prophylactic
> sulfisoxazole in premature babies, and the sulfisoxazole displace
> bilirubin from albumen and caused kernicterus in the intervention
> group, in the group that got it, and that contributed to our
> understanding of kernicterus and how it is causally related to
> bilirubin, but especially unbound bilirubin.
>
> \[Slide.\]
>
> Moving quickly now into the \'60s, that was when Rhogam was developed
> and used, which really has just about wiped out Rh disease. There was
> a lot less kernicterus. Looking in the literature, then, there were
> debates, you know, when the only intervention for hyperbilirubinemia
> was exchange transfusion and Rh disease was going away, there were all
> these other groups who had high bilirubin levels and it was unclear
> how they should be treated - should you do exchange transfusions in
> babies with ABO disease and nonhemolytic jaundice and in preemies, and
> that was debated. Phototherapy was first used in the 1960s.
>
> \[Slide.\]
>
> Moving into the 1970s, the Collaborative Perinatal Project, which
> enrolled babies between 1959 and 1966, a big cohort study looking at
> neurodevelopmental outcome in babies that were followed from actually
> before birth, their mothers were followed.
>
> There was some kind of worrisome data from the Collaborative Perinatal
> Project that suggested that kernicterus might be the tip of the
> iceberg, that is, there was some statistical difference in
> neurodevelopmental outcome in Bailey scores at less than a year in
> babies who had higher bilirubin levels.
>
> This was mostly seen in low birth weight babies, but it raised this
> concern that there is kernicterus, which is one extreme, but there
> might be subtle neurodevelopmental problems, and the same sort of
> concern about lower level bilirubin toxicity was raised by the finding
> of yellow staining of the brain at autopsy in premature babies, which
> was also called kernicterus, so it was a little bit unclear how much
> of that yellow staining was actually primarily due to kernicterus or
> later event.
>
> But certainly in the 1970s is when phototherapy really took off partly
> fueled by these concerns and the fact that the only other treatment
> was exchange transfusion, we could measure bilirubin, we could treat
> it with phototherapy, reduce the levels, so phototherapy became very
> popular.
>
> In the 1960s, most babies in the U.S. were bottle fed. In the 1970s,
> we really saw an increase in breast feeding.
>
> \[Slide.\]
>
> That brings us up to the 1980s where my own personal experience
> starts. I was a resident in pediatrics from 1980 to 1983 at UCSF, and
> I was taught that bilirubin is a neurotoxin, it\'s a brain poison was
> what I was told, and that we did phototherapy when the bilirubin level
> hit above 14 to 15 mg/dl, and exchange transfusions, if it got above
> 20. This was not a good time to be doing exchange transfusions.
>
> This was San Francisco 1980 to 1983. There was a lot of HIV in the
> blood supply. So, part of my formative experience was doing exchange
> transfusions and then later finding out that probably they weren\'t
> necessary and wondering if I had given any babies AIDS and knowing
> that there were going to be babies who got AIDS from exchange
> transfusions.
>
> Also, when I was a resident, this article called \"Vigintiphobia,\"
> fear of 20, came out sort of a light-hearted questioning of why we
> were so worried about 20 and suggesting that maybe in babies who did
> not have Rh disease, that was too low a level of bilirubin to worry
> about.
>
> Then, just sort of incidentally, but a very striking result was that
> in a study, an autopsy series, there was just this abrupt
> disappearance of kernicterus when the benzyl alcohol preservative was
> removed from the bacteriostatic saline in neonatal intensive care
> unit. Again, that might have been displacing the bilirubin from
> albumin.
>
> \[Slide.\]
>
> Moving into the 90s, this is when I started doing research on jaundice
> in babies. Jeffrey Maisels and I published a couple of articles that
> were sort of a more systematic examination of the literature than what
> Watchko and Oski had done, but I definitely give them credit for, at
> least for me, making me think this was something worth reviewing.
>
> Articles suggesting that it really, that the epidemiologic term here
> is effective modification or interaction, it really was not reasonable
> to generalize from Rh disease babies in the \'50s to well, breast-fed
> babies in the \'90s in terms of estimating what is the risk of
> neurologic damage from a high bilirubin level, and this evidence that
> if 20 was the level that we need to worry about in Rh babies in the
> \'50s, then it surely wasn\'t 20 for well babies in the \'90s.
>
> This led to the 1992 paper which had recommendations for less
> aggressive treatment of jaundice in babies, also fewer laboratory
> tests because the laboratory tests that were then recommended were
> mostly not useful.
>
> With Mark Klebanoff, I re-analyzed data from the Collaborative
> Perinatal Project, those data were available to Mark, looking
> specifically at this issue of was there really good evidence that at
> lower levels of bilirubin, there was neurologic damage, and got I
> think very reassuring results for intelligence for the IQ measures and
> for hearing, and reassuring for definite neurologic abnormalities, but
> the sort of small but statistically significant increase as bilirubin
> levels went up in abnormal or suspicious findings.
>
> The trouble is that bilirubin levels in that study were fairly low and
> that the biggest burden of sort of extra abnormal or suspicious
> findings came in babies who had bilirubin levels between 10 and 15.
>
> In that paper, we calculated that if everybody in the whole
> Collaborative Perinatal Project\'s bilirubin level had been kept below
> 10, the population frequency of these abnormal or suspicious
> neurologic abnormalities would have gone from 15.1 percent to 14.85
> percent, so we didn\'t think it was a very important effect.
>
> Then, the AAP practice parameter, which was one of the first practice
> guidelines that the AAP did, was in 1994. Around the same time,
> beginning in the \'80s and into the 1990s, hospital stays for newborns
> got shorter and jaundice really moved from the inpatient problem that
> it was when I was a resident to an outpatient problem and the problems
> of babies with jaundice needing to come back and get a bilirubin test,
> and then come back again and get another bilirubin test, and when they
> needed phototherapy, to be readmitted, and that really was a change
> from the 1980s.
>
> \[Slide.\]
>
> The AAP Guidelines addressed more than treatment, but I think probably
> the most important difference with the guidelines was raising the
> thresholds for treatment somewhat, varying them by age, and then the
> next version of the Guidelines, that will even be a little bit
> smoother rather than changing abruptly at 24, 48, 72 hours.
>
> You can see that most of the jaundice, most of the babies getting
> phototherapy are, because bilirubin peaks after about three days, more
> than 72 hours old. Of course, if it is rising fast, you need
> phototherapy sooner, but this sort of said it is reasonable to do
> phototherapy at 17, but you can individualize and not all babies are
> the same, but you really probably should do it if it gets above 20.
>
> If phototherapy fails, you should do an exchange, and if you are
> starting out above 30, you really probably should just do an exchange
> although some of these babies, the bilirubin drops fast and then they
> end up not getting one.
>
> \[Slide.\]
>
> So, what has happened since then? Well, I will show you some data on
> some of these things. One is that there are a lot fewer exchange
> transfusions being done unless phototherapy, there is a concern about
> kernicterus coming back, about an increase in kernicterus.
>
> In 1996, the Newborns\' and Mothers\' Health Protection Act was
> passed, which mandated coverage for at least a 48-hour length of stay.
> That became effective on January 1st of 1998.
>
> PICK, which has already been mentioned, Parents of Infants and
> Children with Kernicterus, was formed, and I think had a major
> influence on bringing attention to kernicterus as a problem.
>
> I guess there has been more of a focus, not so much on when we should
> be treating jaundice and whether we should be doing phototherapy at 15
> or 20 or when, but I am trying to figure out who is going to need it
> and trying to determine that before babies leave the hospital. We are
> sort of acknowledging this problem of jaundice having shifted from an
> inpatient to an outpatient problem.
>
> Those are some of the things also, it shows some data on.
>
> \[Slide.\]
>
> These are some data from Israel that I think most directly address
> this question of the influence that the AAP practice parameter may
> have had. Anyone who is the practice guideline business, this is a
> totally remarkable change. The Guideline was published in \'94, the
> amount of phototherapy done, a 63 percent drop in these two hospitals,
> and an 85 percent drop in the number of exchange transfusions just in
> this relatively short time period.
>
> I think for those who are trying to change doctor behavior with
> guidelines, the key is to issue a guideline that tells the doctors to
> do what they want to do anyway, and that they don\'t have to do
> something that they didn\'t want to do anyway, and then you get very
> good adherence to the guideline, because most of us never I mean
> really liked to do an exchange transfusion, and to sort of be given
> permission not to have to do that, that is the way you get good
> adherence to your guideline.
>
> My guess is that this has happened elsewhere, as well, that nobody
> really liked doing exchange transfusions, and phototherapy,
> readmitting a baby to the hospital and putting them under the lights
> is not much fun either, so people were happy to be kind of I think be
> given permission not to do as much.
>
> \[Slide.\]
>
> These are data from Kaiser Permanente, even more remarkable. These
> show adherence or lack thereof to the AAP Guideline, just published in
> May of this year in Pediatrics.
>
> Just to orient you here, these are 11 different hospitals in the
> Northern California Kaiser Permanente system. You can ignore the green
> bars for you and just look at the red bars.
>
> The red bars are the proportion of babies who received phototherapy
> for whom the Academy of Pediatrics said it was recommended. Remember
> that slide showed you before of the Guidelines, the AAP said that for
> over 72 hours, consider it at 17, and do it at 20. Well, the green
> bars are the percent for consider, the red bars were the bilirubin,
> most of these babies had bilirubin levels over 20, what percent of
> them got phototherapy.
>
> You can see that it ranged from about 27 percent in hospital 9, up to
> about 75 percent in hospital 10, so a huge inter-hospital variation,
> but overall, almost half of babies at Kaiser with bilirubin levels
> between 20 and 25 didn\'t get treated with phototherapy in 1995-96.
>
> We don\'t have data from before that. My guess is this is somewhat of
> a drop, but also talking to many of the doctors at Kaiser Permanente,
> they were never as worried about bilirubin as we were at UCSF, I
> think. So, big differences by hospital and many babies not getting
> phototherapy.
>
> We did look at the lab tests and the vast majority of babies who
> didn\'t get phototherapy with bilirubin in the 20\'s did have their
> bilirubin repeated, and it was documented that it went down, so maybe
> it was 21 and then the next day it was 19, and it just went down by
> itself.
>
> \[Slide.\]
>
> The next point I was mentioning was the increase in concern about
> kernicterus, and this is kind of a raggedy slide because I scanned it
> from a photocopy of cases in the pilot kernicterus registry.
>
> I show this because this sort of slide has been used to raise concern
> about kernicterus, and I think kernicterus is a problem, but the
> methodology of the registry isn\'t sufficient to answer the question
> about whether there has been an increase because kernicterus wasn\'t
> being looked for, for the registry early on, so the method of
> ascertaining cases which involved asking people to report them would
> lead to an increase or to a picture like this, probably whether or not
> there had been an increase, so I think we think we just have to be
> careful.
>
> The issue I don\'t think really is has kernicterus increased as the
> issue is, is it there and can we reduce it.
>
> \[Slide.\]
>
> In terms of again the Kernicterus Registry, these are the definitions
> from the recent paper in Journal of Pediatrics, the criteria for case
> eligibility. I think one of the things we are going to come back to, a
> central question really in deciding whether to treat
> hyperbilirubinemia with drugs is how bad is hyperbilirubinemia, how
> dangerous is it, how many cases of kernicterus are there.
>
> The problem that we are going to come to is that kernicterus is not
> always a yes or no definite thing, and there is going to be a tradeoff
> between sensitivity and specificity.
>
> The criteria to be in this registry included either acute symptoms of
> kernicterus, which are listed there, or chronic sequelae abnormality
> in at least two of the following including extrapyramidal movement
> disorder, gaze abnormalities, auditory disturbances, intellectual
> deficits, enamel dysplasia of deciduous teeth.
>
> Although many or most or maybe all of the kids in this kernicterus
> registry may have kernicterus, I don\'t think we can say that. We
> don\'t know that, certainly not from these inclusion criteria, because
> these are nonspecific. There are many, many children who have
> intellectual deficits and auditory disturbances who clearly do not
> have kernicterus.
>
> Many, many kids with cerebral palsy have enamel dysplasia of their
> teeth. Many kids with hearing loss have teeth problem, so these may be
> sensitive criteria for kernicterus, but they are certainly not
> specific, and it makes it hard to interpret data from the kernicterus
> registry.
>
> \[Slide.\]
>
> So, what do we know about how common kernicterus is, because I think
> that is a key question. In the recent publication, 90 cases in 15
> years in the U.S., if they had complete ascertainment, which I think
> is not possible, not even close, that would be an incidence of 1 in
> 700,000, so there is both way underestimation from underreporting and
> possibly overestimation from non-specificity of the case definition.
>
> We have been looking for many years now for cases of kernicterus of
> Northern California Kaiser, where there are about 28,000 births per
> year in term and near-term babies, and in 111,000 cases, we have
> looked very closely because we have all the bilirubin levels, and
> looked at all those with very high bilirubin levels.
>
> In this month\'s Pediatrics, we have a paper describing the 11
> children who had bilirubin levels over 30 out of those 111,000, so 1
> in 10,000, and none of them got kernicterus.
>
> We have also started looking in earlier years. We don\'t have the lab
> data, so this is relying on discharge diagnoses, but I am working with
> a neurologist, Dr. Yvonne Wu, who is studying cerebral palsy, and she
> has reviewed the charts of all the kids with cerebral palsy diagnoses
> in this cohort, and we still haven\'t found any cases of kernicterus
> in this now about 230,000 babies.
>
> In the California cerebral palsy project, this is a personal
> communication from Susan Cummins who was involved with that study.
> They had 1 case in 155,000 out of a total of 192 cases of cerebral
> palsy, so a small proportion of cerebral palsy.
>
> One other population-based report comes from Denmark where there is a
> report of increasing kernicterus between 1994 and 1998, 5 cases, but
> with a denominator there, that would be about 1 in 65,000.
>
> That is kind of hard to interpret because it is hard to know whether
> this is the right denominator, 94 to 98, or it should include a few
> years before or a few years after, but that would be an increase.
>
> The trouble is that we don\'t have that sort of data in the U.S.
> because it\'s a much bigger country and we don\'t have an easy way of
> knowing how many cases there are.
>
> \[Slide.\]
>
> So, the problems in trying to figure out how common kernicterus
> is\--and I am sure you will hear more about these later\--there is no
> uniform surveillance, there is a trade-off between sensitivity and
> specificity in case definition. If you don\'t want to miss anything
> that might be kernicterus, you will include a lot that probably
> aren\'t, and the diagnosis of kernicterus is often delayed and
> uncertain and contentious.
>
> This is especially true if the baby didn\'t show symptoms in the
> newborn period, and it is very hard to tell someone who has some of
> the symptoms of cerebral palsy or kernicterus from someone who just
> happened to have a high bilirubin and had those anyway.
>
> My best estimate is that it is probably somewhere between 1- and
> 200,000, or 1- in 500,000, which would be between about 8 and 20 cases
> per year in the U.S., and just to mention that people should be very
> careful about extrapolating from the U.S. to other countries because
> kernicterus appears to be much more common in some other countries,
> especially in Africa.
>
> I was just struck at the Pediatric Academic Society\'s meeting just
> last month, the report from Southern Nigeria, where they described
> kernicterus in 9 of 20 infants admitted with bilirubin levels over 15,
> or 40 percent, and this is because they were putting camphor on the
> umbilical cord stump, probably in some kids who had G-6 PD deficiency.
> So, kernicterus is definitely a problem some places in the world, a
> much bigger problem than in the U.S.
>
> \[Slide.\]
>
> So, moving on now to the selected research findings, and I think the
> things that I talk about are jaundice in the first 24 hours, how much
> does that tell you that this is a baby who is at very high risk and
> needs bilirubin measurement and close, careful follow-up, using
> bilirubin measurements before discharge to predict who is going to
> develop hyperbilirubinemia, end-tidal carbon monoxide, and a risk
> index sort of as a placeholder for just the idea that the history and
> physical gives you a lot of information about the risk of developing
> hyperbilirubinemia.
>
> Just most recently last month we presented the idea that combining
> clinical information with bilirubin measurements is probably the way
> to go.
>
> \[Slide.\]
>
> This first slide, there is a tendency I think in the medical-legal
> cases especially, and this actually I think comes up not infrequently
> to sort of paint a picture.
>
> Here is a baby who was jaundiced at less than 24 hours and no one
> checked the bilirubin level, and now the child has kernicterus and
> there is this very clear causal relationship and the doctors messed
> up, but if you actually look at studies to say, you know, is jaundice
> at less than 24 hours really pathologic, you first have to say, well,
> there has only been, as far as we know, one study that looked at
> babies at less than 24 hours to see whether they were jaundiced or not
> systematically, and that was by Davidson in the \'40s, and they
> compared that to bilirubin levels, and I think it is generally
> accepted that when the bilirubin level gets above 6, most observers
> can observe jaundice, but there is quite a few data about how many
> babies have bilirubin levels more than 6 at less than 24 hours, 41
> percent at a mean of 72 hours in Alpay\'s study, 25 percent at a mean
> of 21 hours, 47 percent at 24 hours, so to say that anyone with any
> jaundice at all in the first 24 hours automatically has pathologic
> hyperbilirubinemia probably wouldn\'t fit most people\'s definition of
> pathology.
>
> \[Slide.\]
>
> We looked at this at Kaiser because we reviewed charts for a nested
> case control study trying to predict which babies would develop
> bilirubin levels of 25 or more, so we had charts on just a random
> sample at birth.
>
> These are not the cases, these are mostly controls, babies who never
> developed high bilirubin levels, and we just looked at when jaundice
> was first noted in the chart.
>
> Of course, having something noted in the chart and having it be there
> are two very, very different things. Presumably, the ones that are
> noted in the chart are a subset although sometimes people noticed
> jaundice at nighttime and then in the daytime, it seems to be gone
> when the light is better and babies are in the sunlight, but this
> shows the percentage of babies in whom jaundice was noted in the chart
> at Kaiser almost always by the nurses up to about 6 percent at 24
> hours.
>
> So, that is few enough that you would think that it would be pretty
> abnormal and taken seriously.
>
> \[Slide.\]
>
> But then what we looked is, okay, so how soon after this supposedly
> pathologic jaundice was noted in the babies at less than 24 hours, how
> soon did bilirubin levels get done, and these are cumulative, so
> within six hours in 19 percent, within 12 hours in 38 percent, less
> than half actually had a bilirubin level measured within 24 hours of
> when they were noted to be jaundiced, if they were noted to be
> jaundiced at less than 24 hours, and two-thirds eventually got a
> bilirubin level.
>
> So, one of the themes here is that, number one, we have had very
> little or no kernicterus at Kaiser Permanente in many years and with a
> couple hundred thousand babies; and, number two, it is hard to say it
> is because jaundice is managed very aggressively or according to
> guidelines there.
>
> The phototherapy slide and this slide suggest that this is true, that
> the low frequency of kernicterus at Kaiser I think is due mostly to
> the fact that at Kaiser, we have a denominator, it is not due to
> extraordinary efforts to treat jaundice.
>
> I think in the interests of time I will skip that one.
>
> \[Slide.\]
>
> So, continuing with free discharge risk assessment, and everyone will
> be familiar I think with this graph from Bhutani, et al., looking at
> bilirubin levels over time, showing how important it is to know the
> baby\'s age in hours when interpreting a bilirubin level, but again
> for pre-discharge risk assessment, I want to emphasize that babies are
> going home between 24 and 48 hours.
>
> These points, the points between the 40th percentile and the 95th
> percentile are not all that far apart, and this I think is very
> relevant for predicting jaundice using transcutaneous measurement, so
> just keep these numbers in mind - 5 mg/dl is the 40th percentile and 8
> is the 95th percentile at about 24 hours.
>
> \[Slide.\]
>
> This is one of the instruments that is used. It is wonderful not to
> have to poke babies and do heel sticks for bilirubin levels. It costs
> \$4,000 and \$7.00 each time you use it.
>
> \[Slide.\]
>
> These are data looking at how accurate that machine is compared to
> HPLC. What I just want to call your attention to is that, you know, it
> is pretty good especially when the bilirubin levels are between or
> less than about 10, but that the error range is really plus or minus
> about 2, 2 or 3. It says it is up to plus 3 or minus 2 would be the 95
> percent range. What is being plotted here is the difference between
> the HPLC and the transcutaneous measurement.
>
> So, if, for example, you measure the value and it\'s 7, then, it
> means, well, probably it\'s between about 5 and 10, but if you
> remember that 5 was the 40th percentile and 8 was the 95th percentile,
> the ability of a transcutaneous measurement at about 24 hours to
> predict who is going to develop subsequent jaundice is probably going
> to be pretty imperfect.
>
> \[Slide.\]
>
> This is another technology which it had been hoped would help
> determine who was hemolyzing and therefore how much bilirubin was
> being produced and who would be at risk of subsequent severe
> hyperbilirubinemia.
>
> It turns out that for each molecule of bilirubin that is made, a
> molecule of carbon monoxide is made, so as long as you have a
> non-smoking mother and not a bad air pollution day, you can measure
> the carbon monoxide in the baby\'s breath and get a direct index of
> bilirubin production.
>
> \[Slide.\]
>
> The good news is that it is better than a direct antiglobulin test,
> better than Coombs\' test of predicting who is going to get jaundice,
> but a Coombs\' test is really not very good, and it is not as good as
> a total serum bilirubin measure, which is not too surprising because
> the bilirubin measurement sort of reflects both production and
> excretion, and the carbon monoxide only reflects production, and it is
> kind of pricey - Herschel pointed out it is cheaper than a Coombs\'
> test, but the machine costs about \$20,000 and about \$14.00 each time
> you use it.
>
> \[Slide.\]
>
> A low tech approach, which just involves a history and physical, we
> suggested, and again at the Pediatric Academic Society\'s meetings a
> year ago and last year, validated this for another two-year birth
> core.
>
> This was developed for babies born in \'95 and \'96 to predict who
> would develop a bilirubin level over 25, which actually should be
> easier. It should be easier to predict who is going to get over 25
> than over 17 or 20, because it should be a higher percentage of kids
> who have risk factors.
>
> Without going through it in detail, these are the risk factors -
> exclusive breast feeding, having had a family history of jaundice,
> bruising, Asian race, cephalhematoma, and so on, and those give you a
> lot of information about who is subsequently likely to run into
> problems.
>
> \[Slide.\]
>
> I know the AHRQ folks will be talking about this later, so I will be
> very brief here, but if you use the area under the ROC curve to
> estimate how well can we predict who is going to develop
> hyperbilirubinemia subsequently, there is a range. Most of these
> values are in the 0.8-something range.
>
> This is the original study that used that graph that I showed you,
> that used the bilirubin percentile group, came up with a high area
> under the ROC curve, but probably the babies with lower bilirubin
> levels were less likely to get a subsequent one, so that it is
> probably biased a bit towards being high, and this is probably the
> better estimate of the accuracy of the bilirubin level measured at 24
> to 36 hours because Stevenson, et al., used the same Bhutani groups,
> but this was in a multicenter study, it wasn\'t just in Philadelphia,
> and this was calculated by me from their data.
>
> The area under the ROC curve, by the way, 1.0 would be perfect and 0.5
> would be worthless. This was the estimate for the end-tidal carbon
> monoxide. It was quite a bit worse. The risk index, this is actually
> the 0.83 is when we validated on a separate group of babies, but again
> it is trying to predict much higher bilirubin.
>
> What we did most recently is we just showed that by combining the
> bilirubin and information from the risk index, this was done all with
> computerized data, so we didn\'t have breast feeding, but we had a
> substantial increment in the ability to predict bilirubin level by
> saying now only what was your bilirubin when you were 36 hours old,
> but what was your gestational age, which turns out to be key. Babies
> who are 36 weeks, 37 weeks, much higher risk, how old was your mother,
> what was your race, and so on, that enhanced prediction.
>
> \[Slide.\]
>
> Moving on to the long-term effects of hyperbilirubinemia, what are the
> bad things that it can cause, and certainly at the top of the list is
> kernicterus, it turns out the next most bad thing that
> hyperbilirubinemia can cause is probably exchange transfusion. We
> really would like to avoid doing that. It is a risky procedure and
> especially people have less practice with it than they used to.
>
> Phototherapy, phototherapy is something we would rather not do. It is
> not totally benign. It probably doesn\'t have long-term effects, but
> it involves separating the mother from the baby, and it\'s costly and
> disruptive.
>
> Then, I want to address this issue of more subtle neurodevelopmental
> effects. I know other people will be talking about this, as well.
> There are definitely transient effects on brain stem responses and on
> behavior, and one of the questions is are there any long-term effects
> on hearing or motor or cognitive outcomes or behavior.
>
> \[Slide.\]
>
> I just want to tell you a little bit about a study that we are just
> finishing year 4 or 5 of this study, looking at babies with very high
> bilirubin levels, bilirubin levels of 25 mg/dl and up.
>
> There is another case group, which is babies who were readmitted with
> significant dehydration and randomly selected controls, all born
> within a defined cohort 1995-98 Northern California Kaiser Permanente
> Medical Care program hospitals.
>
> What we are doing is bringing these children back when they are 5
> years, 1 month, and having full neurodevelopmental evaluations by
> psychologists and child neurologists who are blinded to whether the
> child is a dehydration case, a bilirubin case, a control, or both. We
> have a few who were both dehydrated and had hyperbilirubinemia.
>
> I am going to go ahead and show you some data for this, but they have
> to be regarded as preliminary. The data collection, if everything is
> on schedule, will end in February 2004, when the last of the babies
> born in 1998 turn 5 years, 1 month.
>
> \[Slide.\]
>
> The outcome variables for this study are a standard neurologic exam by
> a child neurologist. These are IQ tests, the Wechsler Preschool and
> Primary Scale of Intelligence for children and Visual Motor
> Integration test all done by a psychologist.
>
> A Motor Performance Checklist, which was developed by an Australian
> occupational therapist for five-year-olds, turns out to be just the
> sort of thing that we were interested in because it is very practical
> items with a lot of face validity like jumping, throwing, hopping,
> catching, you know, using scissors to cut out a square, and we measure
> how well they follow the lines, putting beans, how many beans can they
> put into a bottle in 20 seconds, and so on.
>
> These are all blinded, and then the Child Behavior Checklist and
> Parent Evaluation of Developmental Status by the parents.
>
> \[Slide.\]
>
> Here is where we are as of a few months ago. Of the 140 babies who had
> bilirubin levels over 25 in a four-year period, we were able to get 86
> of them to agree to this study. We would have liked to do more, but
> this is pretty good considering this involves the family taking
> basically a half a day off to come to a site to get all these tests
> done, and we have done about 70 percent of the exams completed, so I
> am going to be showing you data on done and entered 60 babies who had
> bilirubin levels over 25, about twice that many controls, a lower
> consent rate from the controls. You know, we tried very hard, but
> there just isn\'t too much way that we can get the controls to be as
> interested in the study as the parents who have experienced a
> dehydrated or very jaundiced baby.
>
> \[Slide.\]
>
> This slide shows, I will try to show now just a description of the
> patients in the study. These are the bilirubin levels. Of course, the
> cases all had bilirubin levels over 25, but I have to say this is
> mostly a study of babies with bilirubin levels between 25 and 28. We
> already have reported on these babies who had bilirubin levels over
> 30.
>
> Remember, there were 11 babies with bilirubin levels over 30, but a
> number of them weren\'t in the study or hadn\'t been examined yet.
>
> Some of the controls had bilirubin levels in the teens, even a couple
> over 20, the vast majority never had a bilirubin measured.
>
> \[Slide.\]
>
> As expected, there were differences in the maternal race and ethnicity
> with an excess of Asian moms among the cases and a fewer than expected
> Blacks and Whites and Hispanics about the same.
>
> \[Slide.\]
>
> Not much difference in education. The trend toward the bilirubin cases
> being a little bit better educated.
>
> \[Slide.\]
>
> No difference in family income. This is 28 or 27 percent had family
> income more than \$100,000, so this was not an impoverished group.
> This is what you have to make to live in the Bay area.
>
> \[Slide.\]
>
> As expected, the gestational age was quite a bit younger among the
> cases. See this big excess of 38, 37, 36 weeks. We added the
> 35-weekers later, so we actually recruited additional controls at 35
> weeks.
>
> \[Slide.\]
>
> This one sort of surprised us, the duration of breast-feeding because
> we thought this would be a big confounder we would have to worry
> about, that the cases would much more likely to have been breast-fed
> for longer. This wasn\'t the case.
>
> The big risk factor was exclusive breast-feeding, exclusive
> breast-feeding during the birth hospitalization, which is what was
> associated with being the case, but not any breast-feeding, not just
> whether you had any breast milk or not, and not duration of
> breast-feeding.
>
> \[Slide.\]
>
> So, now some results, first unadjusted and then I will show you
> adjusted. The short answer is that there is only one statistically
> significant finding so far, I will show you on it. It goes in the
> direction of favoring the bilirubin cases.
>
> The verbal IQ, the trends were towards higher IQ\'s and the unadjusted
> verbal performance, and this is the test of visual motor integration,
> nothing statistically significant, all higher for the cases.
>
> \[Slide.\]
>
> Adjusting for race, ethnicity, parental education, income, and so on,
> nothing is statistically significant, and generally, the two numbers
> move a little bit closer together and usually the bilirubin is still a
> point or two higher although for performance IQ, they did switch
> directions, but not statistically significant.
>
> \[Slide.\]
>
> Remember, this is that test, the Motor Performance Checklist which
> when it was developed, it was considered that scores above 4 were
> abnormal, and this is also not statistically significant. These are,
> you know, you get a point, that is, higher scores are worse, you get a
> point you fail if you can\'t throw or catch a ball, or stay within the
> lines when you are cutting out a square, and so on. So, no difference
> there.
>
> \[Slide.\]
>
> This is kind of unexpected. The blinded neurologic exam, which we had
> the neurologists rate from normal, normal questionable, which is a
> child that they still thought was probably normal, but there was just
> something a little bit iffy, you know, maybe a little bit hypertonic
> or brisk reflexes or not too great at the tandem walk or something
> that they didn\'t think was abnormal, but that in order to maintain a
> high sensitivity, they were just going to say questionable.
>
> Abnormal was where they felt that this was a child who definitely was
> abnormal, but minimal means there was minimal or no functional
> disability, so that it didn\'t really affect the child, but they could
> see that there was a pattern of maybe a very slight hemiparesis or
> something, and then there were very few who had anything more severe.
> This came out statistically significant in favor of the bilirubin
> group. They had fewer questionable to minimally abnormal neurologic
> exams.
>
> \[Slide.\]
>
> I will close with some unanswered questions. I think we still don\'t
> know what the incidence of kernicterus is. We know that it\'s not
> common, but given that we have very few large series with
> denominators, it is quite possible that something other than treatment
> of bilirubin is what makes Kaiser Permanente better that average, and
> it could be higher than I think.
>
> What we really need to know is not just what is the risk of
> kernicterus, but at what level of bilirubin, what the risk is at
> different levels of bilirubin, is there any risk at all between, say,
> 25 and 30, or 20 and 25, and, if so, what is it because what we are
> going to have to do is balance risks and benefits in treating. As you
> get above 30, 35, it is very hard to make guidelines about things like
> exchange transfusion if you don\'t know these numbers.
>
> What factors modify these risks? I think this is key because two
> different babies who have a bilirubin level of 30 may be at enormously
> different risks of kernicterus depending on other factors, such as
> other illnesses the child may have, you know, hemolysis being best
> demonstrated, but I think there is at least good anecdotal evidence
> that babies who are septic have a much higher risk of kernicterus, and
> so on.
>
> We need to know what are the risks and costs and efficacy of
> treatments. We don\'t really have a good feel for that, large series
> of exchange transfusions, careful looking at long-term effects, if
> any, of phototherapy, and certainly any new treatment, this would be
> key.
>
> Ultimately, I am afraid we are going to have to come up with some sort
> of decision about how many tests and treatments it is worth doing to
> prevent one case of kernicterus because there is always going to be
> uncertainty. Kernicterus is very rare, you can\'t always predict it.
> It is always going to involve treating many, many patients who aren\'t
> going to get it anyway in order to prevent one who does, but how many
> that should be, I think that is an unanswered question.
>
> \[Slide.\]
>
> To close, the problem I think is that it is going to very hard to show
> that a new drug or any other treatment will improve neurologic outcome
> in children with jaundice because the bad outcomes are just too rare.
>
> So, we are faced with effects on bilirubin levels, which is really a
> surrogate outcome, and not knowing for sure whether if we lower
> bilirubin levels, we do anything except avoid the treatment.
>
> So, we end up treating with a drug to avoid phototherapy and exchange
> transfusion, which are both things that we choose to do at certain
> levels. So, it is going to be a difficult decision, I think, how much
> data on safety we need to approve a drug intended to prevent
> treatments like phototherapy and exchange transfusion for a risk
> factor, which is a high bilirubin given our current uncertainty about
> when those treatments are indicated.
>
> I think I am out of time, so thank you.
>
> DR. CHESNEY: Thank you very much.
>
> We will have time for discussion of the presentations after the next
> group of presentations, and the next group of presentations have been
> allotted one hour.
>
> Just by way of introduction, in February of 2003, the Agency for
> Healthcare Research and Quality published an evidence report on
> several question with relevance to the issues being addressed today.
>
> We are going to be hearing from three authors of this report, and the
> first presentation is by Dr. Lau, who is Professor of Medicine at the
> Division of Clinical Care Research at Tufts-New England Medical
> Center, Director of one of the AHRQ evidence-based practice centers,
> and Director of the Boston Office of the New England Cochrane Center.
>
> He is going to first discuss the methods that were used to develop the
> report.
>
> **Agency for Healthcare Research and Quality Report**
>
> DR. LAU: Thank you.
>
> \[Slide.\]
>
> My colleagues and I will be talking about the evidence report that was
> produced under the Agency for Healthcare Research and Quality\'s
> evidence-based practice center program.
>
> I would like to acknowledge other investigators on this report.
>
> \[Slide.\]
>
> The evidence report process involved a rigorous, comprehensive
> synthesis and analyses of relevant scientific literature. It uses
> explicit and detailed documentation of the methods, rationale, and
> assumptions.
>
> The scientific syntheses may include meta-analyses and cost analyses,
> and a broad range of experts is included in the development process in
> formulating the research questions and the peer review process.
>
> What is important is that the reports do not make clinical
> recommendations, we primarily summarize evidence.
>
> \[Slide.\]
>
> A systematic review process involved initially formulating
> well-focused research questions because this is a very broad topic,
> and we cannot do all the questions.
>
> They involve forming a technical expert panel and through several
> rounds of iterations of teleconferences, and we finalized a set of
> research questions.
>
> We established the evidence-based practice center protocol for this
> review, establishing inclusion and exclusion criteria, and then we
> perform a comprehensive literature search, screen the abstracts and
> the full articles, and finally abstract data and perform critical
> appraisal of the literature, and then perform the analyses, summarize,
> and interpret the results.
>
> \[Slide.\]
>
> The key questions that were formulated along with the technical
> experts are listed here. What is the relationship between the peak
> bilirubin levels and/or duration of hyperbilirubinemia and
> developmental outcome?
>
> What is the evidence for effect modification of the results in
> Question 1, the previous one, by gestational age, hemolysis, serum
> albumin, and other factors? My colleagues will not be talking about
> this due to time, but you can refer to the evidence report that has
> been published and available on the web site.
>
> \[Slide.\]
>
> The third question. What are the quantitative estimates of efficacy of
> treatment for: reducing peak bilirubin levels, for example, the number
> needed to treat\--I will define that later\--at 20 mg/dl to keep total
> serum bilirubin from rising; reducing the duration of
> hyperbilirubinemia, that is, the average number of hours by which time
> total serum bilirubin greater than 20 mg/dl may be shortened by the
> treatment; and improving the neurodevelopmental outcomes.
>
> \[Slide.\]
>
> The fourth question is what is the efficacy of various strategies for
> predicting hyperbilirubinemia, including hour-specific bilirubin
> percentiles? This will be address later by Dr. Stanley Ip.
>
> The last question is what is the accuracy of transcutaneous bilirubin
> measurements? This will be addressed by Dr. Rebecca O\'Brien.
>
> \[Slide.\]
>
> The medical literature search involved searching the Medline and
> Premedline databases in September 2001. This yielded over 4,000
> citations.
>
> We also consulted other experts and reviewed the bibliography of
> relevant review articles for potential additional studies.
>
> Also, in 2002, we also performed a supplemental search for case
> reports of kernicterus.
>
> \[Slide.\]
>
> The general inclusion criteria for the studies were all human English
> language literature, newborns between birth and one month, healthy,
> full-term infants equal to 34 weeks of EGA or about 2,500 grams, and
> also each study must have at least 20 subjects per arm except for
> Question 1 and 2, which we lower the number to 5.
>
> Additional criteria were also applied to specific questions.
>
> \[Slide.\]
>
> The total number of full articles retrieved based on screening of over
> 4,000 abstracts were about 663. The number of studies included in the
> report, 138, although there was some overlapping in number.
>
> The specific number addressing each of the questions is listed here.
> For Question 1 and 2, there were 37, and then also there were 28
> kernicterus case reports; Question 3, 21 studies; Question 4, 10
> studies; and Question 5, 46 studies.
>
> \[Slide.\]
>
> In summarizing the evidence, there are several parameters that are
> generally recognized that are important to sum up - the methodological
> quality of the study, that refer to the internal validity, the study
> design, conduct, and reporting of the study.
>
> Then, also the applicability, how well the study can be generalized,
> sometimes also called external validity about the patients, population
> and setting.
>
> The study size is also important to capture to represent the weight or
> the precision of the evidence. Then, finally, the effect or the
> results, associations, or the test performance.
>
> \[Slide.\]
>
> In evidence reports, it is typical to also provide some measure of the
> methodological quality, but the quality is something that is difficult
> to measure, so this is some caveat that needs to be interpreted.
>
> It generally refers to the design, conducts, and reporting of the
> study. Because studies may be from a variety of types of design, we
> generally follow three-level classification, and then apply to each
> type of study designs.
>
> There is Grade A, B, and C, least potential bias to C, which is
> significant bias that may invalidate a result, and B is somewhere in
> between.
>
> \[Slide.\]
>
> We also generally use the applicability scale although not directly
> applied in this report, which also is Category 1, 2, and 3. Category 1
> will be a study that is representative of the target population.
>
> So, instead of using this scale, we just report the report in the
> tables, the country of origin of the study, as well as the racial
> composition of the population.
>
> \[Slide.\]
>
> Now, I am just going to describe some of the quantitative methods used
> in the evidence report before I turn it over to my other colleague to
> describe the exact results.
>
> \[Slide.\]
>
> For Question 3, there was a question about the NNT or the number
> needed to treat, and that is what are the quantitative estimates of
> the efficacy of the treatment for reducing peak bilirubin levels.
>
> \[Slide.\]
>
> The definition of the NNT is that if you have a clinical trial, this
> is a typical 2 by 2 table, the treatment and no treatment arm, and the
> event and no event. In this hypothetical example of this trial of
> treating bilirubin level at 15 mg to prevent it from rising, so rising
> is the outcome.
>
> In each of the arms, there will be 100 patients, and in no treatment
> arm, let\'s say 20 patients out of 100 will rise beyond the 15 mg, and
> if you treat at this level, only 10 patients will rise, so therefore,
> one way of estimating the benefit of this treatment will be the risk
> difference or the absolute difference, so it will 10 over 100 in the
> treatment group minus 20 out of 100 in the control group or minus 10
> percent or 10 percent reduction of absolute event rate.
>
> NNT is defined as an inverse of the risk difference or 1 over 10, or 1
> over 0.1 is an error, or equal to 10. What that means is that you need
> to treat 10 patients in order to prevent one baby, bilirubin from
> rising.
>
> So, some believe this is a useful metric for understanding the benefit
> of the treatment for clinicians.
>
> \[Slide.\]
>
> For Question 5, collection of the study reported several measures of
> diagnostic performance. The most common one is the correlation of two
> tests or the r value, and one can also then combine study that address
> similar question, however, combining the correlation value is not the
> ideal approach in examining the agreement between two test methods,
> and the Bland and Altman method, already Tom Newman has shown earlier,
> is the preferred approach. I will describe that in a little bit.
>
> \[Slide.\]
>
> This is the Bhutani paper, that I am sure you will see repeatedly over
> and again, showing the result of the HPLC versus the BiliChek, and has
> reported an r value of 0.91, so sound like a fairly decent r value.
>
> \[Slide.\]
>
> But a problem with the correlation that is shown n this slide is that
> its black diagonal line\'s identity, that is, this is an exact
> matching, the 25 mg measure on the device being investigated is equal
> to the same value by the reference standard, but any other highly
> correlated line or this shown to have correlation of 1, will be maybe
> misinterpreted as being a perfect test where a substantial bias may be
> so, that is, some study may consistently overestimate the actual
> level.
>
> So, correlation is one of the conditions of being a measure of a test,
> but not sufficient.
>
> \[Slide.\]
>
> The limitations of the correlation in assessing the methods are
> summarized here. It provides a measure of the strength and
> directionality of the association, but not agreement.
>
> The correlation measures ignore bias, and the coefficient does not
> provide information as to the clinical utility of diagnostic test, and
> also the correlation is dependent on distribution of the serum
> bilirubin, as Tom also mentioned earlier.
>
> I already mentioned the last point.
>
> \[Slide.\]
>
> Now, the Bland and Altman method assumes that the true value is
> unknown. It takes the average of the paired measurements as the best
> result, the pair of the reference standard and the device being
> investigated.
>
> It plots for each pair of the measurement, the difference in result
> between the device against the average results, and this also removed
> statistical artifact of plotting the difference against either of the
> measurement as long as the built-in correlation problem.
>
> This magnitude of the bias can also be estimated as well as the
> standard deviation of the difference. So, this is again, Tom has shown
> you this slide showing the mean of the reference standard and the
> device being investigated on the x axis, and on the y axis, plotted
> difference between the two devices, and midline is the average of all
> the scatter plot, which is slightly above zero, suggesting there is a
> small bias in the device being investigated, and then also you can
> establish the distribution of what is known as the limit of agreement.
> Tom already mentioned some of the other issues.
>
> But then also out here in the high bilirubin end, you can also see
> that there are more underestimation by the device being investigated,
> so you could then also better appreciate the how the new device being
> compared performs.
>
> \[Slide.\]
>
> Other methods we used in our report is for diagnostic performance
> combining test performance or sensitivity and specificity. There is a
> number of ways that this can be done, not always used, such as
> combining sensitivity and specifically independently, but there is
> some problem with that, but sometime may be useful.
>
> The most common method is the summary ROC curve, and I will just
> describe this very briefly.
>
> \[Slide.\]
>
> This is a meta-analysis method to combine multiple study diagnostic
> performance when study address similar issue. An assumption is that
> studies differ because of different thresholds being reported. The
> solution is to fit a receiver operating characteristic curve that best
> describe the data, and I am just going to show you very briefly what
> this means.
>
> \[Slide.\]
>
> This is a standard diagram showing the population, the certain value
> on a horizontal axis, for example, the bilirubin value from the very
> low to high, and in health population, there is certain distribution
> of the bilirubin level and in the\--well, I guess this is the high
> bilirubin level, the label is disease, and different thresholds may
> then be applied to define what is important or high or low.
>
> The different threshold would then produce different sensitivity and
> specificity, and as shown here, using a low threshold will result in
> high sensitivity and a high threshold will result in the lower
> sensitivity, but higher specificity, so there is an inherent
> trade-off.
>
> Similarly, in the summary, SROC method, this is some examples of it
> with the ellipsis representing the individual studies performance,
> sensitivity and specificity, and when we fit this curve around, we can
> then describe this collection of studies. The X there is the
> independently combined sensitivity and specificity to give you an idea
> where this average overall what this performance may be.
>
> I think I will stop right here.
>
> DR. CHESNEY: Thank you. Dr. Lau, for those of us who are uninitiated,
> could you just say once again what does ROC stand for and what does
> SROC stand for?
>
> DR. LAU: The ROC stands for receiver operating characteristic curve,
> and SROC just adds Summary on top of that. ROC describes the trade-off
> of the threshold effect in the individual study. The Summary ROC is a
> meta-analysis method to combine multiple studies.
>
> DR. O\'FALLON: Would you explain the different shapes of those
> studies? Some of them are oval, some of them are\--
>
> DR. LAU: The oval shape represent the weight of the study, and they
> are not in x and y dimension, it is not the same, because in the
> disease arm and the non-disease group, it is different number of
> patients in the different groups, so they are proportional. It is just
> to give you a visual impression of the disproportion.
>
> DR. CHESNEY: Thank you. I am sure we will have more questions for you
> in the session after this.
>
> Dr. Ip is our next speaker. He is an Assistant Professor of Pediatrics
> at Tufts University Medical School, and he will be presenting findings
> of Question 4 from the AHRQ Report on bilirubinemia, and I assume you
> will tell us again what Question 4 is.
>
> DR. IP: Question 4 is asking what is the efficacies of the different
> strategies for predicting hyperbilirubinemia. Tom Newman actually did
> most of my talk for me, so I will just go over some of the details.
>
> \[Slide.\]
>
> When we reviewed the studies, there are a total of 12 different
> studies and 10 publications. Some of the publications combined two
> different methods into one paper.
>
> In terms of the methods, as listed here, there are cord bilirubin,
> serum bilirubin, the first 24 hours, the ETCOc, the carbon monoxide
> predischarge risk index, and the predischarge risk zone by Bhutani.
>
> \[Slide.\]
>
> As you can see, these studies, they are very, very variable. They are
> from like seven different countries. The subjects ranged from 50 to
> almost 3,000. Some study subjects consist of term babies, some consist
> of term and preterm babies. The proportion of breast feeding varies
> from like 4 percent to 90 percent. Some of them include ABO
> incompatibility, some of them don\'t. Some received phototherapy, and
> some don\'t.
>
> \[Slide.\]
>
> The other issues with these group of studies, out of the 12 studies,
> there are 8 different definitions of hyperbilirubinemia, so it almost
> makes it impossible to compare is one strategy better than another
> strategy.
>
> As you can see, there is even one study that use clinical jaundice as
> an endpoint. In other words, the way they define hyperbilirubinemia is
> just by looking at the baby. If the baby is yellow, they say, yes,
> that kid is hyperbilirubinemic.
>
> On the other hand, after they have identified it, when they measure
> the bilirubin, the range went from 6.4 to 19.3.
>
> \[Slide.\]
>
> I am just going to go over several different papers in terms of each
> method and just highlight certain points. The first method in terms of
> the cord bilirubin, Carbonell in the 2001 paper and the 585
> nonhemolytic babies assessed\--that little sign should be greater than
> or equal to\--2.2 mg/dl in the first, in the cord bilirubin, it will
> predict total serum bilirubin greater than or equal to 17 on day 3 to
> day 4. The sensitivity of this test is only 22 percent.
>
> In Knudsen\'s paper, when he changed the definition from 17 to 11.7,
> you notice the sensitivity went up to 71 percent.
>
> In the very last paper, in Risemberg, his subjects only consisted of
> ABO incompatible babies, so it is a highly selected population. He
> also raised the threshold of definition. You can see the sensitivity
> and the specificity went up quite a bit, 92 and 100 percent.
>
> \[Slide.\]
>
> This is just to show you more of the ROC curve we discussed earlier by
> Dr. Lau, showing that this is from the Knudsen studies, and so you can
> pick any point you would like to set up as your test threshold, so if
> you use 2.05 as the threshold, then, you get certain amount of
> sensitivity, like about 70 percent, and a false positive rate of about
> 20 percent.
>
> \[Slide.\]
>
> The other methods is basically measuring the early serum bilirubin
> level. Some of these papers actually included transcutaneous bilirubin
> as part of their study. The first one was done in India out of 274
> subjects, and basically, they find that if you use 3.99 as a cutoff
> point, this was drawing sometimes between 18 to 24 hours of life, it
> will predict to a TSB of greater than 15. The sensitivity is 69
> percent, the specificity is 66 percent.
>
> The author noted that these are acceptable figures for the India
> population, but they said it needs to be validated, and they said they
> are happy with that result and using that population.
>
> In the Carbonell study, out of 1,500 and some babies, he says the TSB
> at 24 hours greater than 6 predicts to a TSB greater than 17. The
> sensitivity is like 100 percent, and if you combined with a 48 hours
> TSB, greater than 9 predicts like 17.
>
> Carbonell also did transcutaneous measures using the same threshold.
> The numbers are comparable. They don\'t look as high both in terms of
> the sensitivity and the specificity.
>
> Seidman, in Israel, 1999, out of 1,100 babies, he calculated odds
> ratio using multiple logistic regression analysis, predicted that if
> you have a TSB greater than 5 at 24 hours of age, it is high
> significant to predict a day 2 TSB greater than 10, day 3 greater than
> 14, and greater than 17 later on.
>
> The other factors that he looked at, you see at the bottom, the odds
> ratio for day 1 TSB is 36.5, which is high predictive of high
> bilirubin later on.
>
> \[Slide.\]
>
> Anyway, the other significant factors are the day 1 TSB measurement
> and apparently you can calculate, depends how high it goes, and it
> gives you a certain odds ratio, maternal blood type, maternal age, and
> so forth. To, this is one method of predicting high bilirubin is
> looking at risk factors analysis.
>
> \[Slide.\]
>
> Tom Newman did the same. He mentioned earlier the Kaiser studies, and
> these are the original data from his paper. He showed that if you have
> early jaundice the first 24 hours, your odds ratio of having high
> bilirubin is like 7.3, which is like the highest.
>
> So, what he did in his paper was he wanted to know if you can predict
> high bilirubin after discharge, so he used the other factors, not the
> early discharge because they are already in that group, and then he
> basically combined them into an index score and see if you can predict
> extreme bilirubin of greater than or equal to 25.
>
> \[Slide.\]
>
> This is the ROC curve from Tom Newman\'s study. You will notice that
> you can see the risk index of 10, which is at the upper lefthand
> corner, the most upper lefthand corner, which is the preferred point
> if you use that as a cutoff point.
>
> Just to talk about that risk index of 10, Tom did a calculation. If
> you use risk index of 10, because it\'s the low prevalence of the
> disease, your positive predictive value at that setting is like 0.027
> percent, which is very, very low. So, what he concluded is you are
> going to have to treat like 370 kids with a risk index of 10 to
> prevent one kid from reaching greater than 25, so that is a huge
> number of patients to treat to get at one kid.
>
> \[Slide.\]
>
> The other method is basically to use ETCOc as a predictor of high
> bilirubin, which has been done by Stevenson back in 1997 on kids with
> hemolytic jaundice. Also, Okuyama, in Japan, decided to use the same
> technology to see if it will work for kids who don\'t have hemolytic
> jaundice, and he finds that if you have a ETCOc greater than 1.8 ppm
> at 48 hours, it\'s a good predictor that that group will have TSB
> greater than 15.
>
> Notice the very high positive predictive value of 40 percent in that
> particular population.
>
> \[Slide.\]
>
> Now, we talking about the Bhutani paper from \'99, where he had
> started out with 13,000 infants who fulfilled a criteria, and out of
> the 13,000, only roughly 2,800 who had two TSBs done at the same
> institutions, so those 2,800 were the subjects for his study.
>
> \[Slide.\]
>
> What he did was he basically did a bunch of different bilirubin at
> different time, and you can calculate 95th percentile from each group.
>
> \[Slide.\]
>
> This is an early curve that Tom showed, that you can have different
> curves and giving different percentiles.
>
> \[Slide.\]
>
> So what Bhutani did was depending on where you were at the
> predischarge area, you can predict to whether or not you are going to
> stay at the greater than 95 percentile, which is how he defined
> hyperbilirubinemia.
>
> So, for instance, if you look at the upper lefthand corner in A, you
> will see that if you start off at greater than 95th percentile,
> roughly 40 percent of that population stays in that zone, so he
> considered that would be a high risk.
>
> On the other hand, if you look at the lower righthand corner, in D, if
> you start off with less than 40th percentile, none of those kids went
> on to be in the high risk zone in the greater than 95th percentile.
>
> \[Slide.\]
>
> This is the Bhutani curve where Tom showed the calculated area under
> the curve of 0.93.
>
> \[Slide.\]
>
> So, if you use the 75th percentile as a cutoff point, as shown by this
> ROC curve, you get a sensitivity of like 90 percent, a specificity of
> 85 percent, and a positive predictor value of about 21 percent. So,
> what that means is you are going to have to treat roughly 5 kids who
> have greater than 75th percentile to prevent 1 kid from reaching
> greater than 95th percentile in his population.
>
> \[Slide.\]
>
> It is of note that Bhutani\'s study population is very different from
> a typical U.S. population. As you can see in his study, he had 41
> percent African-American while the national population is 15 percent.
> He had 4 percent Hispanics, and the national population is 21 percent.
>
> \[Slide.\]
>
> Stevenson decided to look at both ETCOc and TSBc to see if it will
> improve the prediction. As Tom mentioned earlier, it really didn\'t
> improve the prediction of the accuracy of hyperbilirubinemia.
>
> \[Slide.\]
>
> The interesting thing about the Stevenson study, because it was done
> over in like nine different multinational centers, he actually used
> the raw data from the Bhutani population and see where the 95th
> percentile is for his study population.
>
> As you can see, the 95th percentile varies anywhere from 38 percent to
> 6 percent, so it\'s very, very highly variable.
>
> On the other hand, if you just look at the ones with the study size
> greater than 100, the variability is not too bad, and then it\'s from
> like about 5 percent to about 10 percent, but nevertheless, it is not
> really comparable to the Bhutani population.
>
> \[Slide.\]
>
> In summary, it is not possible to directly compare the accuracy of
> various strategies for the many reasons we have stated before. It is
> also very apparent that the higher you have the TSB at an early age is
> associated with hyperbilirubinemia three to four days later. In fact,
> that is probably a better prediction than if you try to say that if
> you have a low TSB, you won\'t get a high hyperbilirubinemia later.
>
> The hour-specific nomogram looks promising. It has a high AUC, but
> further validation in different populations should be done.
>
> DR. CHESNEY: Thank you.
>
> Our next speaker, and then we will have a question and answer session,
> is Dr. Rebecca O\'Brien, who is an Assistant Professor of Pediatrics
> at the Floating Hospital for Children at Tufts-New England Medical
> Center, and she is going to review for us the accuracy of the
> transcutaneous measurement of bilirubin.
>
> DR. O\'BRIEN: I have 10 minutes, is that right? I will try to do my
> best to get through this.
>
> DR. CHESNEY: Actually, you have plenty of time. I don\'t mean two
> hours, but you do have 20 minutes.
>
> DR. O\'BRIEN: I will go through some of it quickly, though.
>
> \[Slide.\]
>
> I am addressing Question 5, which was looking at the accuracy of
> transcutaneous bilirubin measurements in our evidence report. I think
> these terms are familiar to all of you, but I will use TcB to reflect
> transcutaneous bilirubin, TSB to reflect total serum bilirubin, and
> HPLC, which was used in some of the newer studies of the BiliChek
> device as either high performance or high pressure liquid
> chromatography.
>
> \[Slide.\]
>
> We had 47 qualifying studies in 50 publications that actually looked
> at the test performance of the transcutaneous bilirubin instruments to
> predict total serum bilirubin.
>
> The four devices that were included in these studies included the
> Minolta AirShields bilirubinometer, and clearly this has been the most
> studied device. At the time of our review, there were three studies on
> the BiliChek device with 809 subjects, the Icterometer was in 4
> studies, and 1 study reflected the Colormate III.
>
> \[Slide.\]
>
> We will start with the AirShields bilirubinometer, which is in 2002
> called an AirShields jaundice meter. This is a handheld device, I
> think similar to the picture you saw with the BiliChek. It uses
> fiberoptic techniques that illuminates the skin and subcutaneous
> tissue, and then you analyze the intensity of the yellow color
> spectrophotometrically.
>
> This particular instrument requires development of an index, and it
> appears to be institution dependent, and their correlation curves have
> different intercepts on the y axis, and we will talk a little bit
> about that, and it does require daily calibration of the instrument.
>
> \[Slide.\]
>
> It has been studied for over 20 years. It has been studied in diverse
> patient populations. In about half of the studies we looked at, they
> actually looked at test performance generally reported as a
> sensitivity and specificity of the transcutaneous instrument to
> predict a threshold of interest of total serum bilirubin.
>
> Measurement sites were generally performed in most of the studies at
> the forehead and mid-sternum, and several of the studies reported on
> other sites.
>
> \[Slide.\]
>
> Again, challenges of combining these studies for meta-analysis include
> that authors use different total serum bilirubin thresholds of
> interest. Some used 10 and some used 12, some used 15, and it does
> limit a little bit of our ability to perform meta-analysis.
>
> The studies that we were able to combine, we combined three studies
> that used total serum bilirubin of about 11, 11 studies we are trying
> to predict total serum bilirubin over 13, and in 3 studies over 15.
>
> \[Slide.\]
>
> The studies predicting TSB greater than 11 were 500 paired samples.
> They were done at the forehead. Using a random effect model, the
> pooled estimates of sensitivity and specificity, as you can see, were
> in each study individually here, and then the pooled sensitivity of
> about 76 percent with a specificity of about 80 percent.
>
> You can really see the variability, though, of this index that is
> developed at each institution and where Maisels used an index of 20,
> Knudsen used an index of 9.
>
> \[Slide.\]
>
> Then, to predict total serum bilirubin of 13, there were 11 studies,
> so I didn\'t show you a table, but I will show you this summary ROC
> curve for this particular predicting total serum bilirubin over 13.
>
> There were 1,560 paired measurements. Again, the cutoff index ranges
> in the various studies anywhere from 13 to 24, and we will show you
> the summary ROC curve that while it isn\'t quite a clean threshold
> effect as we will show you, so there does appear to be some
> heterogeneity in the way this performs.
>
> Using a pooled estimate, however, of all of these 11 studies, we have
> a sensitivity of about 85 percent, a specificity of about 77 percent.
>
> \[Slide.\]
>
> So, this is the summary ROC curve. Again, I guess the perfect test,
> all of these gray points would all be kind of right along this line,
> and this would be the lowest levels of the transcutaneous measurement,
> and then you would lose sensitivity as you went to higher levels of
> the index.
>
> It sort of fits. This is 15 index, this is a 22, this is a 21, but
> there is a lot of scatter over here, this is 20. So, it is not a
> totally neat fit as a test.
>
> \[Slide.\]
>
> Then, for predicting total serum bilirubin over 15, again, there were
> only three studies that could be combined here. Overall, they actually
> looked pretty good with a sensitivity of 95 percent and a specificity
> of 67 percent for the Minolta AirShields.
>
> \[Slide.\]
>
> Now, looking at just how well does the transcutaneous measurement from
> the Minolta AirShields correlate with the total serum bilirubin, and
> again with all the limitations that Dr. Lau spoke of, this was really
> what most of the studies actually do talk about and do present as
> data. It does help us when we look at some of the factors that may
> affect how well this device works though.
>
> \[Slide.\]
>
> So, in these studies, the r values ranged from 0.52 to 0.96. When they
> were pooled, the correlation is about 0.84. There is details in the
> evidence table on page 241 for those who are interested later.
>
> \[Slide.\]
>
> Again, he spoke about the limitations, I will skip this slide.
>
> \[Slide.\]
>
> But when we were looking at the factors that affect the test accuracy
> of the Minolta Airshields bilirubinometer, again the study designs
> varied. Some of these studies were screening all infants, some were
> screening only jaundiced infants. They varies as to racial background,
> measurement sites, age at measurement, and then what was their
> reference or gold standard, which particular lab method did they use.
>
> There was, however, some subgroup analysis done, and we attempted to
> look at some of these factors in the slides coming up.
>
> \[Slide.\]
>
> Just as a summary, there was higher correlation of the transcutaneous
> measurements by the bilirubinometer when the sternum or forehead sites
> were used in term versus near- term. It seems to correlate better with
> White versus Black infants, and those who had not received
> phototherapy versus those who had received phototherapy.
>
> \[Slide.\]
>
> Again, just sort of showing, you can see the correlation sort of drop
> as you move to some of the sole, the palm areas, and seem to be most
> highly correlated at the forehead and sternum sites.
>
> \[Slide.\]
>
> Looking at gestational age, there were five studies that actually gave
> separate correlation coefficients. While in the individual studies,
> there were not significant differences, there did appear to be a trend
> lower in near-term infants, and you can see this in the results here.
>
> \[Slide.\]
>
> Looking at race or skin color, there were six studies that compared
> correlation coefficients across race or skin color. Half of those were
> at the sternum site.
>
> There were two U.S. studies that did find significant differences in
> White versus Black infants. The other racial groups that were studied
> were Malay, Chinese, Indian, and there were no Hispanic subgroups
> analyzed for the Minolta device.
>
> \[Slide.\]
>
> Looking at, as you can see, the correlation coefficient in black,
> there were three studies with this sample size of 258 and pooled
> correlation coefficient is 0.59 compared to the White, which was 0.75.
> Overall, this is how they performed.
>
> \[Slide.\]
>
> Looking at phototherapy, there were six studies that reported on the
> effect of phototherapy. All of these studies had lower correlation
> coefficients if the children had received phototherapy. That was
> significant in two of the studies. With meta-analysis of the
> correlation coefficients, again, you can see there is a small
> difference in the results.
>
> \[Slide.\]
>
> The next device was the Ingram Icterometer, which has been around for
> a long time. It\'s transparent plexiglas that has five painted
> transverse strips or precise and graded hue of yellow color. You press
> this device against the infant\'s nose and the skin blanches.
>
> The yellow stripes are then compared and a number is applied. Most of
> the studies used a number, 1 to 5 used 3 as their cutoff point. It is
> I think only about 7 or \$8.00, so it is a low cost device.
>
> \[Slide.\]
>
> The studies reported the correlation coefficient here. There were four
> studies of the Ingram Icterometer. The reason why there is two in
> India, these were near-term, preterm infants, and these were term
> infants. You can see there is really sort of a variability in how it
> performed, but overall, pooling the results, it appeared to be fairly
> highly correlated.
>
> \[Slide.\]
>
> Looking at test performance of the Ingram Icterometer, there were
> three studies that actually reported on the test performance,
> generally, a sensitivity and specificity. Two of these studies were
> looking at a TSB of 12.9. The threshold of the Icterometer TcB
> measurement was 3, and Bilgen\'s study in Turkey found 100 percent
> sensitivity, Schumacher found an 82 percent sensitivity although, with
> experience with the device, apparently this goes up to 95 percent, and
> then in the Indian studies, again performing a little bit less well in
> preterm versus term in terms of sensitivity.
>
> \[Slide.\]
>
> The next device is the BiliChek device. At the time we did this
> review, there were three studies. This is a device that used
> multiwavelength reflectance and therefore, theoretically, can improve
> on the transcutaneous measurement by accounting for bilirubin,
> hemoglobin, melanin, and thus things like skin color, skin thickness,
> pigmentation.
>
> There is a fiberoptic probe that is placed on the forehead and
> multiple measurements are made and averaged together after contact.
>
> \[Slide.\]
>
> These three studies, again, we have heard certainly the Bhutani study,
> it is very similar to what he did with the hour-specific nomogram
> although he was trying to use a transcutaneous measurement with the
> BiliChek to look at the same.
>
> The difference in these studies is this is the first time we sort of
> saw people using a gold standard or reference standards of the high
> performance liquid chromatography, and this was used in the Bhutani
> study and in the Rubaltelli study.
>
> Rubaltelli also used lab serum bilirubin and actually compares the
> transcutaneous instrument to the lab, and we will go through these in
> the next several minutes.
>
> \[Slide.\]
>
> I am sorry this is such a busy slide, but again here are the three
> studies, Bhutani, Lodha in India, and Rubaltelli. Again, very high
> correlation was found in the Bhutani study, and he again using the
> threshold of the transcutaneous bilirubin instrument as measured by
> the BiliChek, and the transcutaneous measurement at the 75th
> percentile to predict serum bilirubin of the 95th percentile.
>
> By using this, again lower threshold of the transcutaneous instrument
> has 100 percent sensitivity. I think it was 23 out of the 419 actually
> fell into that range, so it is a small number of infants who are
> falling into that 95th percentile.
>
> The study in India did not perform quite as well, and certainly
> appeared to perform less well when you were looking at higher total
> serum bilirubin levels with a sensitivity of only 20 percent.
>
> Rubaltelli is probably best seen on an ROC curve again because he uses
> multiple thresholds, but again it sort of summarizes that as you lower
> your threshold, your sensitivity is higher, and he did this at several
> levels, which we will show in the next couple slides.
>
> \[Slide.\]
>
> In the Bhutani study, again, this was a sample size of nearly 1,800
> samples with 490 term or near-term infants. He had a very low Hispanic
> population, I think as Stanley had alluded, he had Whites and Blacks
> were represented.
>
> There were 11 different devices used in the study, BiliChek devices,
> and as noted, his correlation was high.
>
> \[Slide.\]
>
> Again, this sort of shows graphically, and I think that the one point,
> though, most of these points are at bilirubin levels, HPLC bilirubin
> plotted here, and transcutaneous, and you can see that there may
> be\--and again it\'s hard to say\--a little bit more variability at
> the higher levels.
>
> \[Slide.\]
>
> Again looking at this as a Bland/Altman or error distribution plot, I
> think Dr. Lau sort of pointed out that maybe there is a little bit
> more variability at high levels, but you are dealing with sort of a
> plus or minus 3.23 and 2 negative here, the BiliChek does appear to
> slightly underestimate, so that the mean is a little bit higher, the
> HPLC value.
>
> \[Slide.\]
>
> Rubaltelli again was a multicenter study. It was in six different
> European hospitals and it used infants who were going to have a TSB
> done as part of their care. There were multiple users. He was trying
> to look at how this might actually perform in real life, multiple
> users of the BiliChek. There were multiple lab measurements of serum
> bilirubin, and then all of these were compared to a gold standard of
> the HPLC serum bilirubin.
>
> There was one single lab that did the HPLC measurements, and he found
> that the correlation of the transcutaneous measurements with HPLC were
> high, although not quite as high as the laboratory, they were fairly
> close.
>
> \[Slide.\]
>
> This is sort of graphically looking at correlation, this being the
> BiliChek versus\--I am sorry you can\'t see this\--but BiliChek versus
> HPLC here, the lab versus HPLC here. They again both had very high
> correlation, perhaps a little bit more variability with the BiliChek.
>
> \[Slide.\]
>
> Then, again, looking at an error plot, again, this is the BiliChek
> device. I know you can\'t really read this. This is plus or minus
> probably about\--this 2 standard deviations here\--I think this is
> about plus or minus, probably 3 positive, 3 negative here, and again
> looking at the HPLC serum bilirubin versus the lab serum bilirubin,
> perhaps a little bit narrow, but again these are sort of comparing
> these two. He also compared the BiliChek to the lab, but sort of, of
> interest, how those two compare.
>
> \[Slide.\]
>
> Then, looking at how they perform as a screening test. Again, we see
> these ROC curves and looking at how this is an ROC curve here to
> predict a bilirubin over 13, again by the HPLC method, predicting
> bilirubin over 15, and again predicting bilirubin over 17.
>
> In this, the solid line represents the treatment measure, and the
> dotted line, the serum bilirubin as measured by the lab. While they
> seem to operate closely, it is probably maybe here we can see that the
> lab and the dotted line probably performs a little bit better than the
> transcutaneous. Again, anything, the perfect curves are going to be as
> high up into the lefthand corner as you can be, and that is why people
> use sort of the area under the curve, although at this higher level,
> they seem to perform very comparably, if not a little bit better with
> the transcutaneous instrument.
>
> \[Slide.\]
>
> Then, in this final study by Lodha, there was 109 jaundiced Indian
> infants with serum bilirubins of 8, showed fairly high correlation,
> but the subgroup with higher bilirubins appear to perform less well
> with a correlation only of 0.64.
>
> \[Slide.\]
>
> There was one study that compared the Minolta to the BiliChek, and it
> does appear to perform better, at least by looking at correlation
> coefficients with the BiliChek correlation coefficient of 0.94 and the
> jaundice meter or the Minolta AirShields jaundice meter of about 0.7,
> and skin color was significant for the jaundice meter, but not for the
> BiliChek.
>
> \[Slide.\]
>
> Again, this just shows you sort of graphically, again with this
> Bland/Altman error plot, there is a lot more variability using the
> jaundice meter as opposed to a lot tighter fit here using the
> BiliChek.
>
> \[Slide.\]
>
> Finally, just one other device, there is only one study, and it only
> reports on correlation coefficients. It is the Colormate III, and I
> guess for the sake of time, I will kind of just go quickly with this,
> that it requires a baseline measurement prior to the development of
> jaundice, so it requires sort of all infants to have some measurements
> done and then it is done by computer analysis to correct for some of
> the color luminosity, redness and yellowness.
>
> It does appear to have a very high correlation, they are reporting
> 0.956. Again, it has only been studied up through about serum
> bilirubins. It tends to underestimate again, and only up to serum
> bilirubins here probably of about 15.
>
> \[Slide.\]
>
> This is the only other interesting thing in the study. They sort of
> actually compared how does visual inspection do compared to this
> transcutaneous device, and you can see that the transcutaneous device
> does appear to improve with a better correlation than our visual
> inspection for detecting jaundice.
>
> \[Slide.\]
>
> I think this is looking at phototherapy.
>
> \[Slide.\]
>
> Just to kind of finish up here, just to say that it appears that the
> transcutaneous bilirubin measurements by all three devices definitely
> appear to have a linear correlation to total serum bilirubin, but as
> noted by Dr. Lau, the correlation coefficient alone doesn\'t really
> provide us information on how well this particular diagnostic test
> works, however, many of these studies did not really report
> performance data. At least half of the Minolta studies only reported
> correlation.
>
> It is going to be highly dependent on where you are measuring your
> distribution of serum bilirubin. It appeared that the devices may
> perform less well as screening tests at higher levels of bilirubin,
> but I think we need more information and more study there.
>
> Again, the Minolta AirShields tends to perform best at the sternum or
> the forehead, less well in Black infants versus White infants, did not
> appear to perform quite as consistently across the studies when we
> look at the summary ROC curve.
>
> I think the limitations with the Ingram icterometer, there really were
> a small number of studies that evaluated that, and it does have some
> observer visualization, some issues around objectivity. It does seem
> that it performs better after people have used it for some time.
>
> There is a new BiliChek device that theoretically corrects for the
> effect of melanin and hemoglobin that may be an improvement over the
> older devices, and I think we recommend future research to confirm
> these findings in larger sample sizes with more diverse populations
> and really look at the effects of phototherapy.
>
> Thank you.
>
> DR. CHESNEY: Thank you very much.
>
> We now have some time for questions and discussion of the
> presentations by Drs. Murphy, Newman, Lau, Ip, and O\'Brien.
>
> Dr. Fost.
>
> **Discussion of Presentations**
>
> DR. FOST: Two questions. One I think is for Dr. Ip, and the second for
> Dr. Newman and Dr. Murphy.
>
> It seems to me negative predictive value would be more helpful than
> positive predictive value. That is, if we had a number at discharge
> that could confidently tell us that this child will almost certainly
> not develop a worrisome bilirubin level, that that would be very
> helpful.
>
> I just want to make sure I understand your slide on page 9 of your
> handout, called \"Predischarge Risk Zone.\"
>
> Do I understand that to say that if a bilirubin around discharge is
> less than the 75 percentile, that has a 99.5 percent negative
> predictive value of a worrisome bilirubin?
>
> DR. IP: That\'s correct. Basically, the symbol is wrong. It is greater
> than equal in 75th percentile. What that says is if you have a child
> who is less than equal to 75th percentile, then, that kid is not going
> to get in trouble according to the Bhutani population.
>
> DR. FOST: Thank you. Then, a question for Dr. Newman and Dr. Murphy.
>
> There has been a lot of discussion of risks and benefits, but not much
> about cost. You just alluded to it in your last slide. I am wondering
> if you or any of your colleagues are doing any studies or estimates of
> cost-benefit or cost effective analysis of various interventions.
>
> That is, suppose there were a drug that was completely safe and could
> completely reduce the risk of serious hyperbilirubinemia, are there
> any estimates of what the cost per case of kernicterus averted would
> be?
>
> My question for Dr. Murphy is what do you see as the FDA\'s role in
> those sorts of policy question, that is, suppose there were a drug
> that were 100 percent effective and completely safe, but it cost a
> million dollars to prevent a case, does that have any role to play in
> the approval process?
>
> DR. MURPHY: I think I can answer that pretty quickly, which is our job
> is to assess whether a product is safe and efficacious. We don\'t
> determine the price, and that other agencies would determine the
> utilization of that product. It clearly is a concern to us, but really
> our mandate is to make sure it works and how to describe it, so it
> would be safely used, and then work with other agencies in trying to
> integrate that information with any decisions that they make.
>
> DR. NEWMAN: You ask I think an excellent question, one in which we
> don\'t have enough data. It is actually the next grant I am planning,
> which would be if you add up sort of all the bilirubin levels, all the
> extra days in the hospital, all the extra outpatient visits, the home
> phototherapy, the hospital phototherapy, the exchange transfusions,
> all of the money we spend to try to prevent kernicterus, and even then
> we are not successful, so there is still cases of kernicterus.
>
> So, if there were a magical, totally safe drug that would just
> basically eliminate all that or a whole lot of it, it would be worth a
> lot. I can\'t give you a cost per patient of what it would be worth. I
> am sure the company making it would figure out a way to price it, so
> that it would make them money, but it could conceivably save a lot of
> money.
>
> What happens is that there are some cases of kernicterus, there are
> some kids who are destined to develop jaundice, who are easy to find
> and obvious in preventing kernicterus and the ones who present early
> with jaundice or who have all the risk factors, who are easy to
> follow.
>
> It costs a lot less money than trying to prevent those last few, sort
> of unpredictable cases that show up without risk factors, so that it
> will be unless you are going to give the drug to everybody, there will
> some sort of incremental cost-benefit thing where the cost per case
> prevented and the cost efficacy is much better in the higher risk kids
> and eventually it tails off to where it might just not be worth it.
>
> But if the drug were completely safe, you would give it like vitamin K
> to everybody.
>
> DR. CHESNEY: Other questions? Yes.
>
> DR. MATTISON: In the evidence report, you commented on the relative
> lack of information in a single bilirubin value, and spoke about the
> need to think about other strategies for measuring bilirubin, so it
> brings to mind sort of a common theme in developmental toxicology,
> which is to try to understand mechanism and then relative value of
> peak concentration versus area under the concentration curve.
>
> I imagine that as we talk more today, we will get at some of this, but
> I wonder if you would like to comment a little bit on strategies or
> ways of thinking about improving strategies of measuring bilirubin,
> single versus multiple values, frequency of sampling, and so on.
>
> DR. IP: Dr. Mattison is referring to our conclusion on a separate part
> of the evidence report, which we did not discuss. Basically, it is
> what happens to the majority of the kids who gets high bilirubin, but
> they don\'t have kernicterus.
>
> When we reviewed the studies, there were a very limited number of
> studies that actually address that question. In fact, most of the
> other studies, they all had kids who are preterm, term, they are sick,
> they have comorbid factors. It is very difficult to sort out if those
> factors are not responsible, if they have any kind of detrimental
> incomes, so our conclusion was using one single bilirubin is really
> insufficient to predict what is going to happen to these kids seven,
> eight, 10, 12 years down the line.
>
> The problem that I see is, first of all, way that the peak bilirubin
> is measured, the way it is even reported in the literature, it seems
> to me a lot of times it is not necessary, the peak bilirubin level.
> That is one problem. I glanced at some of the kernicterus case
> reports. They have peak bilirubin done like 24 hours before something
> happened, you don\'t know what happened 24 hours later, it could be
> higher, it could be lower.
>
> The other thing is everybody talks about there is a huge variability
> of bilirubin measurements between laboratories, so when you are
> comparing studies across different nations, across time, that it is
> not really a good predictor model.
>
> So, as you said, maybe we can use the time of exposure, how long have
> these kids been exposed to under certain bilirubin and see what
> happens in the long run, or maybe have to look at other factors.
>
> The other issues, we can discuss this at length, is how we define
> kernicterus in the first place. The problem that I see is the
> terminology is that we always say if you have neurological impairment
> with a history of hyperbilirubinemia, that is how you have
> kernicterus, so what that means you can\'t really say that it is the
> bilirubin causing it because you define it that way, so it gets
> involved.
>
> DR. CHESNEY: Yes, Dr. Oh.
>
> DR. OH: I have a comment and a question for Tom Newman. I would agree
> wholeheartedly that a key outcome for any intervention in
> hyperbilirubinemia is neurodevelopmental outcome, and yet as you
> pointed out, the kernicterus incidence is so low, and we don\'t quite
> know the new developmental outcome of hyperbilirubinemia, so it brings
> up he issue of the follow-up that you have.
>
> Ideally, compliance rate of 80 percent or greater is desirable in any
> follow-up study, with 60 percent, I was just wondering if you had a
> chance to compare the variables of the 40 percent that you didn\'t
> follow with those that you followed, particularly with reference to
> the bilirubin level and the socioeconomic status.
>
> Can you comment on that?
>
> DR. NEWMAN: It\'s an excellent question. The biggest concern we have,
> I mean, of course, we would like to have 100 percent in both groups,
> but the potential for bias is that we have a higher percent
> participating in the bilirubin group than in the control group, and
> the concern is what if the controls who choose to participate are
> those who are a little bit more worried about their child, and
> therefore, they want this free neurodevelopmental assessment.
>
> We haven\'t looked at these data yet, but the ways that we are
> addressing that is that all the data I showed you are in what we call
> the full participants, but when people say no, then, we still ask
> them, well, will they at least fill out the questionnaires for us.
>
> One of the questionnaires I didn\'t show data on is called the PEDS or
> the Parent Evaluation of Developmental Status, where we specifically
> ask the parent, do you have any concerns about your child, and there
> is 10 questions, you know, how your child understands speech, how your
> child speaks, how he uses his hands and fingers or arms and legs, and
> so on.
>
> What we at least will be able to do is besides the socioeconomic
> variables and race and other variables, see whether we do see evidence
> of increased participation in the control group according to whether
> the family was worried, and then, of course, we can stratify in those
> variables and just compare among both the cases and the controls.
>
> We do know that most of these parents of these five-year-olds think
> their kids are fine, and most of the kids are fine, so if we stratify
> just on whether the parents said they had any concerns, and we started
> the study before, so we have whether they had any concerns at age
> three, age four and five, and so on, we can address that, but we
> haven\'t looked at data comparing participants to non-participants
> yet.
>
> DR. CHESNEY: Dr. Ebert.
>
> DR. EBERT: A lot of your information was directed towards specifically
> looking at identifying individuals with high bilirubins, but yet you
> also mentioned earlier that because the risk of kernicterus is so low,
> perhaps we should look at more the risk or the need for therapy.
>
> Is there a way that we can overlay the AAP guidelines for treatment
> with some of these risks to look at what would be the predictor for
> the need for phototherapy or the need for exchange transfusion?
>
> DR. NEWMAN: I am not positive I understand your question. I mean I
> think we can look at predictors of bilirubin at a certain level, and
> that I think has the advantage that since phototherapy is, as you saw
> in the slide of the different hospitals, varies a whole lot from
> doctor to doctor or hospital to hospital.
>
> I think we are better off trying to predict bilirubin level above 15,
> 20, 25 than trying to predict something like exchange transfusion or
> phototherapy, but even then, these are retrospective observational
> studies and we are restricted by whether the doctor chose to do a
> bilirubin or not, and if you have doctors who don\'t believe jaundice
> is a problem and don\'t choose to measure bilirubin, all of our data
> from Kaiser on sort of incidence of bilirubin at different levels are
> all minimal estimates because when we get up above 20, 25, we just
> assume that if it wasn\'t measured, they didn\'t have it, so there may
> be slightly higher estimates.
>
> I am not positive if that answered your question.
>
> DR. EBERT: That really was what I was getting at, but looking at the
> ultimate outcomes and the issues on impact on health care and the
> things that we need to do to treat patients effectively, I guess the
> end result, the true treatment is a lower incidence than it is of
> finding that elevated value.
>
> DR. NEWMAN: Yes, and again, I think if you allow as an outcome, doing
> less phototherapy, then, of course, another way to achieve that
> outcome is to change your guideline. One of the problems with the
> surrogate outcome of bilirubin is that given that the bad outcomes are
> so rare, you know, we could less phototherapy. We could say, well, we
> are going to do 22 instead of 20.
>
> That would have a big impact on cost on phototherapy. Actually, in one
> study looking at comparing hospital and home phototherapy, and looking
> at the cost, the biggest determinant of cost wasn\'t whether you did
> it in the hospital or whether you did it at home, it was whether you
> decided to do it at all, because there was so much variability, and
> the variability results from the rarity of the outcome and the lack of
> data.
>
> DR. CHESNEY: Dr. Gorman has a question, but if I could ask one first.
> Dr. Newman, do we know anything about autopsies of premature and
> normal infants today in terms of how much bilirubin staining there is?
>
> DR. NEWMAN: David may know this better than I do. There was sort of a
> flurry of activity in the \'80s about autopsies in preterm babies, and
> then I haven\'t seen much more of that, that it went away when they
> took away the benzyl alcohol, but I do bigger, \"weller\"\--more well
> babies, so if any of the neonatologists here knows that\--I haven\'t
> followed closely autopsies in preterm babies.
>
> DR. CHESNEY: Dr. Gorman, do you have a question about \"weller\"
> babies?
>
> DR. GORMAN: I was going to let the neonatologists with expertise try
> to answer that question first.
>
> DR. STEVENSON: I am not aware of any large, systematic review of
> autopsy data that would address that directly, at least recently, and
> I am not sure what your experience is, but anybody else who knows
> anything about it could comment, as well.
>
> DR. HUDAK: I think that is correct. I think the literature shows that
> basically, premature babies who die because they were very sick had
> bilirubin staining of the basal ganglia at relatively low levels, and
> I think that is sort of uninterpretable information, and it certainly
> doesn\'t address the broader issue, and it doesn\'t say anything about
> whether premature babies are more at risk for kernicterus at lower
> levels although it was certainly interpreted by neonatologists for
> many years that way, but there is nothing recent.
>
> DR. CHESNEY: Thank you.
>
> Dr. Gorman.
>
> DR. GORMAN: This question is to both Dr. Newman and to whoever
> reviewed the 38 case reports of kernicterus. I also had several
> formative experiences. One was measuring theophylline levels in the
> thought that it might help people with asthma for many years.
>
> I have that same deja vu all over again while I look at all this
> chasing of bilirubin levels. I am going back to the question of
> causality of bilirubin and kernicterus.
>
> I will ask the question in a reverse way. We have talked about the
> confounders and the potentiators for bilirubin or in bilirubin and
> kernicterus. In that series, has there ever been a well child who has
> developed\--a well infant\--I ask this question at the risk of
> offending my neonatology colleagues\--a well infant, term, at any
> bilirubin level, who has developed kernicterus?
>
> DR. NEWMAN: I would say yes. Some people say, but if developed
> kernicterus, you must not have been well, so there is a little bit of
> circularity there. There are children who, at the time they were
> discharged from their birth hospitalization, looked perfectly fine,
> who are readmitted with very high bilirubin levels, who have what
> looks like the kernicterus that babies in the 1950s with Rh disease
> used to get.
>
> To me, the causality is more convincing if they started out well and
> come in symptomatic. I mean they come in with a high-pitch cry,
> arching, and opisthotonos, maybe seizures, and there are some of those
> kids who then, you know, they get an exchange transfusion, and some of
> those acute symptoms seem to get better, and if they are left then
> with the classic sequelae like used to be seen with Rh disease, to me,
> that is pretty convincing.
>
> It is much harder when they don\'t have that acute picture or when
> they end up with something which is sort of a partial syndrome. They
> have cerebral palsy, but it is spastic, and not athetoid, and they
> don\'t have the hearing loss, so they have just the hearing loss, but
> otherwise they are fine.
>
> The courts often end up settling these or they lead to lawsuits, and
> it\'s people arguing about is it kernicterus or not, because the child
> has something which is abnormal, which in the parent\'s mind may be
> very much associated with the jaundice and the treatment for it,
> because treatment for jaundice, especially when it involves exchange
> transfusion, is a very salient and frightening event, but what the
> child has, it becomes unknowable.
>
> The MRI findings of the increased T-2 signal and the globus pallidus
> would be very suggestive, but I haven\'t seen enough studies that
> looked at kids who have athetoid CP, who never had a high bilirubin,
> to see how often they have similar basal ganglia findings on MRI.
>
> DR. GORMAN: So, in your review of the case reports, you think the
> answer is yes, well babies with high bilirubins and no other disease,
> trying not to be circular, develop kernicterus?
>
> DR. NEWMAN: Yes, apparently well babies, babies who have nothing else
> wrong with them that we can identify, but it\'s rare.
>
> DR. GORMAN: Well, always placing the most emphasis on the most recent
> data, Pediatrics arrived on my doorstep yesterday and because of this
> meeting today, I actually scanned the titles and saw your article on
> bilirubin without kernicterus in several babies.
>
> I know everybody in California is above average, your IQ scores are
> all above average despite whether they were high bilirubin\'d or not,
> but I will leave that as it is.
>
> I had a second question which I am now blocking on completely, but it
> will come back to me.
>
> DR. NEWMAN: Just commenting on the babies over 30, it was only 11, so
> the quick rule of 3, if you observe zero out of 11 or zero out of 10,
> because one of them did die of apparent SIDS, you know, the upper
> limit of that could be a kernicterus rate of 30, 40 percent in babies
> with bilirubin levels over 30.
>
> There is no question in my mind that it occurs, but probably somewhere
> in the range of 1 and 2 in 500,000.
>
> DR. GORMAN: If you had to predict, and this is the other question,
> which of the potentiators or confounders are going to be most
> difficult to sort out, which would you point to? I will use that to
> any of the group that presented. Is it the hemolysis, is it the
> sepsis, is it the gestational age, is it medical intervention?
>
> DR. NEWMAN: Oh, that\'s a tough one. I would say medical intervention
> is going to be very hard to sort out, because babies who have
> symptoms, you know, that is one of the indications, that is one reason
> they would be more likely to get an exchange.
>
> In reviewing some of these case reports, I mean that come from
> medical-legal consultation, I have seen ones where the child came in
> with a high bilirubin and seemed to be okay, and the exchange
> transfusion seemed to make them worse, you know, they either had a
> seizure during the exchange or something happened, because it\'s kind
> of, you know, it\'s a big thing to do, so I think that would be\--I
> was looking through the cases on the plane that I have reviewed, you
> know, there is several of them that have this sort of iffy infection.
>
> They have a little bit of a fever, but people say you can get fever
> from kernicterus. They have staph epi or something in their blood
> culture, maybe a little low platelet count, it is just not stuff where
> you can tell, maybe there was an infection. A lot of them have some
> white cells in their urine, but negative urine cultures, but they got
> antibiotics, so I would say sorting out infections, some have like a
> little CSF pleocytosis, you know, sorting out those things has also I
> think been hard to say, was this just a well baby or was this a baby
> who maybe had an infection.
>
> DR. CHESNEY: I think, as always, infections are the most important
> thing, but I would like to take a break for 10 minutes if we could,
> and we are going to have more discussion after the break. It\'s about
> 10 of 11:00, if we could come back at 11 o\'clock and then we will
> address Question 1, which really is general enough that we can
> continue some of this question and answer.
>
> Thank you.
>
> \[Break.\]
>
> DR. CHESNEY: For the next 10 to 15 minutes, although there was an
> initial and very general question, what we would like to do is two
> things. One is to allow people to continue to ask questions of the
> speakers, but also please raise any issues which you feel have not yet
> been discussed about this area, that have not been raised by this
> morning\'s speakers.
>
> Any questions, any issues that haven\'t yet been raised? Dr. Danford.
>
> DR. DANFORD: I have a question primarily addressed to Dr. Newman. It
> has to do with that multiple logistic model for predicting people who
> end up with total serum bilirubins greater than 25.
>
> I was wondering about the methodology of that because the performance
> of a risk index like that is generally better when you assess that
> performance in the cohort in which it was derived than it would be if
> you took an independent sample afterwards and tried to apply it.
>
> I don\'t know, is the kind of encouraging looking ROC curve for that
> index on the derivation cohort, or is that an independent sample?
>
> DR. NEWMAN: That\'s an excellent question. In fact, it hasn\'t been
> published yet, but the derivation sample is babies born in \'95 and
> \'96, and we validate it for \'97 and \'98, and it performed just
> about as well. The area under the ROC curve went from 0.84 to 0.83,
> and 0.83 was the one that I showed in my table there.
>
> That is higher than what Stanley showed because that is using all of
> the data, and anytime you categorize it, as he did, the ROC curve that
> he showed from our study only I think had four points, you know, more
> than 15, you know, cutoffs at 10, 15, 20, and so on, but when you look
> at the whole data, you, of course, get additional credit for
> information that is contained between values that are in between
> there.
>
> In fact, this would be true of the total serum bilirubin measurements,
> as well, which is that the area under the ROC curve for those, which
> when Bhutani said was replicated, was about 0.84, in the study by
> Stevenson, 0.4, 0.85. If instead of categorizing it, they actually
> looked at the actual value, that would probably go up a little bit, as
> well.
>
> DR. DANFORD: Thanks.
>
> DR. CHESNEY: Dr. Stevenson.
>
> DR. STEVENSON: This is a question for Dr. Ip or maybe Dr. Newman. I
> think Dr. Law and I think Dr. Ip mentioned that they were not going to
> be commenting about hemolysis although it has been mentioned several
> times, also infection is associated with up-regulation of the
> hemoxygenase gene with increased production of the pigment, and
> oftentimes hemolysis occurs in that context. Empirically, jaundice is
> associated with infection.
>
> But I wondered what the quality of the data are with respect to the
> issue of risk for not so much bilirubin level, but injury in
> association with hyperbilirubinemia between hemolysis, anything on
> that at all, what is the state of the evidence.
>
> DR. IP: We didn\'t really review specifically to address the
> hemolysis, but from what I gather, at least our task was to review
> healthy term/preterm, near-term babies without any kind of diseases,
> and all the kids with Rh, we excluded that from our analysis.
>
> On the other hand, there are quite a large number of kids with ABO.
> There is no way you can exclude them because they are part of a lot of
> the studies. As Dr. Stevenson knows well, the Coombs\' test is not the
> best predictor of hemolysis, and a lot of times we just have to look
> at the raw data and say, well, some authors assume that if mom is O,
> baby is A, they must have an ABO problem regardless of what the Coombs
> shows, and some authors say no, you have to have the Coombs, so it is
> difficult to say what the end result should be.
>
> DR. NEWMAN: I agree. I think the data here are in the form mostly of
> case reports. There are some studies where here is a series of babies
> who had high bilirubin levels and what percent got damaged, and
> clearly, those series of Rh babies in the \'50s and the series of G-6
> PD deficient babies, another group that seemed to have a higher risk
> of kernicterus in series at a lower bilirubin level.
>
> The other things are case reports and sort of informally looking at
> case reports when you say here is a baby that looks like he or she
> might have kernicterus, and the bilirubin level is only 28, and then
> you say, yes, but the baby had a urinary tract infection or some other
> infection or something else that if you look at the kernicterus cases
> where it occurred, say, at bilirubin levels less than about 30 or 35,
> children with other problems are overrepresented. I think that is
> about the best I can do.
>
> DR. CHESNEY: Dr. Luban.
>
> DR. LUBAN: I think we can\'t underestimate the number of children that
> have G-6 PD deficiency or have G-6 PD deficiency combined with sickle
> cell disease who are FS on screen, but eventually become children with
> sickle cell disease at a rate of 1 out of 400 African-Americans, and
> that is a group that I know we are not concentrating on with this
> data, but we shouldn\'t underestimate.
>
> DR. CHESNEY: I have a question. Dr. Newman, I will address it to you,
> but maybe other people know of. We keep talking about hemolysis as
> being a high risk factor. Is there anything about the hemolytic
> process per se as in liberation of lipid red cell envelopes that
> enhances blood-brain barrier access for the bilirubin, do we know
> anything about that, are there any animal models where lipids have
> been given along with the bilirubin?
>
> I realize this is a far-out thing, but we just sort of accept that
> hemolysis is more likely to give it, and we assume it is because there
> is more bilirubin, but I wonder if there isn\'t some other issue.
>
> DR. NEWMAN: I don\'t know the answer to that because those are sorts
> of studies I don\'t have the expertise to evaluate very well, the
> ones, you know, with animals, so I defer to any of the other people
> here who know those studies better.
>
> I don\'t think it is clear why babies with hemolysis are at higher
> risk, but part of it is, you know, they were born in the 1950s. Mostly
> now, I mean our data is coming from the 1950s. Many of them, labor was
> induced, they were electively delivered prematurely.
>
> You know, there are so many things different between Rh babies in the
> 1950s and babies now. We don\'t know what the risk of kernicterus is
> with babies with severe arch disease or hemolysis now when they get a
> very high bilirubin because we don\'t let them get a very high
> bilirubin.
>
> It has become very, very hard to study. Other people may know the
> animal data, I don\'t.
>
> DR. CHESNEY: Yes, Dr. Freeman.
>
> DR. FREEMAN: I am just revealing my ignorance, but there is a recent
> paper out on bilirubin as a cytoprotective agent, picking up as a
> scavenger molecule. Is there any level of bilirubin in the newborn
> which is good?
>
> DR. CHESNEY: We were discussing that during the break. It is sort of
> like fever. I mean fever is actually a very good thing. Maybe
> bilirubin is a desirable thing in those infants who have lower levels.
>
> Dr. Stevenson, you were going to answer that.
>
> DR. STEVENSON: There is considerable data that demonstrates
> conclusively that bilirubin is a naturally occurring antioxidant. At
> levels that occur in circulation after birth within what would be
> considered the physiologic range, although we are still debating what
> that range might be, it will confer that kind of protection.
>
> You can even thing about the teleology behind having a naked ape
> exposed to sunlight and oxygen, having a naturally occurring
> antioxidant in circulation temporarily while your other antioxidant
> systems up-regulate after birth.
>
> One of the comments that I will make later is that everything is dose
> dependent, and if there is a level at which bilirubin is safe and may
> be essential, there is also a level which bilirubin is toxic, there is
> no question about that from the animal work. Clearly, from our
> experience clinically, there are conditions in which bilirubin is
> associated with injury, there is no doubt about that.
>
> DR. CHESNEY: Dr. Oh.
>
> DR. OH: I clearly agree with Dr. Stevenson on that. My own gut feeling
> is that a little bit of bilirubin may be okay as an antioxidant, but
> too much is bad I think. That is my own feeling.
>
> DR. FREEMAN: What is that range, Bill?
>
> DR. OH: We don\'t know that. That is the question that we need to
> know.
>
> DR. CHESNEY: That is comparable to fever - a little bit is good, too
> much is not so good.
>
> Other questions? Dr. Glodé.
>
> DR. GLODE: I had a question for Dr. Newman. I realize that he was kind
> enough to just share with us his preliminary information, but it was
> really a comment and a question.
>
> The comment would go to potential bias in the study. You already
> brought up the issue that perhaps the control families would be more
> likely to enroll although I think you could also argue that the
> families of the children with the high bilirubin might bias the study
> in favor of enrollment because they were concerned about neurologic
> development.
>
> But my question refers to the one area, neurologic exam area, where it
> was statistically significantly different in preliminary analysis,
> favoring the children with the high bilirubin.
>
> I was just interested if you knew of those 86 children who had been
> enrolled at least, could just give us some sense of the interventions
> that were done. Do you know what percent had phototherapy or exchange
> or anything else?
>
> DR. NEWMAN: I know that for not the 60 who have had exams, I showed
> data on, but for the whole group of about 140 who had bilirubin levels
> over 25. I think four of them got exchange transfusions, and all but
> one got phototherapy. The one that didn\'t get phototherapy, you know,
> was like at 25.2, and they repeated it the next day and it was lower.
>
> So, not very many exchange transfusions, a lot of phototherapy. In
> terms of the bias, you are right that families of jaundiced babies who
> are worried about what effects it might have had might be more likely
> to participate in the study.
>
> I am focusing on the other bias because that would bias us in the
> direction of finding that jaundiced babies did worse, and since our
> trend is that they did a little bit better, the concern I have is that
> the controls selectively enroll who are more worried.
>
> DR. CHESNEY: Thank you.
>
> We have two presentations over the next hour. The first is by Dr. Oh,
> who is a neonatologist and Chair of the Department of Pediatrics at
> Brown Medical School. He is also the pediatrician and Chief at Rhode
> Island Hospital, and the Sylvia K. Hassenfeld Professor of Pediatrics
> at Brown.
>
> He will be discussing the safety and efficacy of phototherapy for
> treatment of hyperbilirubinemia in the term and near-term infant.
>
> Dr. Oh.
>
> **Phototherapy**
>
> DR. OH: Thank you very much, Dr. Chesney.
>
> My job is to review the intervention for hyperbilirubinemia, which is
> actually the standard of care today, in the next 35, 40 minutes or so.
>
> \[Slide.\]
>
> What I will do is just briefly discuss the historical event that led
> to the introduction of the phototherapy for the treatment, spend some
> time on the mechanism, in other words, how it works, and some data on
> the efficacy and acute side effects, as well as some long-term
> outcome.
>
> \[Slide.\]
>
> The first paper actually was published in 1958, in Lancet, by Cremer
> and others, showing that when they exposed infant with jaundice to
> sunlight, it has a reduction in serum bilirubin, and actually that was
> based in laboratory, in vitro observation that when they exposed the
> serum to light, the bilirubin level actually goes down.
>
> So, they used this in vitro experience to perform a clinical trial
> that shows that in vivo, by sunlight, it also reduced the bilirubin,
> as well.
>
> \[Slide.\]
>
> Subsequent to that report, there were several clinical studies
> including some that were done here and some in South America in the
> \'60s, which confirmed the efficacy of phototherapy in lowering the
> serum bilirubin level, which then made phototherapy a standard of care
> up to today.
>
> There is also some trials showing that the efficacy is somewhat more
> than the full term in terms of the low birth weight infants, and the
> reason for that is actually unclear.
>
> \[Slide.\]
>
> In terms of mechanism, we know that it works on the basis that
> bilirubin absorbs photon from the light at certain spectrum, light
> spectrum, which is at 400 nanometer in vitro. Following the absorption
> of this photon, it results in a series of photochemical reaction with
> the formation of three major products, and these are the isomeres that
> are different physical properties that allow for elimination of the
> bilirubin without going through the conjugation system in the liver.
>
> \[Slide.\]
>
> This is the spectrum of the absorption spectrum for the bilirubin,
> which is somewhere between 400 and 500, the peak being around 450.
>
> \[Slide.\]
>
> But the in vivo absorption of spectrum light for bilirubin is actually
> a little different from the in vitro, because the in vivo setting, the
> bilirubin is bound to the albumin, and the albumin has some fatty acid
> that might change the spectrum of maximum absorption from 450 to
> somewhere around 475, 480 nm.
>
> That explains some of the reason that the different kinds of light has
> variable results when the infants are exposed to this light.
>
> \[Slide.\]
>
> This is the series of photochemical reactions that are known to occur
> when the bilirubin is exposed to light. When the photon is absorbed by
> the bilirubin, it makes the bilirubin sort of excited. It excites the
> bilirubin, that then produce photo-oxidation. That is one of the
> byproducts.
>
> It also has a change in the structure in another reaction that will
> form lumirubin, a substance called lumirubin, and then there is also a
> process called configurational isomerization, in other words, the
> structure is not changed, but the isomere was formed because the
> configure was changed, the bilirubin structure was changed, forming
> three different photoisomeres - 4E, 15Z, 4Z, 15E and 4E, 15E, and I
> will get back to that in a minute in terms of what those numerical
> numbers mean.
>
> \[Slide.\]
>
> One of the interesting observations is that for 20 years or so, since
> Cremer\'s report of the efficacy of light, of phototherapy introducing
> bilirubin, the assumption was that the major mechanism was through
> photo-oxidation, and not until the early \'80s, when the other
> mechanism was discovered or described, that people began to realize
> that it is not the photo-oxidation product that accounts for the major
> route in the elimination of the bilirubin, but it is rather the other
> two formation of the isomeres.
>
> \[Slide.\]
>
> One of them is the change in configuration that I talked about
> earlier. This is a molecular structure of bilirubin. On your left is
> the native bilirubin. You will note that the carbon 4, the two double
> band bridging the two pyrroles on the left and on the right.
>
> Just look at the carbon 4 on your left, which is a Z, and the carbon
> 15, also Z, on the right. What happens is that the change in this
> particular model occurs in the carbon 15, so that the Z, the double
> band, is rotated 180 degrees, allowing for the hydrogen ion to be
> essentially \"exteriorized,\" quote, unquote, that change the polarity
> to make this molecule more water soluble than the native bilirubin.
>
> The water solubility or the less lipophilic characteristic of this
> molecule will then allow for the particular product to be excreted
> through the bile and also through the urine.
>
> \[Slide.\]
>
> Now, this is a situation where the change is occurring in the
> structure itself, it is not the configurational change. There is an
> actual change in the structure. Again, on the left is the native
> bilirubin. You notice the 4Z and 15Z bilirubin. In this particular
> case, the left pyrrole ring, the structure is changed, so that again,
> the hydrogen ion is exteriorized and allows for the bilirubin to
> become water soluble and be able to be eliminated through the bile or
> through the kidney.
>
> \[Slide.\]
>
> The major issue here is that the native bilirubin, the 4Z, 15Z is
> hydrophobic and lipophilic, in other words, they are not water
> soluble, they cannot be eliminated through the bile or through the
> kidney in the urine because of the physical property of the molecule.
>
> The only way that the native bilirubin can be excreted or eliminated
> is by conjugation in the liver with the glucuronyl-transferase, the
> enzyme responsible for glucuronide of this particular bilirubin.
>
> But when the bilirubin is exposed to light, the isomeres are formed,
> and they are less lipophilic and less hydrophobic, in other words,
> they are more water soluble, and therefore, it enhances elimination
> through the bile and the urine.
>
> \[Slide.\]
>
> The studies have shown that in terms of formation of this various
> product, the formation of the 4Z, 15E isomere, meaning the one that
> occurred through configurational isomerization, is greater than the
> structure change, the lumirubin, and those, in turn, are much greater
> in amount than the photo-oxidation products.
>
> But the important thing is that in terms of elimination, the rate of
> excretion is far greater for the lumirubin than the photo isomere 4Z,
> 15E, and over the photo-oxidation product, so that the rate-limiting
> process in terms of elimination is actually the lumirubin and
> therefore it is very important to remember that lumirubin is the key
> isomere in terms of the elimination of the bilirubin when they are
> exposed to light.
>
> One other important phenomenon that one needs to keep in mind is that
> once the baby is exposed to the light, the formation of the various
> isomeres is almost instantaneous and they maintain a level that
> maintain a fairly good steady-state in the bloodstream. The
> rate-limiting state, as I said, is the elimination process, and that
> is what takes time.
>
> That might explain some of the reason why the so-called continuous
> versus intermittent phototherapy has no difference in terms of the
> ability to reduce bilirubin, because the rate-limiting step is not the
> amount of lumirubin being formed, but the way it is being eliminated
> through the kidney and through the bile.
>
> \[Slide.\]
>
> This cartoon summarizes what happened to the various products of the
> bilirubin. The ZZ that you see here is the native bilirubin in the
> center. As you can see, they are transported to the liver by binding
> to the albumin, and because of the nature of this molecule being
> lipophilic and hydrophobic, they cannot be eliminated unless it is
> conjugated by glucuronyl-transferase.
>
> On the other hand, when they are exposed to light, it forms the either
> ZE by configurational change or lumirubin by a structural change that
> again are bound to the albumin, and for the ZE, it gets excreted
> through bile into the intestine, where then it\'s a reversible
> process, as well.
>
> Once it\'s in the dark, once it gets into the intestine, it reverts
> back to the native bilirubin, ZZ, and recycle it to the blood.
>
> On the other hand, lumirubin, or LR, again is bound to the albumin,
> gets to the liver, excreted through the bile into the intestine, and
> part of it is also excreted through the kidney through urine, so there
> are two ways that lumirubin can be excreted from the body, either
> through the bile into the intestine or through the kidney through the
> urine. The photo-oxidation product is primarily excreted through the
> kidney.
>
> So, I think we have a fairly good knowledge to date in terms of the
> mechanism of how light works. It involves the formation of the
> isomeres and the photo-oxidation product, but the major route of
> excretion is through the formation of the lumirubin, the structural
> change, and excreted through the bile and through the kidney.
>
> \[Slide.\]
>
> Now, what are some of the factors that might affect the efficacy of
> phototherapy? It all boils down to four major factors. One is the type
> of light used, either blue or green or white. Those are the three
> major light sources that are used clinically today. The light
> intensity itself, the surface area of the skin exposed to the light,
> and then the distance of the light to the baby.
>
> So, all of this boils down to the irradiance that the baby receives,
> and that irradiance is dependent on the light intensity, the type of
> light used, the surface area being exposed to, and the distance from
> the light to the baby. Today, in clinical practice, although we don\'t
> use equipment to measure irradiance in most cases, the ideal setting
> will be to try and achieve an irradiance of approximately 15 to 20
> microwatt per square centimeter per nanometer.
>
> That is the setting where the maximum degree of reduction of the
> bilirubin takes place.
>
> \[Slide.\]
>
> Let me just walk through a few types of phototherapy devices available
> clinically today. One is generic fluorescent tubes, which can come in
> three different kinds of light - daylight or white light, which is the
> usual fluorescent light that you see in the household, a blue light,
> and then the green light.
>
> Then, there is halogen lamps also used, fiberoptic system, and I will
> go through this in detail, and then more recently, a gallium nitride
> light-emitting diodes has also been developed and used clinically.
> Again, as I said, I will go through each one of these in detail.
>
> \[Slide.\]
>
> Now, in terms of the fluorescent light, this is a comparison study
> done by KL Tan in Singapore, published in 1989, comparing the percent
> reduction in serum bilirubin when the infant was exposed to either
> special blue or green light or daylight.
>
> What he found is that the special blue is more effective in reducing
> the serum bilirubin by about 33 percent compared to green and
> daylight, which is about 20 percent reduction over a period of time,
> or the duration of exposure are all constant.
>
> Now, what he concluded was that it is preferable to use either
> daylight, because it provides enhancement of clinical observation and
> adequate efficacy, or blue light because it has a better efficacy, but
> the green light is not recommended by him because it provides neither.
>
> \[Slide.\]
>
> I have to make a note here in terms of what the blue and the green
> light ends up with when you do a clinical care in this baby. The blue
> light makes the baby cyanotic and the green light makes the baby sort
> of, you know, somewhere between cyanotic and being under-perfused, so
> it is very difficult for the nursing staff and the physician to
> evaluate these babies when they are under blue or green light.
>
> So, today, in most settings, the white light is the most commonly used
> because it produces efficacy very similar to the green light although
> less effective than the blue light, but it has the advantage of a
> better clinical assessment compared with the other two lights.
>
> \[Slide.\]
>
> The halogen light, also called a spotlight, is advantageous in the
> sense that it is more compact, but the problem is that you cannot
> bring it too close to the baby. It has some significant amount of heat
> emitted that could sometimes burn the infant if you get it too close.
>
> \[Slide.\]
>
> The fiberoptic system, also called Wallaby light, is essentially a
> blanket wrapping around the baby, also called a Biliblanket. It has
> some advantages in that you don\'t have to use eye patches since the
> eyes are not exposed to the light. It is more portable, it is more
> convenient for mother and baby in case the mom wants to breast-feed
> the infant, it becomes more advantageous in the sense that you could
> simply have the blanket wrapped around the baby, and the mom can
> continue to breast-feed the infant while under phototherapy.
>
> It is also used quite often in the home phototherapy setting. The
> disadvantage is that it has much lower spectral power.
>
> \[Slide.\]
>
> In fact, the study by Dr. Gale and Holtrop comparing the fiberoptic
> versus conventional, in this case they used halogen lamp as a
> conventional therapy, showing that there is less decline in bilirubin.
> The yellows are fiberoptic and the black bar are the conventional. You
> will see the decline in serum bilirubin is much greater particularly
> in the Holtrop study, which has a p-value of 0.05, in the conventional
> therapy versus fiberoptic system.
>
> So, one of the disadvantages of the Wallaby is that because of the
> lower spectral power, it has less efficacy in terms of reducing the
> serum bilirubin level.
>
> \[Slide.\]
>
> The most recently developed system is called light emitting diodes,
> which employs a narrow band of light spectrum, and the commercial
> company in this particular setting used the blue-green combination. It
> is power efficient is one of the advantages, and also has a low heat
> emission, but the one disadvantage is the fact that it is a very
> eye-irritating system. In fact, we just brought two of them into the
> nursery recently, and I have already got nurses at my office door
> saying take those away because it is very irritating for them to watch
> the baby under this LED phototherapy light.
>
> \[Slide.\]
>
> This is the light spectrum of LED, and as I said, the company that
> developed this particular device used the blue-green spectral system.
>
> \[Slide.\]
>
> Again, in terms of efficacy, this is the study by Seidman, published
> in Journal of Pediatrics a couple of years ago, comparing the efficacy
> of LED versus halogen lamp, and you will see that the yellow bars are
> the bilirubin level of entry, the black bar is bilirubin level during
> the therapy, and you will see that there is no difference in the
> decline of bilirubin between the two methods of treating the baby.
>
> \[Slide.\]
>
> Now, let me just say a few words about the different modes of
> phototherapy.
>
> \[Slide.\]
>
> One is the continuous versus intermittent phototherapy. The reason why
> this was studied is the attempt to demonstrate that there is no
> difference in the ability to reduce the bilirubin level and allowing
> for the caretaker or the mothers to breast-feed the infant on an
> off-phototherapy setting.
>
> So, this is a study by Caldera where they compared the percent
> reduction in serum bilirubin of those that were treated with
> continuous phototherapy versus those that were intermittently treated,
> two hours on, two hours off strategy, and showed no difference in the
> ability of these two modes of therapy to reduce the serum bilirubin
> level.
>
> As I said earlier, knowing the kinetics of how the bilirubin is
> excreted or eliminated, the fact that the level of the various isomere
> goes up instantaneously and maintains a steady state, and that the
> rate-limiting step is the elimination phase, it is not a surprising
> finding that there is no difference between continuous versus
> intermittent therapy.
>
> \[Slide.\]
>
> This is another study by Rubaltelli and Lau showing that although the
> numbers were small, there is no difference again in terms of the
> continuous versus intermittent therapy. This is the basis for our
> clinical practice of allowing mothers to feed infants on phototherapy
> because the infant can be taken out of the crib or the isolette and be
> fed a certain period of time, then go back to phototherapy setting.
>
> \[Slide.\]
>
> The other mode of therapy that I would like to just touch on briefly
> is the difference between single versus double phototherapy. This is
> three studies that are put together in one graph, showing that the
> yellow bars are single phototherapy, and the double phototherapy in
> black bars. You will see that in all three studies, there is a
> significant difference in the decline in serum bilirubin between
> single versus double phototherapy.
>
> Again, it is not surprising to see this in terms of a more
> effectiveness in terms of double phototherapy because you increase the
> light exposure of this baby. This is actually the basis for the AAP
> guideline calling for so-called intensive phototherapy. Essentially,
> it is recommending that if you have a level in the high range, that
> the intensive phototherapy using either double or some unit even used
> triple phototherapy, because of the greater efficacy in the double
> bank or triple bank phototherapy setting.
>
> \[Slide.\]
>
> I just have one slide on the home phototherapy. I noticed someone is
> going to speak about this issue. For several years, the committee of
> the AAP was very vague about whether home phototherapy is desirable or
> should be recommended or not until the most recent guideline, which
> was just published a few months ago.
>
> This is the statement set in that guideline that I essentially put
> together here. It says that home phototherapy is an acceptable
> alternative, but the institution for the home phototherapy company
> should set up criteria for eligible infant that will be treated with
> this mode of phototherapy, and that there should be an appropriate
> follow-up of bilirubin levels.
>
> This is one issue that I think is important, and that is to make sure
> the serum bilirubin level is done in the same institution, in the same
> laboratory to maintain a good consistency, and that if the bilirubin
> level does not decline appropriately, then, it should be admitted for
> more intensive therapy.
>
> So, the AAP has decided to endorse this particular mode of therapy,
> but has some suggestion in terms of the guideline of how this
> particular mode of therapy be, not regulated, but supervised by a
> person within the region.
>
> \[Slide.\]
>
> Now, there are a number of side effects known of phototherapy. Many
> years ago I actually did a study using fairly crude methodology to
> document that the insensible water loss is about 50 percent higher in
> the infants who receive phototherapy. It is probably related to the
> heat emitted by the phototherapy and the increased respiratory rate,
> which is also a finding that we documented in order to maintain heat
> balance. In fact, if heat balance is not maintained appropriately, the
> infant may develop fever or elevation of body temperature.
>
> There is also some documentation that these infants may have loose or
> watery stool, and that the mechanism is not clear, but this has been
> confirmed by a couple other anecdotal studies showing that there is a
> change in the gastrointestinal tract in terms of a more frequent and
> loose, watery stool when the infant is under phototherapy.
>
> I should point out that although insensible water loss is an issue,
> and it has been confirmed by two subsequent studies, Paul Wu and Ed
> Bell have confirmed this observation, that it is probably more
> relevant in the low birth weight infant because the insensible water
> loss is so high, the insensible water loss is indirectly proportional
> to gestational age, so that an infant who is in the 26-, 28-week
> range, the insensible water loss can be three times higher than the
> full-term infant, so the change in the 50 percent would need to be
> accommodated in the fluid balance, otherwise, the infant may get
> dehydration.
>
> But in the term infant, the subject that we are talking about today,
> the insensible water loss is much lower, it\'s in the range of 20
> ml/kg/day, so if 50 percent increase is 10 cc, all you need to do is
> make sure that the infant has enough fluid intake to maintain water
> balance, so it is not a huge issue in the term infant from this
> particular standpoint.
>
> \[Slide.\]
>
> Now, there is also some concern about toxic effect on the optic nerve.
> This was demonstrated in animal study, but human study actually has
> not confirmed this. There was one control trial showing very elaborate
> visual assessment, infants who had received phototherapy versus those
> who did not, and showing no difference in terms of the visual
> performance, but since eye patch is such a benign, non-invasive
> procedure, our current practice is still to use eye patch for babies
> under phototherapy.
>
> \[Slide.\]
>
> Just a few words about low birth weight infants. Although this is not
> the subject of our discussion for this particular committee, I just
> wanted to point out the effect of phototherapy on low birth weigh
> infants is probably more, to me, is more worrisome than the full term
> and near-term infant.
>
> The NICHD study done in the early \'80s suggest that there is a higher
> mortality among the infants who are enrolled in the phototherapy
> group, and there is also some suggestion that phototherapy may have
> some influence on the patent ductus arteriosus, a common problem in
> the low birth weight infant, not in the full term infant, and that
> there is some concern about association with increased incidence of
> blindness due to retinopathy of prematurity.
>
> Again, these are all related to low birth weight infants, but let me
> show you a couple of slides on the second and third bullets here.
>
> \[Slide.\]
>
> This is a study by Warren Rosenfeld showing that the infants\--these
> are low birth weight infants who were subjected to phototherapy\--the
> incident patent ductus arteriosus is lower when they shielded the
> chest with aluminum foil, essentially, that is what they did, compared
> to those that were not shielded.
>
> They didn\'t quite explain why, the increased incidence of patent
> ductus arteriosus was not as clear as it should be. Also, the other
> problem of this particular study is that this is not a blinded study,
> obviously, because they had to put the aluminum foil on the baby\'s
> chest. Also, the assessment of the PDA was not done by echo in those
> days, it was done primarily by clinical assessment, and that may have
> some bias involved in terms of documenting the incidence of PDA.
>
> This had never been confirmed one way or the other, so this remains a
> question. To me, it is not as serious as it seems to be. Also, we now
> have a very good way of treating these infants using the indomethacin
> in terms of PDAs. It is not a concern in terms of morbidity.
>
> \[Slide.\]
>
> There is also some concern about the effect of phototherapy on
> blindness due to ROP, retinopathy of prematurity, and this is the data
> from Yeo, published in Pediatrics about three years ago, showing that
> the OR, the odd ratio for greater incidence of blindness due to ROP is
> 4.48 with a p-value of 0.03 when the peak serum bilirubin level is
> less than 160 micromole/liter, and that the same thing is true for the
> duration of phototherapy.
>
> So, what they are saying here is that if you are aggressively treating
> these infants, these are very low birth weight infants, with a longer
> duration of phototherapy and bring the bilirubin down to a lower
> level, you have a higher incidence of blindness due to ROP.
>
> \[Slide.\]
>
> The problem with this data is that it is a retrospective analysis,
> this is a small sample size, relatively small sample size, and that
> the eye exam was not done uniformly. Again, the results have not been
> confirmed. So, this is some lingering concern that people have in the
> low birth weight infants from the standpoint of phototherapy itself.
>
> \[Slide.\]
>
> Briefly, it is very difficult to assess the effect of phototherapy per
> se on neurodevelopmental outcome because you always have the
> co-morbidity of bilirubin. You use phototherapy only for bilirubin, so
> there is no way you could compare the phototherapy in itself in terms
> of outcome because by virtue of the use of this intervention, you use
> it when the bilirubin is high, so you need to be able to separate out
> the effect of bilirubin versus the effect of phototherapy itself.
>
> Let me just show you a study that Dr. Scheidt did in 1990 using the
> cohort from the 1980s NICHD trial where they enrolled a group of
> infants into the group that received phototherapy when a certain level
> of bilirubin is reached and those that were not treated with
> phototherapy.
>
> \[Slide.\]
>
> What they found is that at one year, the MDI and PDI scores were
> similar between the two groups. These are all full term infants.
>
> \[Slide.\]
>
> Then, when they assessed the six-year-old outcome, they combined both
> pre- and full-term infants, again, it shows no difference in terms of
> the verbal performance between the two groups at six years of age.
>
> \[Slide.\]
>
> Again, in the low birth weight infants under 2 kilograms, they did a
> separate analysis, and again showing no difference between
> phototherapy and the control group in both one- and six-years of age
> in terms of neurological finding\--they were using cerebral palsy as
> the endpoint\--and in developmental performance.
>
> Now, as I said, it is not clear whether this is truly a negative
> outcome from the standpoint of phototherapy itself because you have so
> many confounding variables particularly with respect to the low birth
> weight infants. Many of these infants are sick, they have a certain
> bilirubin label, and we don\'t know what the bilirubin level dictates,
> I mean dictate the neurodevelopment outcome, in a much larger study,
> it is very difficult to assess the phototherapy itself with reference
> to the population that receive this treatment because of
> hyperbilirubinemia.
>
> \[Slide.\]
>
> So, my summary is as follows. Phototherapy, there is no question it is
> an effective treatment for jaundice. There is so many data over the
> last 40, 45 years, showing that it is an effective intervention and
> that the mechanism is well defined. There is no question about how it
> works.
>
> There are some acute effects that are known, and if you are talking
> about full term infants, it is a manageable problem, in other words,
> the increased insensible water loss, the watery stool, and the
> increased respiratory rate, those are minor, to me, a minor effect
> that could be managed without significant concern.
>
> At least in term infants, at least in that one study, there is no real
> significant adverse outcome in term infants. I went through the
> Medline and I couldn\'t find any long-term follow-up. It is amazing,
> in a therapy that has been on-board now for almost 45 years or 50
> years, and yet I didn\'t see any clear-cut outcome study comparing
> directly phototherapy versus no phototherapy.
>
> But I need to point out, in the last bullet, that there are some
> lingering concerns about low birth weight infants because I think, not
> only that there are some concerns about a PDA, the blindness, and the
> one set of data which I did not present today because it really
> pertained more to the low birth weight infant is the data I just put
> together, will be published in Pediatrics sometime in the next few
> months, documenting the association between relatively low levels of
> bilirubin in extremely low birth weight infants\--I am talking about
> infants below 1,000 grams\--between serum bilirubin, much lower level
> than we are talking about with a two-year-old neurodevelopmental
> outcome.
>
> There is significant association. The higher the bilirubin is, there
> is almost a linear relationship between serum bilirubin and the number
> of infants with neurodevelopmental impairment including hearing loss.
> So, there is some concern about low birth weight infants, but probably
> not in the full term infant. That is my conclusion.
>
> Thank you very much.
>
> DR. CHESNEY: Thank you, Dr. Oh.
>
> We do have a few minutes if anybody has questions for Dr. Oh before we
> have our last presentation.
>
> Dr. Freeman.
>
> DR. FREEMAN: Bill, when you measure bilirubin, do you also include the
> measurement of biliverdin? I mean are they separable by the standard
> techniques that we talked about earlier?
>
> DR. OH: No, I think it is bilirubin that we are measuring although,
> yes, biliverdin is not measured, it is bilirubin primarily.
>
> DR. FREEMAN: Okay, but biliverdin doesn\'t show up in those\--
>
> DR. STEVENSON: No, it doesn\'t.
>
> DR. FREEMAN: The second question is do we know anything about the
> neurotoxicity of biliverdin?
>
> DR. OH: I don\'t think we know. Do you?
>
> DR. FREEMAN: No.
>
> DR. OH: I don\'t think we know. If you don\'t measure it, we wouldn\'t
> know what the effect that molecule would be.
>
> DR. CHESNEY: Dr. Newman, you had a question?
>
> DR. NEWMAN: You didn\'t present any data on this, but from my own
> experience, I am probably one of the few general pediatricians here.
> To kind of paint a picture of what phototherapy is like, some of the
> problems with it that you didn\'t mention are that a lot of the babies
> just don\'t like it because they are unwrapped, they have to be
> unwrapped and many babies are much more calm if they are wrapped up,
> often this involves, you know, the baby is in an isolette or away from
> the mom, and unwrapped, which they don\'t like, so they start crying,
> but you can\'t pick them up and comfort them because they are under
> phototherapy.
>
> Then, the mothers start crying, and, you know, the mothers, they are
> three or four or five days post partum, it doesn\'t take very much to
> make them cry, and it is a very\--I think hospital phototherapy, that
> aspect of it, which is that it is upsetting, I would just add that to
> what you mentioned about physiologic effects.
>
> DR. OH: California may be different, but I don\'t see that often in my
> nursery.
>
> DR. CHESNEY: It is clearly a California phenomenon.
>
> Dr. Stevenson.
>
> DR. STEVENSON: Well, being from California where it is always sunny,
> we don\'t have to worry about jaundice that much. One of the comments
> I wanted to make in response to what Bill said is that light, it is a
> drug in the way that it is being used for this purpose, and yet it has
> not been really handled in the way that we handle evaluations for
> particular drug applications.
>
> In other words, there are dose ranges recommended, but no one is
> really monitoring, as Bill mentioned, the doses that are being
> applied, so given all the different light sources and all the
> different ways in which they can be applied in the nurseries, the
> range of doses is considerable, and it is hard to know what, in fact,
> is happening in those environments related to this particular
> medicine, and much more can be done in that regard.
>
> I know that is not the topic of this group\'s concern right now
> either, but the other thing I would like to mention from work that we
> have done, we have published it in the abstract form, but not
> published the paper yet, is that clearly, with the cool white lights,
> in applications in the range that we would expose human neonates to,
> you can see photo-oxidation in translucent small animals.
>
> The expectation is that in translucent human beings like these small
> infants that Bill was talking about, they also would probably be
> accessible to that light, and there could be, in fact, photo-oxidation
> going on in those infants independent of the predominant pathways that
> have been described biochemically, that is, the generation of
> lumirubin in that mechanism.
>
> So, I think there is considerable concern about the use of light as a
> medicine particularly in the smaller infants, and it probably has some
> impact on the larger infants which is just not measurable with current
> technology.
>
> To give you a hint about the patent ductus, again, this would be a
> hypothesis, but we know from the work that we have done that one of
> the potential alternative sources of CO, carbon monoxide, is, in fact,
> photo-oxidation. That has been confirmed in the absence of heme.
>
> So, if you apply light to small translucent animals, you can generate
> carbon monoxide, not only at the surface level of skin, but probably
> in tissues, in sufficient amounts that you could actually influence
> the vascular behavior of a vascular tissue. CO works through the same
> pathways.
>
> So, that is a hypothesis, but it shows you that light, in fact, does
> have an impact and probably needs to be considered is not entirely
> understood with respect to all of its effects in certain categories of
> infants.
>
> DR. CHESNEY: Very interesting. Any other questions?
>
> All right. We will move on to our last speaker before lunch. Connie
> Schomann is a nurse supervisor with the Medstar Visiting Nurses
> Association, and she is going to demonstrate for us how phototherapy
> is administered in the home, and she will review how home visiting
> nurses instruct parents in the proper use of this therapy.
>
> **Outpatient Phototherapy**
>
> MS. SCHOMANN: Good morning. My name is Connie. I am a registered nurse
> with Medstar and I have been doing pediatric home care for seven years
> now. A large part of our pediatric population consists of babies that
> are being followed for hyperbili.
>
> Occasionally, we get babies that are discharged from the hospital with
> phototherapy. Maybe they have had phototherapy for a couple days and
> they are sent home with a blanket to continue their therapy at home,
> but the greatest portion of them are babies that were discharged from
> the hospital between 24 and 48 hours of age without any evidence of
> significant jaundice and the jaundice is picked up after they were
> home.
>
> It might have been an initial pediatric visit, maybe if they had risk
> factors and the doctor wanted to see them in a day or two, and then
> they would pick up the jaundice, or maybe when the visiting nurse
> would go for an early maternity discharge visit, I know in Maryland, a
> lot of insurers provide for a home health visit from a nurse their
> first day or two at home, and we pretty often pick up jaundice at that
> time.
>
> The important thing here I think is that most parents do not recognize
> jaundice in their infant unless they have experienced it before. I had
> had parents tell me, oh, gee, I just thought he had a little suntan
> going, thought he had good color.
>
> I have walked into some homes and could tell from across the room that
> the baby was jaundiced and started thinking about where is the closest
> STAT lab, and the parents didn\'t have a clue. So, you can\'t always
> depend on their assessment of the baby\'s skin color because they just
> don\'t have the experience with that.
>
> So, typically, what happens once the baby gets a blood level drawn for
> serum bilirubin, it might have been at the doctor\'s office or in a
> morning visit, hopefully, in the morning. It takes several hours
> before the report comes back from the lab, and a decision might be
> made that the baby needs phototherapy at home.
>
> Then, you have to contact the DME company, sometimes several of them,
> to find an available blanket, and you also have to talk to the
> insurance company and get authorization for the home phototherapy, so
> it can be day long process just getting this started.
>
> It usually ends up with a phototherapy blanket being delivered to the
> home 9:00, 10 o\'clock at night, so the parents are generally
> exhausted anyway.
>
> Most companies\--this blanket here came from Medstar Medical
> Services\--most companies manage their Wallaby equipment or
> phototherapy equipment along with their oxygen supplies and equipment,
> so that the delivery to the home is actually made by a respiratory
> therapist, who will give the parents some instruction on how to set up
> the blanket and then leave them on their own for overnight until the
> visiting nurse arrives in the morning.
>
> I have Baby Billy here. I had a little girl who very willingly let me
> borrow her baby for demonstration purposes. He is kind of small, he is
> not very jaundiced, but he is a very willing participant, and he
> doesn\'t complain too much, so I will show you how it gets set up and
> what some of the limitations are.
>
> There are some limitations and problems with phototherapy in the home,
> but generally, parents are very happy to learn that they can have this
> treatment at home and not have to go back into the hospital. That is
> not what they want to do and especially when they realize that
> readmission to the hospital means the pediatric unit, and not that
> nice, big family centered care room with the TV and the VCR and the
> separate sleeping accommodations, but it might be a room for two with
> a lounger for mom to sleep in or something like that. So, they are
> very willing to do whatever it takes to be able to stay at home with
> their baby.
>
> When they get the blanket delivered, this is what it looks like. This
> is called a blanket. It is not very soft, it is a little pliable, but
> this is your fiberoptic pad and it\'s a light, a light source if it
> works, the light comes right from this pad.
>
> It needs to be applied with the correct side to the baby. It needs to
> be applied to the baby\'s skin, not on top of their clothing. It is
> wrapped around the baby\'s middle, so that as much of the baby\'s
> abdomen is in contact with the light.
>
> They send these pieces of tape that are absolutely worthless to tape
> it together, so I usually tell parents to use masking tape, electrical
> type, or duct tape. Everybody has duct tape these days, right? It
> works very well to help hold these in place. They tape it around the
> baby with just enough space that the fingers can go in, so that it is
> not too tight and constricting.
>
> The baby needs to be dressed over top of that. Normally, you wouldn\'t
> turn the light on until they were dressed, which means that a T-shirt
> can over top or they can be wrapped in their blanket.
>
> The fiberoptic pad itself does not produce heat, it is cool, so that
> parents need to be instructed that they still need to dress their
> babies or they are going to get cold if they don\'t dress them
> appropriately.
>
> Once they are wrapped, then, you have your baby receiving
> phototherapy. It looks pretty easy, right? But this baby is tethered
> to this machine, it is not very portable. The directions will tell you
> it needs to stay on a firm, flat surface, so you have got this much
> room to move.
>
> It can be awkward, if the mom is learning how to breast-feed, she is
> not very good at it, and then all of a sudden she has got all this to
> deal with, too. It makes it a little bit more difficult.
>
> Basically, they are just tethered to one spot for a few days. I
> usually instruct parents to expect three to five days of phototherapy
> in the home. It does take a little bit longer than when they are in a
> hospital under lights. That way, if it\'s less than five days, they
> are happy.
>
> Basically, that\'s it. Then, when the nurse arrives the next morning,
> her visits consists of head to toe assessment, she weighs the baby,
> and the biggest part about assessment has to do with feeding issues.
> As Dr. Oh talked about, a lot of these babies are breast-fed, and when
> the nurse gets in there and assesses the baby, may find out that the
> baby has lost a lot of weight, maybe 10 percent or more.
>
> If the baby\'s urine output is not very good, maybe the baby hasn\'t
> had any stools since they have been home or last stool was still
> meconium, then, feeding issues have to be addressed. So, a lot of
> times the pediatrician will order supplementation with formula or even
> withholding breast-feeding for 24 hours and using formula instead.
>
> It sounds really easy, but when you have a mom who has been prepping
> herself for breast-feeding her baby for the last six months, and you
> tell her to stop, that can be pretty upsetting. It also can be
> difficult for them to manage because they are usually not prepared for
> formula.
>
> Lactation consultants, they do a great job in the hospital preparing
> their patients, but one of the implementations that they have made in
> recent years is they have stopped giving formula samples to
> breast-feeding mothers because they feel that it encourages them or
> sets them up for failure, \"Here, you are going to need this when you
> can\'t breast-feed.\"
>
> So, they no longer send this home with them, so that means that
> somebody has got to go out and get formula for the baby, they have got
> to get bottles for the baby. They have got to figure out how to make
> the formula.
>
> Then, on top of all that, the mother has got to get a breast pump and
> hook herself up to another machine for 24 hours, every two to three
> hours, to maintain her milk supply So, the visiting nurse plays a very
> large role in helping the parents with that process, to get through
> that, so they can maintain good lactation and meet their goals with
> the baby, and continue to care for their baby at home.
>
> Generally, they are very successful. Occasionally, a baby will turn
> around and have to be admitted because the bilirubin is just not
> responding. Usually, it\'s because of ABO or some other factor, but
> for the most part, we have very successful outcomes with this, but a
> major part of that success, it\'s not just the machine.
>
> I think, if I can put in a plug for visiting nurses, the support and
> teaching and education that the nurses provide are really a major
> factor in the success of this treatment.
>
> Thank you very much for having me.
>
> DR. CHESNEY: Thank you.
>
> MS. SCHOMANN: Any questions?
>
> DR. CHESNEY: Dr. Fost.
>
> DR. FOST: I am trying to get a ballpark idea of the total annual cost
> of home and hospital phototherapy. Can anyone tell me what a typical
> charge for hospital/home phototherapy is, and the approximate number
> of babies a year that get phototherapy.
>
> MS. SCHOMANN: I can tell you that this machine, the rental costs about
> \$100 a day. The visiting nurse, the initial visit for my company is
> \$150 for the initial visit and then \$115 for revisits. They usually
> do visit on a daily basis. And then the lab costs. The nurses usually
> draw a lab each time and transport it. There is usually STAT fees at
> the outpatient lab, usually run around 35 to \$40 for a total
> bilirubin.
>
> DR. FOST: Does anyone have an estimate of the total number of babies a
> year?
>
> DR. NEWMAN: For hospital phototherapy, it is a few percent, it varies
> a lot from place to place, but I don\'t know for home phototherapy.
>
> DR. FOST: So, like 3 percent of 4 million, so 120,000 a year roughly.
>
> DR. NEWMAN: Yes. It might be higher than that. It is 2 percent at
> Kaiser, but they do I think quite a bit less phototherapy maybe than
> some other places.
>
> DR. FOST: And the charge for a hospital\'s phototherapy?
>
> DR. NEWMAN: Figure a few thousand dollars a day, a couple of thousand
> dollars a day probably. But at least when we do a hospital
> phototherapy, it is short, it is about a day. We use three lights, we
> figure just get it over with quick, so it is typically about a day. It
> is much shorter in the hospital, it is not three to five days. It is
> usually a day or two in the hospital.
>
> DR. FOST: Thank you.
>
> DR. CHESNEY: Dr. Nelson.
>
> DR. NELSON: I guess this is for Dr. Oh.
>
> Have there been any studies on the intermittent versus continuous
> issue using the home blanket phototherapy?
>
> DR. OH: I was going to comment that I am not aware of\--the studies
> that have been done were all using the fluorescent lamp, the white
> lamp\--I am not aware of any comparative study between the Biliblanket
> with intermittent versus continuous exposure.
>
> It is probably not an issue because as she demonstrated, the mom can
> breast-feed the baby, so there is no need to discontinue the
> phototherapy.
>
> DR. NELSON: Well, there may not be a need, but from the inconvenience
> I suspect that intermittent therapy is probably the norm.
>
> DR. OH: I suspect if somebody does a comparative study, it will
> probably show the same result as the others, I mean the principle is
> the same. The mechanism of excretion and the elimination is very
> similar.
>
> DR. CHESNEY: Dr. Stevenson and then Dr. Ebert.
>
> DR. STEVENSON: The mechanism is the same, but I think one of the
> points that Bill made would make you suspect that the differences
> would hardly be noticeable, the reason being is the dose that you are
> receiving is quite limited, so it is not a very potent way to treat
> hyperbilirubinemia.
>
> So, most of us who believe that phototherapy is required as an
> intervention would be more inclined to use it intensively in the
> rating flux range where you are going to have demonstrated efficacy.
>
> The difficulty here is not so much that fiberoptic blankets can\'t
> generate an intense light, it\'s the surface area of application,
> which you could see is quite limited, and if you think about the total
> surface area, you are only dealing with part of it, so you are going
> to have a very limited impact on the person.
>
> Also, you say, well, why not get a longer and more convenient tether,
> but then you are farther from your light source and once again you are
> going to lose your power, so there is a limit to how long that tether
> can be, and there is also a limit with respect to surface area as to
> how you can actually apply it.
>
> So, there is going to be not much advantage or difference between
> either having it on or having it off, and that leads some people to
> say if you need phototherapy, use phototherapy and not home
> phototherapy.
>
> I am not being critical of these options. These are only the only
> technical options right now available in a uniform way.
>
> DR. CHESNEY: Dr. Oh, could you clarify for the uninitiated, when you
> talk about double and triple therapy, is that two and three banks of
> lights or two or three colors?
>
> DR. OH: Double is typically what you do is you have an overhead and
> then you put two side, you know, sort of exposing the baby to three.
> Is that what you do in California?
>
> DR. NEWMAN: We just use the halogen spotlight. It makes a circle of
> light on the baby, and the more of them you have, the more of the
> baby\'s surface area you can get covered by one of those circles from
> the spotlight.
>
> DR. OH: There are many ways you could do it, but we use overhead and
> two sides, and sometimes one over one side and one spotlight, so any
> combination would work fine.
>
> DR. CHESNEY: I read somewhere about having the baby lie on this kind
> of bed and the do it over. Would that be called double?
>
> DR. NEWMAN: We typically will have a blanket underneath the baby and
> two spotlights up above.
>
> DR. CHESNEY: Triple?
>
> DR. NEWMAN: We call that triple, yes.
>
> DR. OH: The problem with the blanket and then the light is that you
> already covered the surface, so the light on the top is not going to
> work. You know what I mean?
>
> DR. NEWMAN: We have the blanket. The baby is lying flat on top of the
> blanket.
>
> DR. CHESNEY: Dr. Stevenson.
>
> DR. STEVENSON: One quick comment. You can begin to see the complexity
> of the application of this medicine. You can imagine the shadowing
> with numbers of halogen lamps and also these different devices.
>
> So, if you look critically at the light exposure and the shadowing on
> a particular infant when people are doing their intensive
> phototherapy, tremendous variation across the surface of the
> individual and differences between institutions in terms of where the
> lights are relative to the individual.
>
> So, dose is very hard to control unless you are measuring precisely,
> and then it is only good for where you measure it.
>
> DR. CHESNEY: Dr. Nelson.
>
> DR. NELSON: Just a follow-up question. Have there been no head-to-head
> comparisons controlled for starting bilirubin level in the absence of
> any other condition that would increase production of looking at
> in-hospital intensive phototherapy short of duration against home less
> intense, longer duration, had there been any head-to-head comparison
> at all?
>
> DR. OH: I don\'t think so. That would be a good study to look at, I
> mean a good issue to address, home versus hospital setting. I had the
> same kind of strategy in our place, and I don\'t use home phototherapy
> a lot. Once the kid needs the phototherapy, they get admitted for
> phototherapy, very intense, and they stay one to two days and go home.
>
> DR. CHESNEY: Dr. Oh, would you comment on the rebound? I think I read
> in our materials that there has been a question of rebound in
> bilirubin. If you do just a one day intense, do you get any rebound or
> more than you might with a prolonged?
>
> DR. OH: Typically, what we do with the rebound issue is once we stop
> the phototherapy, we generally keep the baby in the hospital for
> another 6 hours and do a rebound bilirubin, and if that doesn\'t go
> up, then, we send the kid home, or if there is a good follow-up
> system, we would do a rebound 12 hours, 24 hours later.
>
> DR. CHESNEY: How significant is the rebound?
>
> DR. OH: Actually, not very much. Most of the kids will be down to
> between 12 to 15, 10 to 15, and then once you get the rebound, to
> maybe 15\'s. Usually, the age also is much older and we have less
> concern on the kid who is two days old versus 6 days old.
>
> So, even if the kid rebound to the 15\'s, we are not as concerned as
> if it were to be two days old.
>
> DR. CHESNEY: Is doing a rebound level standard of care?
>
> DR. OH: I don\'t think so. David?
>
> DR. CHESNEY: Dr. Stevenson.
>
> DR. STEVENSON: Just Maisels has actually done recent work on this and
> made the case that for the otherwise well term infant who has this
> application, it is not required because it\'s such an infrequent
> event.
>
> The one caveat that I would suggest is that if you have a hemolytic
> condition where you need to reduce the pigment at a very high rate,
> it\'s in those contexts where you might see a rebound if your
> conjugating capacity is not improved. That is typically what you see.
>
> If you make the mistake of doing an exchange transfusion on a child
> who has been breast-feeding, that is really the cause of their
> jaundice, you will not see any rebound whatsoever. If you do an
> exchange transfusion on a baby that has been producing bilirubin at a
> high rate with this large amount, not only in circulation, but also in
> the body, you will see a rebound that can be quite dramatic in that
> context.
>
> So, I would say in the context of increased production, you are more
> likely to have a rebound, but for the general population that is not
> hemolyzing, which is most everybody, then, it should not be a problem.
>
> DR. CHESNEY: Thank you.
>
> It\'s 12:15 and I am collecting a list here if any of you would like
> to add to it of interesting phrases, so this morning we have
> \"weller\" babies and we have \"excited\" bilirubin, and we have
> another use for duct tape.
>
> I think we could break for lunch now and if everybody could please be
> back at 1 o\'clock, we are going to hear from the mother of a child
> who has kernicterus on behalf of her organization.
>
> Thank you.
>
> \[Whereupon, at 12:20 p.m., the proceedings were recessed, to be
> resumed at 1:00 p.m.\]
>
> [A F T E R N O O N P RO C E E D I N G S]{.underline}
>
> \[1:00 p.m.\]
>
> DR. CHESNEY: Our first speaker this afternoon is Sue Sheridan, who is
> president of PICK, the Parents of Infants and Children with
> Kernicterus. Susan is the current president and the co-founder of
> PICK. She is going to present the perspectives of her organization and
> of a parent of a child with kernicterus. I understand she is going to
> have a short video, as well as a PowerPoint presentation.
>
> **A Parent\'s Perspective**
>
> MS. SHERIDAN: Thank you. I am David Stevenson. I am glad to see you
> made it back because I notice you have 45 minutes, and I have 20, so I
> would like to ask if I could borrow 5 minutes of yours. Thank you.
>
> Also, Tom Perez, when I was coming up here, asked me if I was nervous
> about today, and typically, I really don\'t get nervous when I speak
> about this because I am so passionate about preventing kernicterus,
> but if I am nervous today, it is because I want to make a difference,
> I want every word that I say today to influence you on helping prevent
> kernicterus.
>
> I am very grateful and honored to be included in this and to be quite
> honest, I am relieved that this dialogue is taking place today. I have
> been following this debate for almost a decade.
>
> I look at kernicterus and, well, the prevention of kernicterus as
> actually a patient safety initiative rather than how to manage
> jaundice. I am passionate about patient safety, not only because my
> little boy suffered brain damage from kernicterus, but I also lost a
> husband last year because of a medical error.
>
> He had a cancer that was diagnosed properly as a sarcoma, but it was
> communicated to us as a benign tumor, so while the pathology was lost
> for six months in the mail, the tumor grew into my husband\'s spine
> and it eventually killed him.
>
> So, I hope that my words today can reorient you to a patient safety
> focus because there are a lot of things that we can do to prevent harm
> to babies and daddies.
>
> As you know, my name is Susan Sheridan. I am from Eagle, Idaho. I have
> two children. My little girl McKenzie, is 5. She had severe
> hyperbilirubinemia from AO incompatibility. She got a TSB, she was
> tested, she was diagnosed, she was treated, and she is fine today.
>
> I have a little boy Cal, Cal Patrick, who is 8. He was born a well
> baby\--somebody asked a question about well baby\--almost 38 weeks
> gestation. He was visually assessed at 16 hours to be jaundiced, at 23
> hours to be jaundiced, at 33 hours to be jaundiced with no TSB taken.
> He was discharged head-to-toe jaundice, no TSB with the words that
> jaundice is normal, don\'t worry, put him in the sunlight if you are
> worried about it.
>
> I took Cal back two days later to the pediatrician. He was becoming
> lethargic and his suck became weak with breast-feeding. I took him to
> the pediatrician. He was board certified, he\'s an AAP fellow, was
> familiar with the AAP guidelines. He sent us home to wait 24 hours.
>
> Again, no worry, no indication that anything abnormal was going on.
> Well, we chose not to wait those 24 hours because our son was
> deteriorating, and we took him to the hospital. When Cal was admitted,
> his bilirubin was 34.6.
>
> Again, there was no concern. We were told that kernicterus did not
> happen anymore in the United States, and they chose not to do a blood
> exchange transfusion because he was close enough to 30, they recalled,
> which was the new benchmark that the AAP had indicated for an exchange
> transfusion. This was their interpretation of the AAP guidelines.
>
> So, we watched Cal. Twenty-four hours after readmitting Cal\--and this
> was a hospital that delivers 5,500 babies a year, this is a
> JCAHO-accredited, Level 3 NICU hospital, so this was not a country
> hospital\--we sat there for 24 hours. At 24 hours, Cal began arching
> his neck backwards, and he developed a high-pitch cry that sounded
> kind of like a cat, it was very disturbing.
>
> I indicated to the doctor something was happening to my son, and the
> nurses of 20 years experience on the pediatric floor, neurologists,
> ENT, and pediatrician, we all watched Cal suffer brain damage before
> our eyes, and we didn\'t know it. Nobody knew that these were the
> classic indications, these are the classic symptoms of the onset of
> bilirubin encephalopathy.
>
> They used phototherapy, a double phototherapy for Cal\'s treatment,
> and it failed him. Like 25 other babies in the pilot registry that I
> think Tom was talking about earlier today, Cal has kernicterus.
>
> Actually, Cal likes to be a part of my presentation sometimes and he
> was helping me prepare a presentation a couple weeks ago, and he knew
> his sister when she was born, when she had severe hyperbilirubinemia
> and was treated, and he asked me, \"Mom, why doesn\'t McKenzie have
> kernicterus?\"
>
> I thought that was an excellent question, and that is precisely why I
> am here today. I am also here today, as they mentioned, as co-founder
> and president of PICK. PICK stands for Parents of Infants and Children
> with Kernicterus.
>
> We formed about two and a half years ago, right after I was invited to
> testify at the AHRQ First National Summit on Patient Safety and
> Medical Errors. My son Cal was highlighted in a USA Today feature
> article, and then that day I received all day phone calls from parents
> throughout the United States.
>
> So, we got together and we formed PICK, and PICK\'s mission is to
> eradicate this preventable devastating condition by partnering with
> the healthcare system, by implementing a universal systems-based
> approach. We believe that by implementing a universal bilirubin screen
> with the use of the Bhutani nomogram, we can significantly reduce
> kernicterus.
>
> To demonstrate our partnership, PICK\'s partnership, I want to show
> you a video that we produced just this past January with a generous
> grant from Partnership for Patient Safety. This will show eight moms
> who have children with kernicterus, two kids with kernicterus are on
> this tape, and then what we refer to as our dream team. These are all
> the government agencies that have joined PICK, partnered with PICK, to
> eradicate this condition.
>
> \[Videotape shown\]
>
> MS. SHERIDAN: In preparing my remarks for today, I was inspired by the
> mission of the Health and Human Services Department, which reads, \"To
> protect the health of all Americans and provide essential human
> services especially for those who are least able to help themselves.\"
>
> I think newborns would fall under that category.
>
> Much of the debate today has been about prevalence on kernicterus, and
> I guess it all depends on perspective - is the glass half empty or is
> the glass half full.
>
> Frankly, the answer to what is the prevalence of kernicterus is we
> have no idea how much kernicterus is out there. Anybody who is
> guessing is doing just that, you are guessing. We know of 125 children
> in the pilot kernicterus registry that has been shared voluntarily by
> doctors, families, and attorneys.
>
> That is like I think Tom said the tip of the iceberg. These are kids
> that are so severely affected that they are hard to miss although my
> son wasn\'t diagnosed until he was 18 months old because either the
> doctors wouldn\'t or they couldn\'t. It\'s a tough diagnosis to give.
>
> But, you know, I was actually somewhat disturbed that in the binder,
> it referenced prevalence at 1 in 250,000 because that is a guess. What
> about the rest of the kids in that spectrum? No one will argue with me
> that when there is any kind of disorder, you have got the very severe
> down to the very mild. We are not capturing the rest of that
> population. We have got the very severe in this pilot registry.
>
> But even if we accept the guess at 1 in 250,000, I ask you, is that
> acceptable? You know, I ask you, what is rare, what is rare? It is not
> acceptable in other industries. It compares to the number of children
> that choke and died on toys in 1998. Twelve kids died because of
> choking on toys. Yet, millions of dollars were spent on recalls,
> labeling, and the reengineering of toys because of those deaths.
>
> It compares to the number of children that died annually from
> strangulation from venetian blinds, yet 800 million of those were
> recalled because of that.
>
> There was a popular toy made by Playschool that was called the
> Klackeroo. I actually saw a big poster in my pediatrician\'s office
> about the recall, how dangerous this was for children, that we call
> this 1-800 and we could get reimbursed for this toy, so I called the
> number, and it was the National Product Safety Commission.
>
> I asked about the history of this toy, and there was a web site for me
> to go to, everything about this Klackeroo, millions were being
> recalled, and I asked about the deaths and injuries. They had 12
> reported complaints from parents, no deaths, on injuries, 2 pieces
> were found in babies\' mouths.
>
> So, 12 in the other industries is intolerable. Millions of dollars are
> spent to protect our babies. Why are our babies and our children safer
> in other industries than they are in the healthcare industry? It
> doesn\'t make sense to me.
>
> So, when we talk about rare, even though 1 in 250,000 kids, I think it
> tragically underestimated. In other industries, it would be
> outrageous.
>
> Action by our regulatory agencies, the FDA, the National Consumer
> Product Safety Commission, their actions, their bans, and even their
> fines on industry is not due to prevalence, it is due to the perceived
> risk. It is due to the potential harm to Americans.
>
> So, nobody knows the prevalence, but let\'s, instead of trying to make
> the number 1 in 500,000, 1 in 700,000, why aren\'t we looking at the
> other way around? Instead of saying of those 125 kids in the pilot
> registry, you know, some of them may not be, well, some of them may
> be, and what about these other kids that have mild auditory neuropathy
> and mild cerebral palsy, instead of saying well, it is probably not
> due to kernicterus, why don\'t we turn that around and say, gosh, that
> could be due to kernicterus, and the reason is because bilirubin is a
> toxin.
>
> Bilirubin, like Tom said, is a brain poison. It\'s a naturally
> occurring neurotoxin. Sure, there might be some antioxidant benefit,
> but, you know, a glass of red wine to end the day is also good for
> you, but two bottles a day is too much. So, you know, bilirubin hurts
> babies.
>
> This morning I heard the AHRQ evidence-based report, and I read that
> report, and something in that report, it talks about that the
> preponderance of kernicterus cases occurred in infants with serum
> bilirubin levels over 20. This is evidence. This was in the AHRQ
> report.
>
> Yet, the AAP recommends exchange transfusion at 25 and even 30. I must
> ask this committee, why is the healthcare system complacent about the
> dangers of hyperbilirubinemia, the documented dangers of a neurotoxin?
> How can we knowingly and willingly take these babies into a known and
> documented danger zone?
>
> And like it was expressed earlier, how do we know what the long-term
> effects of this exposure of hyperbilirubinemia is now that kids in the
> 1990s to present, they have been exposed to hyperbilirubinemia at
> higher levels for longer periods of time? We do not know the effect of
> this on their long-term development.
>
> As a matter of fact, I feel that Cal, Cal was born in \'95, the AAP
> guidelines came out in \'94, the kinder, gentler approach, and, of
> course, the AAP had no intention of the reemergence of kernicterus.
>
> But how did this complacency, how did this complacency happen, and
> now, from this, I have always felt that Cal was an in an undisclosed
> clinical trial, nobody knew what was going to happen to our children
> with these longer duration and higher bilirubin values.
>
> I don\'t believe there is evidence of safety at the level of 25 and
> 30. Sure, some kids don\'t get kernicterus, but there are a lot of
> kids who do get kernicterus.
>
> As a mom, the complacency about hyperbilirubinemia is very concerning.
> In comparison, other toxins, such as lead, get a lot of attention,
> financial support, and vigilance.
>
> I looked at the comparison with lead because I wanted to see what
> industry does with other toxins. They are both not good for children,
> they are preventable types of brain damage, and there is no known
> threshold for the toxic effects of either.
>
> Right now in the United States, it is estimated that 800,000 children
> have elevated, what they call BLLs, blood lead levels over 10 mg/dl.
> By contrast, 2.3 million children develop elevated bilirubin levels
> each year, and 1 in 700 develop bilirubin over 25, which is well into
> the danger zone.
>
> There has been 1 death from lead poisoning in the past decade. That
> was issued in a MMWR put out by the CDC. There have been 6 documented
> deaths that we know of from kernicterus. As we know, they don\'t do
> routine autopsies on newborns, so we don\'t really know the full
> number, but we do know that 6 have died in that same period of time.
>
> So, why is it more important to focus on lead, and not kernicterus? I
> think we need to raise the level of awareness on the toxicity of
> kernicterus, it hurts babies. Also, the CDC has announced or they have
> determined that BLLs over 80 can cause hearing loss and brain damage.
>
> So, as a response to that, the HHS\'s Healthy People 2010 Initiative
> has set a national goal of eliminating BLLs in excess of 10, a level
> far below the danger zone.
>
> This illustrates the need to institute a goal for eliminating
> bilirubin levels over 20 when exchange transfusions and vigilance in
> testing were used and kept bilirubins below 20 historically,
> kernicterus effectively disappeared.
>
> I want to tell you a little bit about my son Cal. He is a bright and
> happy little boy. He loves Pokemon. He loves playing with his sister.
> When asked what he would like to do when he grows up, his answer is to
> be the best daddy in the whole wide world.
>
> He also aspires to be a film maker. Sadly, however, Cal is trapped in
> a body that simply doesn\'t work. He has athetoid cerebral palsy. He
> has uncontrolled movements of his arms and legs. He can\'t walk. His
> speech is very impaired. He has neurosensory hearing loss. His eyes
> crossed when he was 10 months old that were surgically repaired. His
> front teeth have enamel dysplasia problems. He drools. When he gets
> sick, he is reduced to the functional level of a 6-month-old.
>
> Cal can\'t go potty by himself. He is not invited to birthday parties.
> He can\'t tie his shoes. As a matter of fact, I don\'t think he can
> even itch his head.
>
> I have titled my presentation Warning, Bilirubin is a Toxin: Who is
> Keeping Newborns Safe From the Hazards of Jaundice? I chose this title
> because, like the visiting nurse was saying, parents have no clue that
> bilirubin is a toxin and that parents are totally unaware that this
> could hurt their baby.
>
> When we get a toy, when we get a package, when we get wrapping paper,
> when we get tape, when we get household products, when we get shampoo,
> they all say warning, this could harm your baby. Why babies don\'t
> come with this warning tattooed on them?
>
> I ask you who is going to keep our babies safe from the neurotoxic
> effects of jaundice. I am afraid that the answer right now is nobody.
>
> I mentioned that after the AHRQ testimony, USA Today did an article on
> primarily my son, but how two medical errors had affected our family.
> It was that day that I was called by several families throughout the
> United States thinking they had the only child with kernicterus. As a
> matter of fact, I got a call from a daddy from a NICU in Alabama. It
> was 9:00 a.m. in the morning, I had just got this paper out, and his
> daughter was in the NICU with a bilirubin of 33.
>
> USA Today got such read response that they issued this within 10 days,
> and they interviewed other moms about their children and their brain
> injury. As a matter of fact, the day that this came out in USA Today,
> 6 of us moms were on a plane headed to Chicago to meet each other, and
> we actually attended an AAP preconference workshop on
> hyperbilirubinemia and kernicterus.
>
> When we were there, we decided this was an emergency. We met two other
> families with children with kernicterus while we were there. So, we
> formed PICK, Parents of Infants and Children with Kernicterus.
>
> We recruited the nation\'s top bilirubin researchers. We developed a
> mission objective, a timeline. We actually kind of launched it like
> you would a small business. This is our web site which is being
> updated actually today. That film that you saw will be on our web
> site. There is going to be an interactive nomogram and stories about
> children who suffer brain damage from kernicterus.
>
> We hosted the first parent health care workshop that some of you in
> this room were at. The moms invited all of the HHS agencies that we
> could think of along with researchers, Boston Children\'s Hospital,
> Harvard School of Public Health. We showed them the problem. We showed
> them videos of our kids and their medical records.
>
> We proposed a solution by the researchers, that was a universal
> systemwide approach to make sure all babies received the same level of
> safety. We thought by the implementation of a universal bilirubin
> screen, the use of the nomogram was the first step.
>
> The Joint Commission within two months issued a sentinel of an alert.
> USA Today again issued another article. CDC, a month after the Joint
> Commission issued their alert, issued an MMWR on the return of
> kernicterus, and the National Quality Forum, if you are familiar with
> them, they issued a list of 27 adverse outcomes that should never
> happen in the United States, and PICK campaigned for kernicterus being
> one of them, and it is the only pediatric issue that made the list.
> They defined kernicterus as damage from bilirubin or bilirubins above
> 30.
>
> The Boston Globe covered this, as well, and several other periodicals
> and magazines and newspapers.
>
> I wish I could tell you that Cal\'s story is unique. I wish I could
> tell you that he has the only case of kernicterus in the United
> States, but the tragedy is that Cal\'s story is not, as you know.
>
> When I met the moms all in Chicago when we formed PICK, we realized
> that our stories were all the same. Our newborns left the hospital
> well babies without a bilirubin test, just like 80 percent of the
> babies in the pilot registry.
>
> We were told not to worry, we were told that this was normal. The
> parent education consisted of a handout put in the diaper bag. All of
> our children of the original six PICK moms were born in large,
> accredited JCAHO-accredited hospitals with NICUs. Most of the
> pediatricians that managed our children\'s bilirubin were AAP fellow
> and board certified.
>
> The moms that I know, we all questioned our babies\' symptoms - the
> lethargy, the poor suck. We even took our babies to pediatricians and
> to the hospital. We categorized unfortunately as over-concerned
> first-time mothers.
>
> I am going to go off on a tangent because people earlier were asking
> question about cost-benefit, and I want to share some numbers with
> you. When we met with the government agencies, we did our own
> analysis, and actually we did an analysis on the cost-benefit of
> testing all babies, doing a bilirubin test that costs around a dollar.
> It may vary per institution.
>
> The cost of kernicterus is staggering, as you heard. My son\'s life
> care plan\--and this is without fluff\--this is without powered chairs
> and remodeling my home to accommodate these, is \$10 million, and that
> is because my son needs attendant care. All of these kids will need
> attendant care for their lifetime.
>
> In 1998 dollars, for attendant care for a certified nurse assistant,
> that was \$7 million right there. Now, some of those kids you saw up
> there are on feeding tubes, they are on baclofen pumps. They aspirate,
> they have to be suctioned. They are on massive doses of drugs. They
> need R.N. care, and those kids\' life care plans are \$25 million.
>
> The cost of phototherapy to our nation, if you go to the AHRQ Hospital
> Care Utilization Project, HCUP, or is it the Health Care Utilization
> Project, they can give rough numbers. It is not perfect data. But the
> amount is what is billed to patients. Phototherapy, they showed I
> think it was \'98 or \'99 numbers, around 100,000 kids, primary
> diagnosis, this is primary diagnosis, so other kids are coming in
> septic or other problems, primary diagnosis was hyperbilirubinemia,
> around 100,000 kids at a cost of approximately \$700 million a year.
> That is not cheap.
>
> Our children, the public school system, Cal, in Idaho, instead of
> \$50,000 for his education for 12 years, will cost the education
> program half a million. So, you can do the math, because they have to
> use special bus transportation, special ed., physical ed., there is
> therapists, assessments, they are very expensive children. As a matter
> of fact, they rate, I think the highest that the CDC does on the
> economic burden of disability, our kids are the most expensive.
>
> You saw the partnerships that we have formed. NIH, March of Dimes,
> Healthy Mothers, Healthy Babies have joined us. Of course, our mission
> is to prevent kernicterus. In analyzing and just knowing all the moms
> and kids with kernicterus, we are concerned that this is not going to
> disappear with the status quo.
>
> The AAP still recommends visual assessment of jaundice. This is
> guesswork. And their guidelines unfortunately are not followed. I mean
> Tom mentioned that study he did I think on phototherapy, that of the
> kids that the AAP recommended phototherapy, 55 percent didn\'t even
> get it.
>
> So, although the guidelines went through a very long thought process,
> pediatricians simply do not follow them, and to change doctor behavior
> will take decades. Bilirubins are not routinely taken. Neonatal blood
> type and Coombs are no longer done or they are no longer the standard
> of care.
>
> Home Health, to be honest, is disappearing because of financial
> constraints. Timely post-discharge follow-up doesn\'t happen in the
> real world, and kernicterus cases are not being reported because of
> gag clauses, like it was alluded earlier that kernicterus
> unfortunately ends up in litigation, and parents and doctors are
> gagged quite often to come to a settlement.
>
> Our littlest citizens are being harmed by the subjective and
> unscientific approach to jaundice management. Guesswork must be
> eliminated. Our systems-based approach must be implemented. Right now
> in the United States, any newborn is still at risk of developing
> kernicterus. Newborns are not safe.
>
> Who is responsible for that? Nothing has happened since my son was
> injured. A reporter asked me, well, what did I expect. I expected all
> hospitals to stop everything they did, implement a universal screen,
> implement something like an aircraft would do if a 12-inch screw was
> found faulty, they ground all planes, they change it, the public is
> safe. Eight years later, nothing has happened.
>
> All 50 states routinely screen for PKU and hypothyroidism. Babies are
> screened now for their hearing. Why aren\'t we screening babies, why
> isn\'t there a universal screen for bilirubin? How many tests must be
> done to prevent that one case of kernicterus as some of the data
> showed? I think it\'s a disturbing way to look at how we need to
> prevent kernicterus, to be honest. All of them is the answer. We need
> to screen all of them.
>
> I recently read an article in Public Health entitled \"A Conversation
> on Medical Injury.\" It said that to trigger the level of reform that
> is so clearly mandated here, we cannot rely on the healthcare
> professional or stakeholder organizations. We, the public, must demand
> it.
>
> As parents of infants and children with kernicterus, we accept this
> responsibility. We accept this responsibility to partner with you and
> to trigger the reforms necessary to eradicate this. We ask the same of
> you.
>
> We, the parents, unite to prevent kernicterus. We unite to demand
> national implementation of effective understand management standards,
> policies, and interventions to prevent what has happened to our
> babies, and we unite for a call to action to keep our newborns safe
> from the toxic hazards of bilirubin.
>
> I am going to start showing you a list of children in the pilot
> kernicterus registry. They are not anecdotes, they are our children. I
> cannot say with any certainty how many more suffer in darkness because
> their condition was never diagnosed.
>
> I speak for the parents of the 125 identified in the pilot registry at
> Pennsylvania Hospital. I speak for the parents of the countless
> children who have remained undiagnosed and for parents of unborn
> infants who will soon be diagnosed with kernicterus, but most of all,
> I speak for the children with kernicterus, who are prisoners of their
> disabled bodies and cannot speak.
>
> As you deliberate tomorrow, I hope you will be inspired by the mission
> of HHS, particularly the part about protecting those unable to protect
> themselves. You and your sister agencies have a remarkable history of
> protecting children from other hazardous products and substances.
>
> The time has come to apply that same commitment to protecting our
> babies from the hazards of jaundice. As you read this list, I appeal
> to you please do not attempt to minimize the occurrence of
> kernicterus. We do not know.
>
> Please do not attempt to minimize the human devastation or the
> financial impact that kernicterus has on babies, families, and
> society. Please provide the same level of safety and protection that
> you would with other toxins and hazardous substances and commit to
> putting kernicterus back in the history book where it belongs.
>
> I challenge you to ask yourself when you meet tomorrow would you allow
> your own newborn\'s bilirubin to exceed 20? Tomorrow will be a big
> day. You will be making significant choices regarding jaundice
> management. I ask that you put the newborns\' safety at the top of
> your list, dismissing the status quo, personal agendas, professional
> aspirations, and cost-cutting mandates from employers.
>
> Statistically speaking, what is statistically significant when it
> comes to a human life? What is more important than the safety of a
> newborn?
>
> I close my remarks with a reflection of the wisdom of a child. But who
> knows you have the power to protect others, he said, quite simply,
> like you saw on the film, prevent this. I have to tell you that I was
> there during the filming, and the producers simply asked Jess if he
> had anything to say to the world, what would you say, and that was his
> remark. It was totally unsolicited, totally unplanned, but straight
> from his heart.
>
> So, in looking at these names and these numbers, or not the names,
> numbers, I ask you how many more names do we need before we take
> immediate sweeping dramatic action.
>
> Thank you.
>
> DR. CHESNEY: Thank you very, very much. You made many, many points for
> all of us to consider and reconsider.
>
> Our next speaker is Dr. Marshallyn Yeargin-Allsop, who is a medical
> epidemiologist with the Center on Birth Defects and Developmental
> Disabilities at the CDC. She is going to describe for us the CDC\'s
> kernicterus surveillance activities.
>
> **Kernicterus Surveillance**
>
> DR. YEARGIN-ALLSOP: Thank you very much for the opportunity to update
> you on CDC\'s activities in the area of kernicterus surveillance. I
> have heard Sue speak a number of times, and she is a tough act to
> follow.
>
> \[Slide.\]
>
> I would like to just present an overview, a framework, a public health
> framework for developmental disability surveillance because
> surveillance of kernicterus is put into that framework of what we do
> in the area of developmental disabilities.
>
> The first step in this process for us is to develop population-based
> surveillance systems, and the purpose of those systems is to monitor
> prevalence rates, trends, and prevention programs.
>
> The surveillance systems can also provide a registry of cases, and
> these cases can be used for the purposes of service provision or
> provision of treatment. The cases from the surveillance system can be
> used, as well, to create epidemiologic studies, studies where the
> cases are compared to non-affected children or controls in order to
> identify risk and protective factors and the results from the
> epidemiologic studies can address public concerns.
>
> An example would be looking at whether there is an association between
> maternal smoking and mental retardation or cognitive impairment in the
> children.
>
> The third step in this process is to design prevention programs, and
> these programs promote health education and prevention strategies and
> also inform public policy.
>
> \[Slide.\]
>
> I like to compare the complexities of surveillance of kernicterus with
> the complexities of surveillance of developmental disabilities, and we
> have about a 20-year history at CDC beginning in the early \'80s. We
> were looking at the establishment of surveillance for a number of
> developmental disabilities, so based on our 20-year experience, we
> think that we can speak well to the complexities, as well as the
> challenges of developmental disability surveillance.
>
> The first point is our surveillance is based on outcomes that describe
> functioning in children. However the case definitions and the
> conditions are attributable to an impairment in physical, cognitive,
> speech or language, psychological or self-care areas. So, we have this
> comparison of functioning with a level of impairment.
>
> The second point related to the complexity is measurement issues. For
> example, we look at surveillance of mental retardation, and our case
> definition for mental retardation is an IQ test score based on a
> standardized test.
>
> Now, that is objective criteria that we used, but we also do
> surveillance for autism, and when we look at autism, we are looking at
> a range of behaviors, so we have more subjective criteria that may be
> implemented in order to look at surveillance of autism. The behaviors
> are based on the DSM-IV criteria from the American Psychiatric
> Association.
>
> So, the point is that measurement issues are not straightforward when
> we are looking at outcomes related to developmental disabilities.
>
> Our surveillance in metropolitan Atlanta is population based, and we
> have tried to implement this in other areas of the country, as well.
> That means that we define a geographic area and we try to count every
> case within that geographic area.
>
> Although there may be some limitations of that, we feel that our
> population-based surveillance has been informative, such as the
> prevalence rates of autism that we just reported, and it is viewed as
> a landmark study because we don\'t have any other population-based
> data from the United States.
>
> In summary, all of these issues can make generalizing results from our
> population-based surveillance system difficult or impossible to
> interpret, so we always issue some caution we are trying to generalize
> from limited population-based data to say national figures related to
> prevalence.
>
> \[Slide.\]
>
> Let\'s look at the complexities of kernicterus surveillance and how
> they might be similar to surveillance for developmental disabilities.
> Kernicterus presents as a range of impairment and associated
> conditions. Kernicterus is defined as brain damage that is associated
> with athetoid CP, hearing loss, vision impairment, dental dysplasia,
> and sometimes mental retardation.
>
> As we have heard and as we are probably aware, there have been changes
> in the level of awareness and the use of the diagnosis over time. We
> believe that some of the younger physicians may not have ever seen a
> case of kernicterus and may not be aware of the dangers of high levels
> of bilirubin in terms of causing brain damage.
>
> There is also variability in how cases of kernicterus are diagnosed.
> We don\'t have a gold standard in terms of the number of physical
> findings or the number of behaviors, the number and the pattern that
> are necessary to establish a diagnosis of kernicterus, and that means
> a clinical diagnosis of kernicterus.
>
> Of course, there is early onset, but often the diagnosis is delayed
> because these features appear over time.
>
> \[Slide.\]
>
> From a historical perspective, there has never been any systematic
> population-based surveillance of kernicterus in place to monitor
> kernicterus or hyperbilirubinemia. Sue said it best. We don\'t know
> the prevalence of kernicterus in this country.
>
> We do have some case reports from convenience samples or select
> populations, such as from select hospitals, self-reported cases. We
> have information from medical insurance records, but these do not
> represent a systematic approach to looking at the prevalence, and
> there is no accepted standard for surveillance definition, such as
> what would the cutoff be for surveillance of kernicterus.
>
> \[Slide.\]
>
> Therefore, a true population estimates are not known to date. We do
> have I believe now it is more than 100 cases reported from 1984 to I
> think January of 2002, and these are case reports from a convenience
> sample. They have been very informative. These are numerators, they do
> not have denominators because these are children of different ages
> from different geographic areas, and therefore, we can\'t really
> attach a rate to the cases that have been identified. So, we can\'t
> really answer the question of whether kernicterus is on the rise.
>
> \[Slide.\]
>
> In summary, we have issues related to the case definition of
> kernicterus. There is debate about what an appropriate cutoff would be
> from an epidemiologic standpoint. It is a low prevalence condition,
> however, it would require a substantial population in order to detect
> cases.
>
> There is a lack of recognition because it\'s an acute event with
> specific features, but the permanent damage and the long-term clinical
> features do not appear until sometimes even years after the insult,
> and also the litigation may be a possible deterrent for clinicians
> identifying cases.
>
> \[Slide.\]
>
> So, what has CDC done in this area? Well, as Sue pointed out, there
> was a call to action from PICK. In early 2001, there was a meeting and
> CDC was invited to participate, and we became aware of the problem of
> the reemergence of kernicterus.
>
> When we left the meeting, we thought that we could go back and
> establish the prevalence of kernicterus looking at some existing
> datasets. So, our first look was looking at the national hospital
> discharge data, and we looked at years 1989 to 1997, and although
> there were many children with codes of hyperbilirubinemia, there was
> no way to distinguish between those children who had severe
> hyperbilirubinemia from those milder cases. We also found that
> kernicterus codes were not readily used in that we found no cases of
> kernicterus when we did our initial look at data from the national
> hospital discharge data.
>
> We have an existing surveillance system in metropolitan Atlanta. It\'s
> the Metropolitan Atlanta Developmental Disabilities Surveillance
> Program. We looked at our data, and we looked at cases of athetoid CP.
> I think we identified eight cases, and none of them seemed to have an
> association with high bilirubin levels from our record review.
>
> We explored the opportunity to make kernicterus a reportable
> condition. We found out it is the Council of State and Territorial
> Epidemiologists that is responsible at the state public health level
> for determining what conditions are reported to CDC and therefore that
> we get national data.
>
> We think that maybe our approach to them was a little premature
> because we didn\'t have a case definition, so since there is not
> agreement among the experts as to what an appropriate cutoff would be
> for reporting cases, we were not able to make kernicterus a reportable
> condition, and that is something we hope to do in the future.
>
> Our last attempt was to go to an organization of managed care
> organizations and to say that if we developed a cooperative agreement,
> perhaps some of the HMOs would be interested in looking at the rate of
> kernicterus within those HMOs. I will just say that there was a
> limited interest.
>
> \[Slide.\]
>
> But the good news is we have a mechanism at CDC that allows for
> extramural opportunities for research, and through that announcement
> last year, we are able to look at kernicterus in two areas of the
> country.
>
> The objectives of the announcement were that: applicants should seek
> to review cases of extreme jaundice in otherwise healthy full-term
> infants; provide a body of evidence to inform why cases of extreme
> jaundice may lead to kernicterus and why kernicterus may be
> re-emerging; to provide a forum of concerned scientists and healthcare
> professionals to convene and develop a strategic plan for a national
> kernicterus prevention program.
>
> \[Slide.\]
>
> Our awards went to the University of Medicine and Dentistry in New
> Jersey, the Robert Wood Johnson Medical School, and their objectives
> are to look at infant mortality and morbidity related to kernicterus,
> to design a surveillance system for kernicterus, to identify risk
> factors for kernicterus using a case control methodology, and using
> this to focus on early identification and management of
> hyperbilirubinemia, and to provide a support network for families
> affected by kernicterus.
>
> \[Slide.\]
>
> To date, they have submitted requests for IRB approval for their
> activities. There has been initial discussion and a process for
> population-based surveillance with the New Jersey Department of
> Health, and they have analyzed some data on infant morbidity and
> mortality due to kernicterus.
>
> They are allowing me to share with you some preliminary results from
> their look at kernicterus morbidity. They used New Jersey hospital
> discharge data for 1992 to 2001. They identified 82 cases of
> kernicterus. The denominator is the entire State of New Jersey, so
> this is population based, and their rate is 7.5 per 100,000 live
> births. That is their cumulative incidence.
>
> They noted that there was significant variation by race and ethnicity
> with the lowest rate being among Hispanics and the highest rate among
> Asians.
>
> \[Slide.\]
>
> Our second award went to Pennsylvania Hospital, the University of
> Pennsylvania, and they are partnering with PICK, and their objectives
> are to establish surveillance, and their surveillance activity is
> related to analysis of the pilot study data that you have all heard a
> lot about today, to identify risk factors for kernicterus, to
> establish a Prevention Task Force or Steering Committee that would
> advise on the management of hyperbilirubinemia and to launch a
> national prevention campaign.
>
> \[Slide.\]
>
> To date, Pennsylvania Hospital has had a teleconference of their
> Advisory Board. They met along with our other grantee and with CDC to
> begin to develop a consensus on the definition of kernicterus for
> public health purposes.
>
> They are current establishing the database that would allow them to
> systematically report results from the pilot study, and with PICK,
> they have collaborated on the educational video, and you saw part of
> the video just a few minutes ago.
>
> \[Slide.\]
>
> In terms of future direction from the CDC perspective, we are always
> looking to partner with others in our goal on elimination of
> kernicterus and raising awareness of this as a public health problem.
>
> We are planning a forum for developing consensus on a surveillance
> case definition, and the goal of that is to identify a mechanism for
> population-based surveillance at the state level, as well as at the
> national level.
>
> \[Slide.\]
>
> I would like to thank Dr. Rachel Afgen, who is our point of contact
> for our kernicterus activities at CDC, for our collaborative partners,
> as well as our other partners, and for all of the children and
> families that have been affected by kernicterus.
>
> Thank you.
>
> DR. CHESNEY: Thank you very much.
>
> Our next speaker is Dr. David Stevenson, who is the Harold Faber
> Professor of Pediatrics and Senior Associate Dean for Academic Affairs
> at Stanford University Medical School. He is going to review for us
> the metabolism of bilirubin and the metalloporphyrin heme oxygenase
> inhibitor drug class.
>
> **Metalloporphyrin Heme Oxygenase Inhibitors**
>
> DR. STEVENSON: Thank you very much.
>
> It is a pleasure to address you, a little bit different than the last
> two presentations, but hopefully, this will add to the information
> that will be of use to people this afternoon and tomorrow.
>
> \[Slide.\]
>
> Let me begin by giving a quick primer on neonatal jaundice. This is a
> favorite slide of mine and some of my colleagues in the room have seen
> this many times, but it is a very useful way to begin this kind of
> discussion.
>
> Neonatal jaundice can be understood by analogy to a sink. If you let
> the processes of bilirubin production be represented by the turned on
> spigot and the processes of bilirubin elimination be represented by
> the drain, then, you can understand the problem of transitional
> jaundice as a problem of an imbalance, and if the rate at which
> bilirubin is produced exceeds the rate at which bilirubin is
> eliminated, then, the level in the sink begins to rise.
>
> This is exactly what happens in period of time after birth. If there
> are relative increases in bilirubin production or relative decreases
> in the ability to eliminate bilirubin, then, you can exacerbate that
> normal transition, and it is just about that simple in terms of the
> physiology although the biology is fairly complex controlling these
> processes. So, neonatal jaundice is a normal transitional phenomenon.
>
> \[Slide.\]
>
> The turned-on spigot can be represented by this cartoon of the
> reactions that are involved with heme catabolism. Some of the most
> important early work on this biochemistry was done by individuals like
> Dr. Kappas, many others before me.
>
> But this is a very ancient system in nature. It is present in both
> plants and animals. It is a process which is probably essential to
> life on this planet, that is, life making use of oxygen and exposed to
> light.
>
> It\'s a two-step process. This is a cartoon because there are many
> more oxidations and reductions that take place than represented in
> this slide.
>
> The first step is the rate-limiting step in the process. It is
> catalyzed by heme oxygenase and involves absolute requirements for
> oxygen and for NADPH, which is donated from the cytochrome p450
> system.
>
> In this first step, the alpha-methene bridge is broken, carbon
> monoxide, a trace volatile molecule is produced equal molar amounts
> with biliverdin and iron, the latter of which is recycled.
>
> Biliverdin is reduced in the cytosol. The other reaction takes place
> at the microsomal level. Biliverdin is reduced in the cytosol again
> with absolute requirements for NADPH and biliverdin reductase to
> bilirubin, so there are actually equal molar amounts of bilirubin and
> carbon monoxide which are produced.
>
> Historically, carbon monoxide and bilirubin have been thought of as
> waste products, but as it turns out, every part of this reaction
> probably has some relevance in normal biology, just to put it in
> context.
>
> \[Slide.\]
>
> The point that I would like to make is that all substances are
> poisonous. Only the dose differentiates a poison from a remedy, and we
> have had some of this discussion earlier today, but it is an important
> point to make. It does not lessen the importance of understanding, but
> a compound can be toxic under certain conditions that we encounter
> clinically.
>
> But it is also important to remember that some of these compounds like
> carbon monoxide, which I have used as you will see as an index for
> production of a pigment because it is produced in equal molar amounts,
> bound to hemoglobin, circulates in the bloodstream, and is
> continuously excreted in your breath, so it is a window on endogenous
> CO production which mirrors bilirubin production.
>
> We have to remember that CO is also an important biological signaling
> molecule, and a lot of people are now investigating its role in
> neurosciences and vascular sciences.
>
> \[Slide.\]
>
> They are doing that because of the fact that, just like NO, it can
> interact with guanylyl cyclase and activate CGP to cyclic GMP and have
> a whole host of important cellular functions.
>
> The relative potency of CO for doing that is much less, but the
> potential for the body to make CO is much more, and I will make a
> comment about that later, as well. So, even this part of the
> biological system is important to understand in terms of the spigot
> which produces carbon monoxide, biliverdin, and then when the second
> step goes to bilirubin.
>
> Also, it needs to be understood that carbon monoxide may be involved
> in the inhibition of other enzymes with iron/sulfur centers, so its
> impact on other aspects of metabolism needs to be understood, so even
> the CO that is produced and is excreted at a cellular level, it may
> have a very important role biologically, just like bilirubin which can
> serve as an antioxidant in the intracellular environment may be
> involved with maintaining the redox state of the cell and even in
> regulation of gene expression.
>
> \[Slide.\]
>
> So, my world has gotten more complex. Most people think of me in terms
> of bilirubin, but I have become increasingly interested in carbon
> monoxide, and you will see the reason for making these comments at the
> beginning because it has relevance to what I will be talking about
> primarily, which will be the metalloporphyrins.
>
> The main reaction we have been talking about is this one right here,
> down in the middle, where heme is catabolized by heme oxygenase. As
> you can see already there, there is an indication that the
> metalloporphyrins have the potential for acting as competitive
> inhibitors and can block that first step, thus putting our hand on the
> handle of that biochemistry, and they can do that very efficaciously.
>
> The CO is produced, bound in blood, and then excreted in the breath,
> and you can measure either as a continuous excretion rate or as an
> end-tidal carbon monoxide concentration, corrected for the ambient
> exposure. This is all quantitative and mathematically related, so they
> are good indices of what is going on.
>
> But you can see all the other possible sources. The two I will bring
> to your attention, one is light, light actually can cause
> photo-oxidation as you have heard, and one of the products is carbon
> monoxide. Also, lipid peroxidation is another source of carbon
> monoxide. Both of these can occur in the absence of heme. So, that
> would be a confounding event for some of the things that I might be
> interested in measuring in the newborn period.
>
> \[Slide.\]
>
> Fortunately, the endogenous sources of CO are well understood, and
> this goes back many years, and many people besides me have looked at
> this, but heme degradation in the newborn period under most of the
> conditions that we encounter, particularly in the kinds of babies we
> have been talking about today, most of the sources of CO comes from
> heme degradation.
>
> So, from the senescent red cells, it is about 70 percent of that 86
> percent, or from ineffective erythropoiesis approaching 10 percent,
> then, other hemoproteins around 21 percent.
>
> You can imagine what hemolysis does to these relative percentages,
> because if you have an increased rate at which the red cell mass is
> breaking down, you will have marked increases in bilirubin and carbon
> monoxide production. You can see that quite nicely.
>
> There are non-heme sources of carbon monoxide, as I mentioned, but
> they are not really of great consequence for these estimates that we
> are making. Remember, the CO in the breath is an index of bilirubin
> production, it is not a direct measure of the production because it
> includes these other sources.
>
> Lipid peroxidation and photo-oxidation are variable in their
> contributions, but on the average contribute roughly that amount, and
> they are really important in conditions that we encounter in smaller
> infants where proportions might become greater, and this would become
> a more important source to consider under those circumstances.
>
> We were the first really to demonstrate those independent sources of
> CO in these heme-free environments in vivo and in vitro.
>
> \[Slide.\]
>
> We have been measuring carbon monoxide excretion rates in animals for
> literally the last two and a half decades, and this shows you some of
> the systems that we currently use for rats, mice, and monkeys, so we
> do larger animals, as well, again mainly for the purpose of looking at
> bilirubin production under a variety of conditions.
>
> \[Slide.\]
>
> This is a typical diagram of a system that we would use. This is a rat
> in a collection system attached to a reduction gas detector which can
> measure CO in parts per trillion, and this technology actually allows
> us to adapt these measurements to development of a new hemoxygenase
> assay which is now used by many people, a gas chromatographic assay
> using that kind of detection system. Also, we can measure over small
> numbers of cells and tissues, which allows us to extend the work into
> those model systems, as well.
>
> \[Slide.\]
>
> We will point out something which is important for the presentation
> this afternoon. This is one of the earlier experiments that I did
> literally almost 20 years ago. It is the percent recovery of injected
> heme over time as carbon monoxide. Percent of recovery of heme is
> along the y axis and the time is on the horizontal axis.
>
> You can see that when you give a known amount of heme as damaged red
> blood cells and then sample the breath over an interval of time, which
> in this case was about 8 to 12 hours, you can collect 100 percent of
> that heme as CO produced. This is the most valid and accurate way of
> assessing in vivo hemolysis that exists.
>
> This is a little bit of history here. That gap in the data is just
> because we used to have hand cranks and I had to run down the hall to
> a bathroom, and I didn\'t get back in time for that crank. Now it is
> all automated, so we don\'t have to worry about those kinds of things.
> But this validated this approach in this system.
>
> \[Slide.\]
>
> We also devised systems early on for studying human neonates. This is
> a big system for a baby, so babies were in the same kind of systems as
> the smaller animals, and we were able to do large numbers of studies.
> So, this is the way the world has looked to me for over two decades.
>
> This world can be seen even before someone becomes jaundiced, and the
> points I will make here are some important ones in the context of this
> discussion and about the compounds that we are going to be talking
> about.
>
> This is the adult. This is the term infant. This is the excretion rate
> of carbon monoxide on a per kilogram basis. You can see that all term
> babies on the average produce about 2 to 3 times as much bilirubin on
> a body weight basis compared to an adult.
>
> So, increased bilirubin production is in the background of all the
> different patterns of jaundice that we see including pathologic
> jaundice in the newborn period. That is an important concept to
> remember.
>
> It doesn\'t mean that everybody who has increased production,
> relatively speaking, is going to become jaundiced, in fact, many
> people are able to conjugate well, so they avoid that circumstance.
> So, it is not the best predictor, as you have heard Dr. Ip talk about
> when you use it in isolation, but it is the best way to understand
> what is happening with respect to an individual\'s biology.
>
> This is what a hematoma does, polycythemia, so a larger red cell mass
> breaking down at a normal rate. Smaller preterm infants, they have
> shorter red cell life spans and have increased production rates, so
> increased production is a part of the near-term infant problem with
> jaundice. Here is your infant of a diabetic mother. That is probably
> ineffective erythropoiesis most of the time, sometimes polycythemia.
>
> Here is your ABO hemolytic disease and your Rh disease in which you
> see the most brisk hemolysis.
>
> So, you can see all these things even before someone becomes
> jaundiced, usually by about 12 hours of age with this current
> technology, or in a jaundiced infant, you can know whether an
> increased production is a contributing cause to that problem beyond
> what is normally the case in every baby.
>
> \[Slide.\]
>
> We have simplified the technology and have shown that rather than
> having to do things in those big chambers, which were quite cumbersome
> and had to have drills to get the kids out and things like that, which
> was pretty challenging, but you can now do automatic end-tidal
> sampling corrected for the ambient, and you can see a very good
> correlation with the standard index, which is the carboxyhemoglobin
> level measured by GC.
>
> \[Slide.\]
>
> This just shows you in a recent publication that we did, and this a
> part of a multinational, multiethnic study in which some people in
> here also participated. This is what the distribution of carbon
> monoxide production looks like as indexed by the level in breath, so
> it is a mirror of bilirubin production, which is what you are looking
> at, at about 30 hours plus or minus 6 hours.
>
> You can look at a group of individuals, and this included children
> with hemolytic disease\--there they are out there\--you can identify
> the high producers of the pigment quite easily. If you wanted to, you
> could arbitrarily say, well, the part of the population that is of
> interest to me, if they are having trouble with bilirubin, is the part
> of the population that is, let\'s say, 3 standard deviations above the
> mean or something of that sort, so you can actually look at production
> as a way of targeting your population, but remembering that all babies
> have increased production to a certain extent.
>
> \[Slide.\]
>
> Then, you can look at this in the context of the nomogram that you
> have heard so much about. We were recently looking at the same
> multiethic, multinational study, and we have now learned that on the
> average, since there is general impairment and conjugation in the
> period after birth, that these percentiles in the nomogram are, in
> fact, informed in part by production rates.
>
> So, if you look at the average end-tidal carbon monoxide
> concentrations in the different percentiles, you will see that they go
> up as you go up in the nomogram. The babies that we haven\'t talked a
> lot about are the ones who are already outside the nomogram early on,
> and they have increased production.
>
> In other children who are still within the nomogram and you have a
> hard time figuring out what is going to happen with them, you can
> identify some of them who may or may not have problems, but you will
> at least know who is hemolyzing, and they will go out sometimes later.
>
> Then, you have kids who have normal production rates and tend to go
> out much later, and those are your poor conjugators, those are your
> Gilberts and your G71R mutations in the Japanese and other Asians.
>
> So, combining the information about production, which reflects what is
> happening with the hemoxygenase in a person\'s body and the relative
> breakdown of heme, with how a baby is actually performing with respect
> to that challenge, can provide you with a lot of important
> information.
>
> \[Slide.\]
>
> That is the background which establishes the rationale for what Dr.
> Kappas and Dr. Drummond and Dr. Valaes, who helped him later in that
> series of investigations ultimately involving human neonates, that was
> the rationale for getting a handle on that spigot.
>
> There has been no question that over the last two decades with a
> tremendous amount of systematic and exhaustive and very thoughtful
> work done at Rockefeller and also over the same period of time after
> we were introduced to this area of biochemistry at Stanford, we have
> been able to clearly establish the efficacy, and much credit goes to
> Dr. Kappas and his group for making that original observation and
> confirming it over many, many studies, in vitro animal studies and
> ultimately human investigation.
>
> What you are doing when you block the step here is you are inhibiting
> the production of carbon monoxide and bilirubin, and that is what we
> need to remember.
>
> \[Slide.\]
>
> If efficacy is easy to establish, choosing the right drug has been a
> part of that challenge. Of course, the choice has been made, and it
> has been made for a lot of good reasons, and some of those, Dr. Kappas
> and others may want to comment on. It is clearly the most potent of
> the potential drugs, and thereby can avoid perhaps many of the other
> potential side effects of these drugs by using a much lower dose.
>
> But the thing to see here is there are many options. Most of these are
> inhibitors of hemoxygenase, and they differ by virtue of their
> substitutions on the porphyrin macrocycle and the different metals in
> that ring, and it is hard to predict how they are going to behave with
> respect to their various properties, but without actually evaluating
> each of them, there is no easy way to get a relationship between the
> structure and their activity at least chemically.
>
> \[Slide.\]
>
> One of the first things, of course, you have to ask, and I will just
> show this again. The Rockefeller group showed this, as well, and we
> did it after them. This was cannulation of a bile duct in an infant
> treated with one of the first drugs that was tried clinically, tin
> protoporphyrin, which was much less potent than tin mesoporphyrin, and
> the thing that I have been asked over and over again, and Dr. Kappas
> has probably been asked this, as well, don\'t you just accumulate
> large amounts of heme.
>
> What happens is you convert to a circumstance where heme is excreted
> in bile in approximate proportion to the degree of inhibition that you
> get, so you are not going to accumulate heme in the body, at least in
> the aggregate.
>
> There may be transient elevations in specific tissues, but overall,
> this is not a heme accumulation problem. This is, in fact, a way to
> eliminate heme from the system and also iron if you were to give
> dosing over a long period of time, but, of course, what is being
> proposed in this circumstance is single, low-dose intervention, so
> iron loss would not be a consequence of that kind of approach.
>
> This shows you how quantitative these kinds of approaches can be. It
> was done in a rat model in the system that I showed you earlier. So,
> this can be molar accounting for these two compounds.
>
> \[Slide.\]
>
> There are some other effects of the metalloporphyrins. I am not going
> to review these in a lot of detail, but I will mention them. We have
> been able to show that some of these metalloporphyrins can inhibit
> lipid peroxidation. Depending upon the dose, many of them can inhibit
> nitric oxide synthase and cyclic guanylyl cyclase, but if the dose is
> low enough for some of them, then, you can avoid that and they can
> become much more selective with respect to their impact on
> hemoxygenase.
>
> Photo-oxidation has been something that has challenged all of us, and
> I think led to the decision to use the more potent tin mesoporphyrin
> compound compared to the tin protoporphyrin compound because you can
> get it down to a level where it will not have those kinds of reactions
> or at least the chances for anything like that happening will be
> minimized.
>
> \[Slide.\]
>
> So, this is what we are talking about. A lot of these porphyrins can
> be excited by light interacting with oxygen to generate singlet
> oxygen, and singlet oxygen, of course, is very reactive. It can cause
> cytotoxicity and damaged cell membranes. No one wants that to happen
> in this circumstance. These compounds can be used in other
> circumstances to take advantage of this part of their electrical
> behavior.
>
> \[Slide.\]
>
> So, we have established criteria for potential antihyperbilirubinemic
> drugs in this class, and the approach that we have taken is that we
> can\'t fulfill all of these, no drug does that, but the idea would be
> that you would identify a compound with a biocompatible central metal,
> potent hemoxygenase inhibition, that is the primary feature,
> negligible degradation, which sort of goes with that, negligible
> photoreactivity, and negligible HO-1, which is the inducible form,
> up-regulation of that gene.
>
> \[Slide.\]
>
> So, our approach has been in a four-step approach. My intent here in
> this is not to go over a lot of the systematic and exhaustive amounts
> of data that we have produced for these many different compounds, but
> just to give you a sense of how this approach is undertaken and then
> sort of give you a summary at the end of where I think we are.
>
> The first is in vitro screening in two parts and then followed by in
> vivo screening. So, the first part is really the screening for HO
> inhibition, degradation to CO, that is, how do these things serve at
> all as a substrate for the enzyme, which you would not expect if they
> were good inhibitors since this is a competitive reaction, and then
> their photoreactivity.
>
> \[Slide.\]
>
> So, here is just an example of the kinds of data that we can get.
> Again, in some of these slides, the compounds are not always the same
> because we were doing them in different batches, but here is the
> natural substrate heme, and you can see the amount of HO activity when
> you administer the substrate, and you can see that for tin
> mesoporphyrin here, the second one in, it has marked inhibition.
>
> This is a single high dose, so you aren\'t able to discern among the
> different compounds at a high dose like this. A later part of the
> testing will allow you to look at a range of dosing, but just to
> screen for their potential as inhibitors.
>
> You can see the naturally occurring zinc protoporphyrin, which is
> probably the least potent of these compounds, but naturally occurring,
> and then another example which we will track through in a few things,
> chromium mesoporphyrin, because it has some interesting properties,
> but you can see that we can easily see if they are serving as
> competitive inhibitors in this assay.
>
> \[Slide.\]
>
> We can also then quickly look to see whether they can be degraded by
> the enzymatic system, and again, these are slightly different
> metalloporphyrins, but some of the same ones are included here, and
> you can see that we can quite definitively demonstrate that they are
> not degraded, which means the ring is not broken and the metal is not
> escaping.
>
> \[Slide.\]
>
> Then, our photoreactivity determination is done using this assay. It
> uses cool white light at around 30 microwatts per centimeter. We take
> advantage of the fact that carbon monoxide is a product of
> photo-oxidation and we can actually look at the different
> metalloporphyrins in that context.
>
> \[Slide.\]
>
> The system looks something like this with the vials being on top of
> that, and then you can get a picture of how these compounds look.
>
> \[Slide.\]
>
> You can see here now important features which were a challenge for the
> Rockefeller group, but potency won out and they can avoid this kind of
> a problem. You can see the tremendous photoreactivity of the tin
> compounds with zinc mesoporphyrin being in this assay, more
> photoreactive, but the potency allows the drug to be used at such a
> very low dose that in vivo, that is not going to be of any
> consequence.
>
> In this assay, zinc protoporphyrin also appears to have some
> photoreactivity in vivo, that has not been demonstrated, but there are
> some compounds that appear to be photo-inert, like the chromium
> compounds, for example.
>
> \[Slide.\]
>
> Here is zinc bis glycol. This is a derivative of the naturally
> occurring zinc protoporphyrin since it\'s a synthetic molecule, and I
> show this just to show you how paying attention to these properties is
> important for picking a drug.
>
> This is a very potent metalloporphyrin, as well, and like the tin
> compounds, it is also photoreactive, and you can see that in this in
> vivo testing with different concentrations of the drug exposed to
> light, you can see the mortality caused by these exposures, and you
> will see at these lower levels, there is no mortality whatsoever,
> then, there a sudden increase, and then over here on the end, this is
> in the dark, so it is the light impacting the interaction of this
> molecule in the presence of oxygen that can cause this kind of a
> problem.
>
> This compound can also be used in the less than 5 range, so you can
> avoid that kind of toxicity in vivo. This compound has not been used
> in humans and is still being investigated in animals, but it has some
> other interesting properties, which I will mention at the end.
>
> \[Slide.\]
>
> The second kind of testing is HO inhibition in a range of
> metalloporphyrins. Again, I know Dr. Kappas is going to say something
> about the tin mesoporphyrin itself, so I will show you another one.
>
> \[Slide.\]
>
> This is chromium protoporphyrin and chromium mesoporphyrin. You can
> see how in this assay, by looking at different doses, we can
> characterize the relative inhibitory potency of these compounds.
>
> \[Slide.\]
>
> We can also look at the potency of their inhibition against the two
> isoforms. The HO-2 isoform is the constitutive form, is not inducible
> by most of the ways in which we induce this enzyme, and then HO-1, the
> one that would be regulated by exposure to heme, and things of that
> sort.
>
> You can see that tin mesoporphyrin is the most potent compound for
> both HO-1 and HO-2 inhibition, but there are some other ones that are
> right up near the top. Just for people\'s information, chromium
> mesoporphyrin and zinc bis glycol are very important inhibitors.
>
> Then, as you go down the list, they vary in their rankings depending
> upon the compounds. You can see zinc protoporphyrin, the naturally
> occurring metalloporphyrin, at the very bottom. It still is an
> inhibitor, but it is one of the least potent.
>
> \[Slide.\]
>
> The next thing we do is we test them in vivo, and this is an example
> of those kinds of experiments. This is the VeCO over time, the control
> animals at the top, chromium protoporphyrin and chromium
> mesoporphyrin. Both of these are done at 4 micromoles/kg, so very low
> dose, and you can see the relative increased potency of the
> mesoporphyrin, chromium metalloporphyrin here to inhibit bilirubin
> production as measured in the living animal.
>
> So, for each of the metalloporphyrins, you can do studies like this
> and see in vivo that they are, in fact, doing what you want them to
> do. We also checked their tissues, and we can confirm the patterns
> that we saw in vivo in the tissues.
>
> You can also do important things to look, like in this case, as it has
> been done by Dr. Kappas at least for the tin compounds, we don\'t see
> any effect in brain, so brain stays out of the circumstance here.
>
> \[Slide.\]
>
> The last thing I want to show you is how we take it to monkeys. This
> was done for zinc protoporphyrin, which is the first one we worked on,
> the least potent of the compounds. Monkeys are just like people, they
> have relative increased production rates as babies. That is in the
> left sort of bar graphs. They have transient hyperbilirubinemia, and
> their hemoglobins are roughly the same as the adults, they aren\'t
> quite so different as they are in the human circumstance.
>
> \[Slide.\]
>
> This is what their pattern looks like. It is lower and it is shorter,
> but it is roughly the same kind of pattern, so they are a good model.
> If you give them undamaged red cells, you can look at a model which is
> almost identical to the child with increased bilirubin production from
> hemolysis, and then see how these compounds work.
>
> \[Slide.\]
>
> This just shows you how the least potent compound works. This is
> carboxyhemoglobin, an index of bilirubin production on the left,
> saline in the yellow, erythrocytes that are damaged plus the solvent
> in the middle, and then erythrocytes plus the solvent and then 40
> micromoles of ZnPP, that is 10 times the dose you would have to use
> compared to these more potent metalloporphyrins.
>
> You can see the marked reduction in bilirubin production.
>
> \[Slide.\]
>
> Then, of course, bilirubin levels are not directly related to
> production rates, it involves conjugation, so it is not exactly as
> dramatic, but you can still see the overall impact on bilirubin in
> circulation in these animals in the hemolytic condition, so it is
> almost exactly like you would be encountering in the clinical
> circumstance.
>
> So, this is a very good model for what you get when you use a drug
> like this to treat a human neonate who might have increased production
> of the pigment as a cause of their jaundice.
>
> So, the efficacy has been very well established, and the potency of
> the current drug that has been picked is well established and very
> good, and it can keep you out of the range where it is going to cause
> other kinds of problems.
>
> There are other options, other follow-through drugs if people were
> interested in developing such compounds.
>
> \[Slide.\]
>
> The final thing that we do is we do in vivo side effect testing for
> HO-1 regulation because we want to see if this impacts gene expression
> of hemoxygenase. Again, there are different ways to do this, but we
> decided to take advantage of a new technology which is in vivo
> bioluminescent imaging.
>
> \[Slide.\]
>
> Because light penetrates tissue and it can come out of tissues, this
> is an example of an internal light source, a firefly there on the
> right box in the upper part, but you can also take a promoter of
> interest, in this case, it was the HO-1 promoter, and basically create
> a transgene, the HO-1 luciferase transgene, and then under the right
> conditions have these animals report to you when their gene expression
> occurs. So, you can see the impact of these drugs on gene expression
> in living animals. It was one last check to look at safety issues.
>
> \[Slide.\]
>
> The way this works is you can either tag a cell or tag a gene, and you
> can image them. You can digitize, quantify, and archive, and people
> are using these kinds of things now for all kinds of developmental
> biology. It is perfect for gene expression, pick your gene of choice,
> and then build your transgene, build your transgenic model, and you
> can then look at gene expression in real time basically.
>
> \[Slide.\]
>
> The way this works is you get a reference image grayscale, collect in
> low light. You get a low light image with a pseudocolor generated by
> your computer, collected in a dark box. You can superimpose them and
> you can see where the light then emanates from the animal. There are
> now benchtop animal imaging systems for that purpose.
>
> We use this system because I was interested in jaundice and the effect
> of these metalloporphyrins on the system. I used this system because
> there is tight regulation due to toxicity of carbon monoxide, iron,
> and bilirubin, there is tissue-specific expression, it is
> developmentally regulated, it is a key molecular target for therapy,
> and ex vivo assays are slow and provide only a snapshot, so it\'s a
> better way to look at the biology.
>
> \[Slide.\]
>
> We built our HO-luc fusion and created our transgenic animals. This
> allows us then to also do an analysis of about how, in fact,
> up-regulation occurs mechanistically. You can look at the different
> things that might cause induction of that gene, and you can easily see
> your animals in these systems.
>
> \[Slide.\]
>
> This is from a homozygous mating. That is a heterozygous mating. You
> can identify your transgenic animals who make light in response to
> activation of their hemoxygenase gene.
>
> \[Slide.\]
>
> Then, we are able to study important phenomena like this one, this is
> an example. HO-1 transcription early in life in the brain. We can see
> that it has a developmental pattern. That is something important that
> we need to understand. We need to make sure that medicines like this
> don\'t alter those patterns in adverse ways.
>
> We can confirm these reporting systems, these optical reporting
> systems with more traditional approaches looking at protein levels in
> the brain just to confirm that that is happening. We can look at any
> tissue. I am just giving brain as an example here.
>
> \[Slide.\]
>
> Here is where we use it to look at the metalloporphyrins. So, there is
> zinc metalloporphyrin, tin mesoporphyrin, zinc bis glycol. You can see
> that there are differences in the activation or up-regulation of the
> gene in response to these compounds.
>
> None of them are persistent. The tin mesoporphyrin response is
> slightly more protracted than, say, the naturally occurring zinc
> protoporphyrin, probably because it is a more potent inhibitor, but it
> is not protracted, and the zinc bis glycol has essentially no
> perturbation whatsoever in this gene regulation. Just to give you some
> examples of how this tool works for looking at the response of this.
>
> \[Slide.\]
>
> Using this kind of technology, you can begin to see the differences in
> enhancer involvement for that up-regulation, so you can see the
> differences between the compounds. There is zinc protoporphyrin, the
> naturally occurring one, which is distinct and very different from the
> elements that are important for regulation of the gene in response to
> tin mesoporphyrin. There is cadmium chloride on the right side as sort
> of a positive control.
>
> So, the gene activation by different metalloporphyrins differs in
> magnitude and involves different HO-1 promoter regulatory elements,
> which again might help you with some drug selection issues as more
> drugs are developed.
>
> \[Slide.\]
>
> The other thing we were worried about initially was that there might
> be an effect on gene programming. This is what cadmium had done. We
> had seen massive responses and up-regulation response to cadmium, and
> then it would dissipate and disappear like we saw with the drugs.
> Then, when we retested the animals, they had an attenuated response,
> so there was some kind of programming that was going on that the
> mechanism needs to be fully explicated for cadmium.
>
> The preliminary work that we have done does not demonstrate, at least
> to this point in time, for the compounds that are being considered for
> human use to have that kind of a programming effect, which I think is
> important information. That work is still in progress, but at least
> the preliminary information looks good in that regard. Another example
> of how we use this technology.
>
> \[Slide.\]
>
> So, here is my summary and my last slide. Tin mesoporphyrin, after a
> lot of very systematic and exhaustive studies conducted in vitro in
> animals and later in humans, is the drug of choice currently. It is
> very potent and at the dose that is being used can still achieve that
> kind of efficacy, and looks also that it can be used in a way to avoid
> a lot of potential problems.
>
> It is a synthetic compound, it is non-biocompatible with respect to
> the central metal. It has very high potency which allows it to be used
> at a very low dose, and it is most likely not going to affect other
> enzymatic systems.
>
> It has high phototoxicity, but that can also be avoided for the same
> reason. It is not orally absorbable although more recent information
> we have suggests that if you can bypass the stomach, it may be
> absorbable directly from the intestine, which would be a handy thing
> if you package it the right way, and it is currently being used in
> clinical studies.
>
> Just for some other reference points in terms of the things we have
> studied, and none of these have been used in humans yet, and haven\'t
> done anywhere near the amount of work that has been done on tin
> mesoporphyrin by the Rockefeller group, but there is a lot of
> information available.
>
> Zinc bis glycol is a synthetic compound. It has a biocompatible
> central metal. It\'s a derivative of the naturally occurring zinc
> protoporphyrin. It has very high potency comparable to tin
> mesoporphyrin, very high phototoxicity comparable to mesoporphyrin,
> but it can also be used at a lower dose, and also can be shown not to
> affect the enzymatic systems except the one of interest, which is
> hemoxygenase.
>
> This one happens to be orally absorbable, so just a small drop could
> accomplish what you want to do in the oral feeding.
>
> Chromium mesoporphyrin is synthetic, has a biocompatible central
> metal. It is very high potency again, it has no phototoxicity, it is
> photo-inert, it is orally absorbable, and also may not affect the NOS
> or guanylyl cyclase systems.
>
> Finally, the naturally occurring compound, not the greatest potency,
> but it does work and it also is metabolized. It has a naturally
> occurring and trace essential metal, moderate potency, very low
> phototoxicity to none in vivo, it is not orally absorbable however.
>
> So, there are a lot of other compounds that I could talk about, but it
> gives you a good sense of how I look at this biochemistry, this
> developmental biology, and how it translates in terms of applicability
> to the kinds of choices that have been made by my colleagues and what
> other potential compounds might be available for what appears to be
> very powerful agents for controlling hemoxygenase and doing pretty
> much what they were designed to do, which is to get a handle on that
> spigot and control the production rate of the pigment.
>
> I will just stop at that point and see if you have any questions.
>
> DR. CHESNEY: Thank you very much, Dr. Stevenson.
>
> I have been cautioned about the importance of a break, which I was
> willing to have you all work right through the break, but I have been
> cautioned against that.
>
> As I have to go upstairs and build a transgenic model, so I can give
> you a reporting system when I return, I think we should all take a
> 10-minute break. I hope this doesn\'t inconvenience any of those of
> you here for the open public session, but if everybody could be back
> in 10 minutes, we will pick up then. Thank you.
>
> \[Break.\]
>
> DR. CHESNEY: For the next hour we have our open public hearing. We
> have nine people who have indicated an interest in speaking. Just two
> issues. First of all, as Tom read at the beginning of the session, and
> I quote, we ask in the interest of fairness that any of you who are
> speaking in the open public hearing, disclose any current or previous
> financial involvement with any firm whose product they may wish to
> comment on.
>
> The second point is that people in the open public hearing have been
> given different intervals of time to speak, and we would really
> appreciate it if you could do everything possible to stay within your
> time limit. We absolutely want to hear from everybody, and we want to
> get as much information out of today as possible, but if you could
> stay as close to your time limit as possible, we would be
> appreciative.
>
> Our first speaker is Dr. Attallah Kappas. He is the Sherman Fairchild
> Professor and Physician-in-Chief emeritus at the Rockefeller
> University. He is a leading authority in metabolic and genetic
> disorders, and I understand won the NIH\'s first annual award for
> excellence in clinical research.
>
> Dr. Kappas.
>
> **Open Public Hearing**
>
> DR. KAPPAS: Thank you, Dr. Chesney, and I thank David for the elegant,
> extremely full and really beautiful review of the subject. It has,
> however, put me in a spot. He has covered the biochemistry of it from
> bottom to top, leaving the clinical part of it to me, and since I am
> not a pediatrician, that is not so easy a task.
>
> I have had to cut and paste my presentation from a longer lecture
> because I had not been scheduled for this meeting until yesterday.
>
> \[Slide.\]
>
> For those who need addresses and so on, this slide.
>
> My laboratory group has for 35 years focused its research on the
> biochemistry of heme and heme-dependent processes and on related
> clinical and pharmacological issues. Twenty-two years ago, we
> discovered the potentability of certain synthetic heme analogues to
> inhibit heme catabolism, and we have intensively examined the
> biological and pharmacological properties of those compounds since.
>
> In the course of this work, my colleagues, principally Dr. Drummond,
> Dr. Valaes, and Dr. Martinez, and I developed an inhibitor which can
> effectively resolve, we believe, many of the ambiguities surrounding
> the problem of newborn jaundice.
>
> \[Slide.\]
>
> Heme conversion to bilirubin is catalyzed by two enzymes, the
> rate-controlling enzyme is hemoxygenase. Newborns temporarily produce
> bilirubin faster than they can dispose of it. The jaundice, which is
> mild and transient, which they experience, peaks at about 96 hours,
> well after they have left the hospital.
>
> In some babies, however, the jaundice may become severe, unrecognized,
> and then unmanageable, and major brain damage can occur. More subtle
> neurological impairments are now being identified. It could hardly be
> otherwise in the fragile, immature, and developing biological system
> which the newborn brain represents.
>
> Central issues in this problem are the unpredictable nature,
> unpredictable course of jaundice in some babies, the undefined
> susceptibility of individual babies to bilirubin toxicity, and the
> uncertain blood levels at which bilirubin is toxic to the brain.
>
> Phototherapy is quite successful as you all know from personal
> experience. Its side effects and drawbacks are also acknowledged.
>
> Its underlying medical logic in particular seems to us presents a
> problem. Light treatment is initiated only after the blood bilirubin
> has reached a level perceived to threaten the brain. This exact level
> is not known for certainty, and whatever it is, it may be reached
> after the baby is beyond medical care.
>
> \[Slide.\]
>
> We focused our research on the enzyme which controls bilirubin
> production and we ultimately developed an inhibitor of its activity.
> We named this inhibitor, a synthetic heme analogue among the group
> that David presented to you, Stannic-mesoporphyrin or SnMP for short.
> It is now known as Stannsoporfin.
>
> It acts, as shown on this slide, to prevent heme from binding to the
> enzyme site at which bilirubin production is initiated. Its
> pharmacological and toxicological properties have been intensively
> examined over a number of years.
>
> \[Slide.\]
>
> In the studies along these lines which we have conducted, the
> inhibitor was shown to rapidly and effectively suppress bilirubin
> production in all of the models of jaundice in experimental animals,
> shown on the left. In clinical studies, in adult, a single small dose
> reduced blood bilirubin levels by 30 to 50 percent for a period of 10
> days.
>
> The inhibitor acted similarly in adults with liver disease associated
> with jaundice and ultimately was shown to suppress hyperbilirubinemia
> in children and to interdict development of severe newborn jaundice in
> the population shown on the right.
>
> \[Slide.\]
>
> The overall results in five controlled, randomized, blinded where
> possible, clinical trials involving more than 400 newborns are
> summarized here. We had earlier determined the appropriate dose of
> inhibitor in careful dose-arranging studies in several hundred
> additional newborns. These studies were funded for a very long period
> of time by the National Institute of Child Health and Human
> Development, monitored by the FDA regularly, and closely supervised by
> senior neonatologist, in particular Professor Valaes.
>
> Treated babies in these studies have had medical follow-ups for
> periods up to five years. No side effects of treatment have ever been
> observed. There were 279 combined control infants in these trials,
> 129, or 46 percent, needed light treatment to suppress progressive
> jaundice. A total of 443 infants received a single small dose of the
> inhibitor at a suitable time after birth. In these infants, blood
> bilirubin levels were significantly reduced and in 97 percent, the
> need for light treatment was eliminated, and there were not cutaneous
> reactions to treatment in these babies.
>
> In a group of 80 newborns in whom bilirubin levels had reached 15 to
> 18 times normal, that is, close to the level, 19.5 mg/dl, requiring
> phototherapy, the inhibitor rapidly blocked further progression of
> jaundice, and none of the babies needed light treatment.
>
> In contrast, of 86 controls who did not receive the inhibitor, 22
> percent required phototherapy. A direct comparison of the inhibitor
> versus phototherapy was made in other newborns in whom blood
> bilirubins had already reached the critical level requiring light
> treatment.
>
> Forty-four babies received the inhibitor alone. In all 44, jaundice
> receded and none required light treatment. These babies left the
> hospital about 30 hours earlier than the 42 infants who did not
> receive the inhibitor, and they required considerably less medical
> resources to monitor their status.
>
> The inhibitor entirely eliminated the need for light treatment in
> newborns with G6PD deficiency, a gene defect predisposing them to
> severe, unpredictable jaundice. Out of 58 babies in the control group,
> 31 percent became seriously jaundiced and required lights. None of the
> 225 babies receiving the single dose of inhibitor developed jaundice
> requiring phototherapy.
>
> The interdiction of severe jaundice in these infants simplified and
> greatly reduced the cost of their medical care.
>
> \[Slide.\]
>
> Inhibitor effects in these G6PD-deficient newborns are graphically
> shown in this figure. The 58 babies who did not receive the inhibitor
> continued to accumulate bilirubin in their blood during the second day
> after birth, as shown in the top line, and ultimately, many required
> light treatment.
>
> The bilirubin accumulation process was blocked in the 225 babies who
> received the inhibitor, and none needed phototherapy.
>
> \[Slide.\]
>
> A more severe hereditary disorder in children results in jaundice
> which is nearly always fatal. Affected children are unable to dispose
> of bilirubin and survive for a time with bilirubin levels of 20 or
> more times normal as in this 4-year-old girl. They ultimately die of
> brain damage unless they are able to secure a liver transplant.
>
> These children are being studied Rockefeller-Cornell joint program of
> research involving pediatric pharmacology.
>
> A single dose of inhibitor can, as shown on the left of this slide,
> markedly reduce blood bilirubin levels for about 10 days. The effects
> is entirely analogous to what is observed in newborns.
>
> Several doses, as shown on the right, in the same child can moderate
> the jaundice for many weeks. In these children, the inhibitor can
> offer, while they wait for a liver transplant, protection against the
> acute, severe exacerbations of jaundice which prove fatal to them.
>
> \[Slide.\]
>
> The inhibitor can also replace the full blood exchange transfusion, a
> light, last resort procedure when lights do not control severe
> jaundice. Seventy-five hours of intense phototherapy could not stop
> the relentless progression of jaundice in this infant. Blood exchange
> was rejected on religious grounds by the parents.
>
> With emergency FDA approval, the inhibitor was flown to the physician
> caring for the baby in South Dakota, and a single dose was
> administered as shown by the arrow. Blood bilirubin levels declined
> rapidly and the threat of brain damage was eliminated as was the
> matter of taking legal action against the parents.
>
> This experience is well known now in the Jehovah\'s Witness community
> and has been repeated a number of times over.
>
> \[Slide.\]
>
> Periodic reappraisal of clinical interventions is essential if science
> is to advance medical care. Phototherapy in use for 40 years could not
> be reappraised properly because there simply was no serious
> alternative to which its advantages and its drawbacks could be
> compared, thus, pediatricians have become bound to a single
> therapeutic option, and to the logic that newborn jaundice can only be
> treated when the bilirubin level directly threatens the brain. What
> this exact level is remains elusive. This is an unsatisfying and, as
> you know, sometimes dangerous logic.
>
> The use of an inhibitor to temporarily reduce bilirubin over
> production, a key source of this problem, while the bilirubin disposal
> mechanism matures in the infant, has a more secure basis in science.
> It also now has a firm foundation in a clinical experience comprising
> multiple successful trials for more than a decade in which more than
> 800 newborns to date have been treated and studied.
>
> The inhibitor can be used early to control jaundice in select
> populations, such as G6PD-deficient newborns, or it will interdict
> jaundice at any time point in the evolution of this process as the
> physician chooses.
>
> Finally, I think we need to remember that there are underprivileged
> societal settings in this country and abroad in which prolonged
> unrecognized or untreated newborn jaundice can, because of its
> prevalence and the paucity of medical resources, constitute a serious
> public health problem.
>
> The method we have developed provides a simple and rapidly effective
> means for resolving this problem.
>
> Thank you.
>
> DR. CHESNEY: Thank you, Dr. Kappas.
>
> Our next speaker is Dr. Bhutani, who is a neonatologist in the
> Department of Pediatrics at the University of Pennsylvania School of
> Medicine. He is a member of the current AAP Committee on the
> Management of Neonatal Hyperbilirubinemia. He has been an investigator
> of the BiliChek transcutaneous bilirubin monitor and the author of the
> nomogram for detecting severe hyperbilirubinemia.
>
> DR. BHUTANI: While we get started, I would like to wish everybody a
> good afternoon. My name is Vinod Bhutani. I am a baby doctor from
> Philadelphia. I am also an investigator and a rookie in the area of
> bilirubin for the last decade or so, and as a part of that, I received
> mentorship from Dr. Lois Johnson, who has been a great instrument of
> teaching to me personally.
>
> In addition, we have a grant from the CDC to look at the database for
> the kernicterus registry, and I am unsalaried investigator for the
> WellSpring clinical trial. I am not going to be mentioning those
> things in this brief kind of set of comments.
>
> \[Slide.\]
>
> The issue of saving babies from brain damage is something that is
> inherent to all pediatricians and neonatologists and to ensure that a
> baby has a full safe week, we protect babies from six-year, from
> hypoglycemia, from sepsis, from intracranial bleeding as a vitamin K
> injection, as well as from trauma.
>
> Ever since a concern has been raised whether bilirubin causes brain
> damage, we now know from our kernicterus registry based on the year of
> birth of the child the number of cases that have been reported to the
> registry have increased 11-fold from this day in 1990, and that is in
> the handout that is available.
>
> The handout is detailed, but I will just stick to a few slides and a
> few points.
>
> \[Slide.\]
>
> The question that Susan Sheridan asked, and we have asked ourselves,
> is in trying to prevent adverse outcomes and concerns for patient
> safety with newborn jaundice, what is the level of bilirubin that is
> high. The one that I get stuck at is the one which is how sure are we
> that serum bilirubin levels are actually safe or will be safe.
>
> In an attempt to answer that question, many of our studies have
> focused on a structured approach to the management of jaundice, so
> that we can make it easier for the practicing pediatricians who have
> to implement the various guidelines that are passed down to them.
>
> \[Slide.\]
>
> As we review the cases of kernicterus in our registry, we have used
> the Institute of Medicine matrix to analyze the care that these babies
> have received as their families and at all levels related to patient
> safety, patient centeredness, effectiveness of care, and more
> importantly, on the timeliness of care. There have been significant
> lapses, as you will see in the handout.
>
> \[Slide.\]
>
> The primary root cause analysis tell us and shows us the there has
> been an underlying major loss of concern for the neurotoxic potential
> of bilirubin, limitation on the visual recognition of jaundice, and
> the failure to recognize the severity of hyperbilirubinemia corrected
> for age in hours.
>
> In that respect, a nomogram was meant to be of help. Many have
> attempted to read more into the nomogram than there may actually is.
> This nomogram represents, in the simplest form, the rate of bilirubin
> rise that occurs in the first 72 hours. It provides at the magnitude
> of the severity of bilirubin and then it can be also used as a
> predictive strategy, but the rate of rise is important.
>
> If one looks at the 95th percentile track, the rate of rise if 0.2
> mg/dl/hr, which compares at the 75th percentile to 0.15 mg/dl/hr, and
> at the 40th percentile to 0.1 mg/dl/hr.
>
> As you review the cases that were reported to us in the kernicterus
> registry, the readmission bilirubin values, once the babies were
> discharged, some being admitted within the third day, fourth, or the
> fifth day, the ranges of bilirubin on admission ranged from 21.5 to 50
> mg/dl.
>
> Clearly, these babies had high bilirubins before they were discharged.
> In these babies, the estimated rate of bilirubin rise ranges from 0.25
> mg to 0.6 mg/dl/hr.
>
> If you compare the rate of rise of 0.25 mg/dl/hr for the 95th
> percentile track, and margin of safety is extremely small given all
> the issues that we know about bilirubin measurements.
>
> \[Slide.\]
>
> This is a baby with a high bilirubin value as one can see. The babies
> that we worry about are the babies between the 75th and the 95th
> percentile track, who have a 1 in 5 chance or a probability of having
> a severe hyperbilirubinemia once they have been discharged. The other
> 87 percent generally do well, but we do not yet have better predictive
> strategies to differentiate these 13 percent babies from the remainder
> 87 percent babies.
>
> \[Slide.\]
>
> To this end, we look at the limitations of the visual recognition of
> jaundice, and we have compared with a pooled analysis of data, babies
> who were screened by the jaundice-based screening techniques and those
> by bilirubin-based screening techniques, and these are again in the
> handout in detail.
>
> \[Slide.\]
>
> The pooled analysis shows that with bilirubin screening, you can
> reduce by 50 percent the peak bilirubin values of 20 and above, as
> reported in the literature. You can reduce by 50 fold, the occurrence
> of bilirubin above a level of 25, and you can potentially have a zero
> occurrence of the never \[?\] event of bilirubin value above 13 mg/dl.
>
> \[Slide.\]
>
> We view jaundice in two simple forms for pediatricians. One, the early
> onset of severe hyperbilirubinemia, a value above the 75th percentile
> track before 72 hours of age when the bilirubin binding to albumin is
> impaired, so these babies are vulnerable to lower levels of bilirubin
> and toxicity, and then the late onset that Dr. Stevenson mentioned,
> the conjugation defects, who are above the 95th percentile track and
> are more than 72 hours of age.
>
> The concern is of the baby before they go home, those who are above
> the 75th percentile track.
>
> \[Slide.\]
>
> If you follow these guidelines and this level of concern, I think we
> can meet the goals of all the stakeholders and bilirubin, those of the
> clinicians, those of the public health officials, those of the
> society, and those of the family for a safe experience with newborn
> jaundice.
>
> Thank you very much for this time.
>
> DR. CHESNEY: Thank you very much, Dr. Bhutani, and for giving us the
> extra slides that we can peruse tonight.
>
> The next speaker is Dr. Murray Goldstein.
>
> DR. HATLIE: Madam Chair, I am actually not Murray Goldstein. I am
> Martin Hatlie. Murray Goldstein\'s chair was empty next to me for the
> whole meeting, so I stepped up in the interest of time.
>
> DR. CHESNEY: Do you want me to introduce you?
>
> MR. HATLIE: That would be nice, unless Murray is here and we just
> don\'t know who he is.
>
> DR. CHESNEY: I am so sorry.
>
> Martin Hatlie, Esquire, is President of the Partnership for Patient
> Safety and a nationally recognized authority on patient safety and
> medical professional liability issues. He founded the Partnership in
> 2000, which is dedicated to advancing the reliability of healthcare
> systems, and he is a member of the Harvard University Kennedy School
> of Government\'s Executive Session on Medical Errors.
>
> Thank you. MR. HATLIE: Thank you, Madam Chair.
>
> I was given a sliding scale of time today, 5 to 10 minutes, so I will
> stay within the 10 minutes and try to keep closer to 5.
>
> I am a lawyer. I got to patient safety through years of being a
> lobbyist on litigation issues for the AMA. I am not really going to
> talk too much about that today, it is not the topic, and frankly, many
> of you may not care, but I wanted you to know that about me because
> you will see that I come from a different perspective and had the
> privilege of working with organized medicine as this notion of a
> systems approach to safety and a safety kind of science has been
> developing really starting in the mid-1990s although I will say that
> it did start in anesthesia quite a bit earlier, probably the
> mid-1970s, and the CDC and the FDA were very, very involved in
> partnering with the anesthesia field to make that happen.
>
> So, when we did start a National Patient Safety Foundation out of the
> AMA in mid-1990s, it was really the FDA that probably had more system
> and safety knowledge. This is out of the Center for Devices and
> Radiological Health than any other part of government that we can
> find.
>
> I am going to jump around in my slides a little bit today. You have
> some more material in your written materials than you are going to see
> up here today, but I want to leave you with four points at the end of
> my presentation and for the purposes of sort of reinforcement and
> repetition, I am going to start with them.
>
> One is that low prevalence from a system and safety point of view is
> really not a justification for inaction. A lot of industries really
> are pursuing high reliability, and, Madam Chair, that is a term of art
> for your list or extraordinary safety, really focus on their low
> prevalence especially high severity injuries as treasures, they call
> them. They are essentially things that tell you a lot about your
> system, if you can\'t prevent those high severity injuries, then,
> there are some systemic things that you really need to be looking at,
> and every one of these cases becomes something that industries that
> are serious about safety spend quite a bit of resources on to really
> investigate how that could fallen through the cracks.
>
> The second is that an intervention that relies on either vigilance or
> memory, or both, really again from systems thinking and human factors
> thinking is not optimally safe. Those are ways in which we know human
> beings fail no matter how hard they try, and no matter how competent,
> it is not how perfect they are.
>
> Vigilance including visual assessment, memory including know when and
> how to apply a guideline are things that just are not going to get you
> again to that extraordinary safe stratosphere that you want to go to.
>
> The third point is that evidence-based medicine, while a very valuable
> tool and really important for a number of reasons in medicine, is not
> a particularly sensitive safety tool. For a number of reasons that
> have really been articulated best probably in the literature by two
> pediatricians, Don Berwick and Lucian Leape, in an article, a dialogue
> actually, in JAMA last summer, they really focused on a number of
> reasons why evidence-based medicine isn\'t something that is going to
> be particularly helpful to you in making safety happen. It\'s slow,
> it\'s costly, it\'s not good at sort of targeting latent risk or
> emerging risk in a system, so you need other things to complement that
> certainly.
>
> It is not that it has no value, it has great value, but you need more.
> It should not be a rate-limiting step.
>
> The final point I want to make, really based on comments this morning,
> that I really want to leave you with, although I will elaborate all of
> these a bit more, is that accidents, including the kinds of stories
> that are captured in registries like the Pilot Kernicterus Registry,
> are incredibly robust safety tools.
>
> The aviation industry has spent terrific amounts of resources in
> really capturing the kinds of stories that are captured in registries
> like this one, voluntary registries that have a lot of narrative, a
> lot of richness of story telling where you can thematically analyze
> and understand why things went wrong and how they went wrong.
>
> There is much more emphasis from a safety point of view in that kind
> of data than in counting numbers and just looking at frequencies
> because that doesn\'t give you the kind of narrative, the kind of
> richness where you can really understand why processes failed and what
> went wrong.
>
> We really are going to move through these slides pretty quickly.
>
> I also want to stress, though, by saying that complacency is a word
> that has come up here a couple of times, and the IOM report that
> really brought safety into the public consciousness at the end of 1999
> did charge the healthcare system with being complacent.
>
> By that, they didn\'t mean careless, they did not mean callous, what
> they meant is that there is a sense in some industries that we are
> doing as well as we can do especially where prevalence is low, that we
> are sort of at the best place that we can be at, and again,
> organizations that are highly reliable are often seeing that their
> safety initiatives, their big leaps forward in safety come from
> organizations that are already leaders in the field, they are already
> at the top of the game. They might be organizations that either
> themselves would say or their peers would say you don\'t need to be
> focusing on safety because you are already doing as good a job as
> anyone that we know of, those organizations that again really aim for
> perfection and they are often motivated by the Hippocratic Oath. That
> really resonates with a lot of other industries, first, do no harm,
> let\'s aim for perfection. Those are the organizations that are going
> further.
>
> The best case study I can leave you with, and it is not in my slides,
> is the Alcoa case study. It comes out of the Harper Business Review.
> It\'s a wonderful, wonderful story that you will find very applicable
> to what you are doing here, but really focusing on first doing no
> harm, looking at your processes, aiming for perfection, and finding a
> lot of cost savings along the way.
>
> This is Patient Safety 101. I would recommend James Reason\'s book
> which is cited in your slides, and Charles Perrow\'s book which is
> cited in your slides, or the IOM report, you can pick up all of this
> stuff.
>
> These are all the different places that safety science comes from. It
> is not just the medical literature. There is a lot of knowledge that
> is being captured from other fields.
>
> These are the basic models. If I leave you with nothing else today,
> this will be some of the things that are certainly percolating through
> the safety literature right now.
>
> This is the Swiss Cheese model. This is coming from James Reason\'s
> work. It really I think is applicable in many ways to the kinds of
> issues that I heard you discussing today.
>
> One of the basic paradigm shifts that we see in systems thinking about
> safety versus the kind of thinking that I think is driven by our
> current liability system, if nothing else, is that things are
> constantly on the verge of happening. Accidents don\'t just happen
> when there is a breach in the standard of care. They are constantly on
> the verge of happening. You are constantly managing them and keeping
> them from happening through a series of defenses that you all have in
> your systems.
>
> The fact that the prevalence of kernicterus is as low as it is, and
> the fact that you are managing hyperbilirubinemia as well as you are,
> suggests that your defenses have worked pretty well.
>
> What we see, though, in safety thinking is a paradox, sort of the
> better that you do at safety, the more you lose track of the kind of
> risks that are there. Frankly, if you are trained to look for a
> certain kind of risk, if you are trained about the dangers of
> hyperbilirubinemia, but you don\'t see it for 15 years, you tend to
> move it off to the side of your red error screen.
>
> So, one of the hole to one of these defenses is just the kind of
> complacency or lack of alertness that comes with not seeing something
> for a broad period of time. A number of organizations, we use
> different kinds of simulation training to really keep that foremost in
> the minds of the people and keep those kinds of risks alert.
>
> The phenomenon, the human fact researchers call \"the coming of
> attention,\" we just don\'t look for things, we don\'t tend to see
> things that we don\'t see frequently and aren\'t familiar with.
>
> Another thing I want to mention from this slide is that certainly in
> Dr. Newman\'s presentation this morning, he went through a number of
> things in history that have changed over the course of our management
> of this disease.
>
> One of the things that we know from systems thinking is that any kind
> of change introduces different kinds of risks. So, for example, one
> thing that resonated very much with me today is the movement of the
> management of hyperbilirubinemia out of acute care settings into
> ambulatory care settings.
>
> When that happened in the mid-1990s, again with 20/20 hindsight,
> perhaps there was a need to do different kinds of education with
> families, different kinds of risk management strategies to reflect
> that change in the way in which we now see this kind of risk emerging.
>
> Frankly, it is one of the holes that PICK is trying to fill. It is the
> hole in really bringing forward the partners, the families as
> partners, the lay caregivers as partners, and they have a more active
> role to play if this is a fact, something that is going to emerge in
> outpatient care settings.
>
> We have talked a lot about\--this is, first of all, the Sharp and
> Blunt Ends model, another one of the basic models from Safety Science.
> We have talked quite a bit about the guidelines that are in place here
> and the fact that kernicterus does continue to happen even if the
> prevalence may be low.
>
> The purpose of this slide is to really show that where care is given,
> which is the sharp end of this triangle, practitioners are often
> balancing three different things, guidelines in this case, it\'s their
> goals, what they think is going on.
>
> Probably in this case, a good example would be can you diagnose
> kernicterus, can you diagnose hyperbilirubinemia, are you trying to
> balance it with other kinds of things that you are differentially
> diagnosing, and also the issue of attention, and attention is really
> interrupted in most healthcare settings by distraction and by fatigue.
>
> So, a lot of the work that happens in managing safety involves
> managing that attention, that focus of attention. It is one of the
> reasons why vigilance and memory really are not good strategies to
> rely on because they get interrupted by all that action at the sharp
> end of the system.
>
> The sharp end, frankly, what happened to the sharp end is shaped by
> the blunt, and the blunt end includes different kinds of systems
> thinking including the legal system, including the guidelines,
> including the kinds of technologies we have in place. Anything that we
> can do to minimize vigilance, reliance on vigilance, or minimize
> reliance on memory, or simplify or standardize are frankly things that
> will help people perform better at the sharp end, and that is really
> the major take-away I think from this slide in the time that we have
> today.
>
> Hindsight bias. I haven\'t heard it much today, I have heard it in
> most situations where we have talked about this sort of thing, and
> that is the statement that if doctors only followed the guidelines
> that they have up there, we really wouldn\'t see kernicterus.
>
> In fact, it is a very, very well known phenomena in the literature
> that hindsight, that when you look back on a situation, you tend to
> make judgments like that, it\'s internalized blame that it was the
> doctor that was at fault. In fact, because of all that complexity at
> the sharp end of the system, there is many things that are going on
> and really focusing on whether doctors should be or should not be
> following guidelines is not going to get you where you want to go.
>
> Again, you want to focus on technologies, strategies, to simplify, to
> standardize, and to decrease reliance on vigilance and memory.
>
> How do we apply safety science to optimizing the prevention of
> kernicterus? One of the major lessons that we know from looking at
> many years of experience in safety science and other systems is that
> systems never run perfectly, they are prone to failure and
> degradation, we should not be relying on guidelines and protocols as
> our major line of defense because that assumes optimal system
> performance, and the system rarely performs optimally.
>
> Reliance on vigilance and memory, we have talked about already, but
> there is frankly just not strategies that are going to really get you
> to the high reliability sector on this issue.
>
> How do we apply safety science to optimizing the prevention of
> kernicterus?
>
> My time is up. Lots of people have to be involved. Simplification and
> standardization are important tools.
>
> Many of these other strategies are cultural strategies, we are not
> going to talk about them here, but it really is a whole series of
> training and communication stuff.
>
> Evidence-based medicine, I am going to leave you with the slides here.
> They include a number of quotes from Berwick and Leape from that
> series of articles that I talked to you about, but essentially,
> evidence-based medicine is not something that either aviation or
> anesthesia has relied on terrifically in creating safety.
>
> It is much more of a problem-solving technique. It is every story in
> the registry that can be analyzed thematically and really looked at
> with the kind of problem-solving that frankly, commissions are very
> good at doing.
>
> So, you have the steps in place to really move forward and really
> getting to the next level in safety and reducing the prevalence that
> you have of hyperbilirubinemia, whatever it is. It is really just the
> approach that could be different than the traditional approach that is
> important here.
>
> I am going to stop here. There is many more things that I could say,
> would love to say. If you have any other questions about any of this,
> I will be at the cocktail bar at the end of the day and I would be
> happy to talk to any of you.
>
> Thank you so much.
>
> DR. CHESNEY: Are you sponsoring the bar? I don\'t think the FDA is.
>
> MR. HATLIE: No, I think the hotel is, I think it is something that
> they are giving us for free. Thank you very much for the extra time, I
> appreciate it.
>
> DR. CHESNEY: We will be there. Thank you very much.
>
> Many of us have become devout Don Berwick fans and for those of you
> who have not seen the video, Escape Fire, I think if you want to
> understand process and medicine and errors, that has a very profound
> message to it.
>
> Our next speaker is Dr. Duane Alexander, who is the Director of the
> NICHD and has been since February 5th of 1986. His own personal
> interests and training have been in developmental disabilities, and I
> was interested to learn that in his first position at the NICHD, he
> directed their national amniocentesis study that established the
> safety and accuracy of amniocentesis for prenatal diagnosis.
>
> Dr. Alexander.
>
> DR. ALEXANDER: Thank you all for the opportunity to speak to this
> group on this very important topic.
>
> The study that I organized after the amniocentesis study was a
> phototherapy study assessing the safety and efficacy of phototherapy
> for treating jaundice. I never got to finish that one because I went
> on to the National Commission for Protection of Human Subjects
> instead, but this is obviously an issue that has been of interest to
> me for a long time and to the Institute.
>
> During its 40 years of existence, a major focus of our attention has
> been on improving pregnancy outcome and ensuring intact survival of
> newborn infants and prevention of disability. I should state for the
> record that I have no financial relationships to WellSpring or other
> pharmaceutical companies, nor does the Institute.
>
> Bilirubin encephalopathy has long been a major problem for newborn
> infants. The biggest advance came before NICHD was established with
> the development of Rhogam, which eliminated a huge proportion of
> neonatal jaundice and problems associated with it.
>
> Then came phototherapy. The Institute addressed this. It took care of
> much of the problem with premature infants when our collaborative
> study demonstrated its safety and efficacy in reducing the need for
> exchange transfusion and reducing the incidence of kernicterus, and it
> rapidly became standard treatment.
>
> Unfortunately, it is also clumsy and complicated, it takes a long
> time, it interferes with access to the infant, and it is not 100
> percent effective, so we really have needed a better intervention if
> one could be developed.
>
> Sumner Yaffe, the former Director of the Center for Research for
> Mothers and Children at NICHD, came to me one day with a potential
> solution. Based on his conversations with Attallah Kappas, who you
> just heard speak, Dr. Kappas reported on development of a new series
> of compounds that they were working on that could represent a one-time
> injectable drug that would interfere with the formation of bilirubin
> until a baby\'s enzymes matured sufficiently that it could excrete it.
>
> They had tested several different formulations, tin, zinc, proto-,
> meso-, and settled on tin mesoporphyrin as the most effective and the
> safest, as well. We believed, based on the evidence that we saw, that
> this could potentially be the long-sought magic bullet that could
> finally end the problem of hyperbilirubinemia and kernicterus.
>
> We worked with Dr. Kappas to organize some clinical trials. These were
> done by contract in Greece and in Argentina. They included studies of
> term breast-feeding infants, G6PD-deficient infants, ABO
> incompatibles, term infants with hyperbilirubinemia.
>
> In every study, tin mesoporphyrin administered once resulted in lower
> peak bilirubins in the treated infants than in the controls, and
> reduced or eliminated the need for phototherapy. The only infants in
> any of these studies that have been reported who required phototherapy
> after receiving tin mesoporphyrin were some very small preterm
> infants.
>
> In addition to this, there was no evidence of any adverse effects in
> any of studies. Results like this don\'t come along very often. So,
> the number of patients, however, in our studies, was not large, it
> numbered in the hundreds rather than in the thousands, so these data
> have to be regarded as preliminary certainly rather than definitive.
>
> They also were not reported in sufficiently rigorous way to meet all
> the FDA requirements, so more studies were needed. We urged Dr. Kappas
> to license this compound to a pharmaceutical company, which he did,
> and the studies have begun.
>
> The promise of this treatment is so great that it is important that
> these studies needed to provide data for a judgment on approval, need
> to be moving ahead rapidly, so that tin mesoporphyrin can be studied
> for its preventive efficacy, as well as its therapeutic efficacy.
>
> We, at NICHD, believe that this is one of the most important new drugs
> being studied for pediatric use and that it is the only intervention
> on the horizon that holds out the prospect of completely eliminating
> the problem of hyperbilirubinemia and kernicterus.
>
> We are sufficiently enthusiastic about it that we have a protocol
> ready to implement in our neonatal intensive care unit network to test
> its additional applications of tin mesoporphyrin once it is approved
> for use in term infants, so that we will know its efficacy and safety
> before it gets broader application after licensure.
>
> If this proves useful, we will go on to evaluate other possible
> applications. We hope that a way will be found to move current studies
> forward expeditiously, so that the full promise of this drug for
> ending the problem of kernicterus will finally be realized.
>
> Thank you very much.
>
> DR. CHESNEY: Thank you.
>
> Dr. Goldstein is here, but I think we will give him a chance to catch
> his breath and move on to Dr. Andrew Moosa, who is Director of Newborn
> Nurseries and the Infant ICU at St. Francis Medical Center in Linwood,
> California.
>
> DR. MOOSA: Thank you, Dr. Chesney, thank you, Tom Perez for allowing
> me to speak today.
>
> As an initial waiver, I want to say that I have no relationship with
> WellSpring, I am not being reimbursed, I am not involved in the
> clinical trials, I am not salaried, so I have no conflict of interest.
>
> Dr. Lucey asked me who was I representing, so I said I was
> representing the practicing pediatricians who day and night take care
> of babies and children. I am from Southern California, the Los Angeles
> area. Somebody has to speak for the South since Dr. Newman and Dr.
> Stevenson represent the North, which is more affluent, which is more
> sophisticated, but I am from Southern California.
>
> Dr. Newman mentioned to you the Kaiser study in Northern California.
> Kaiser is a very special place in the sense that they have very good
> control of what goes on with both the physicians and the patients, et
> cetera. It is a marvelous system. But in those of us who practice
> outside the system, I practice in a hospital of 520 beds. We have
> 7,000 deliveries a year.
>
> When we look at those numbers, and a lot of our population is the
> working poor, who earn \$20,000 or less a year, many of them are
> single parents, they don\'t have vehicles to come back to the
> hospital. With the new HMO systems, in spite of the federal mandate
> that the kids will stay in the hospital, the newborns will stay in the
> hospital for 48 hours, the mothers are sent home earlier by HMOs or
> they choose to go home because they have got three or four other kids
> at home and they need to go home.
>
> We then say, well, you had better come back and get a bilirubin in two
> days, three days, they don\'t come because they don\'t have
> transportation. Our system is very difficult. It is very different
> from the Kaiser system or other systems in the west side of Los
> Angeles as opposed to where we practice.
>
> I practice in southeast Los Angeles. Then, we have been tracking. One
> of the things I also do is I head California\'s program for hospital
> accreditation. In that role, I go up and down to California hospitals
> and we survey them for accreditation.
>
> One of the things we are looking at now, and one of the things front
> and center, both in Washington and in Sacramento, is patient safety.
> We are now looking at the babies who come to the hospital or show up
> in the emergency room from the time they are discharged from the
> hospital until 21 days of life.
>
> In my hospital last year, I pulled the figures out, we had close to
> 7,000 deliveries. The exact number was 6,987 babies. Out of that, 535
> babies came back to the emergency room in the year 2002 for jaundice
> and poor feeding. We have not been looking at those figures.
>
> I don\'t have the numbers of how many were readmitted to the hospital.
> Now, that is a major problem for us because when these babies go home,
> a large number of our babies belong to parents, as I said, that really
> can\'t afford to come back to the hospital, can\'t afford the taxi
> fare, can\'t afford or do not want to come and get the kids stuck two
> or three times when the bilirubin is up, and they really don\'t want
> the kid in the hospital, they want the kid to go home.
>
> Then, when you say to the mother, when we call the mother say, you
> know, how come you didn\'t bring the baby for the blood test, they
> say, well, my other two children are sick or I don\'t have
> transportation, or my husband is working on the night shift or day
> shift, whatever, it is a problem for us.
>
> So, I have 37 pediatricians. This year I happen to be Chairman of the
> Department of the Department of Pediatrics, have 37 practicing
> pediatricians in my department. You know, they are looking for a
> better way to take care of these kids who are jaundiced. We are now
> using the carbon monoxide studies for the Bhutani graphs, trying to
> find out which babies the bilirubin is going to go up, et cetera, and
> we are having difficulty with that, because we know these kids, it is
> going to go up, we want to measure the bilirubin in two or three days.
> They don\'t come.
>
> So, what I am saying to you as a practicing physician out there, the
> practicing pediatrician out there, we need some help. If there is a
> compound available, a pharmaceutical agent available out there that
> can help us with these kids, because they are really, in the real
> world, they are not going to get two and three blood tests of
> bilirubin to come back.
>
> Somebody said, Dr. Bhutani said it costs one dollar to get a total
> bilirubin, Dr. Lucey said it costs \$35.00 in Vermont, so I don\'t
> know what it costs where, but it is not cheap, and to get the thing
> done, we are allowing these kids to stay at a risk that is there.
>
> Dr. Newman asked a very important question during his talk. He said
> how can we reduce the occurrence of kernicterus. For me, as a
> practicing pediatrician, my question would be how can we eliminate
> kernicterus.
>
> Thank you for allowing me to talk to you.
>
> DR. CHESNEY: Thank you very much.
>
> Our next speaker is Dr. Jerold Lucey, who is a Professor of Pediatrics
> and Neonatology at the University of Vermont, and has been a mentor
> for many of us with respect to his years of writing, teaching, and
> advocating for infants and as the long-time editor of the Journal of
> Pediatrics.
>
> DR. LUCEY: I paid my own way. I am a friend of Dr. Kappas, but he
> doesn\'t have to pay me for that.
>
> Being almost the last one on this program is sometimes an advantage.
> You can always say, well, everything that has been said worthwhile has
> been said already, and I think I can plead that somewhat, but I am
> probably the only one in the room that goes back to the Shaw, Diamond,
> and Allen era in Boston when they invented the level of 20 mg percent.
>
> I have done hundreds, I think I stopped counting, exchange transfused
> at number 500. So, let me say something about exchange transfusions.
> Nobody has made clear the fact that there is about a 1 percent
> mortality rate with these, and it happens in well babies, and there
> have been articles written about it in the old days, but nobody ever
> really solved the problem of why these babies died.
>
> I can remember probably every single one of the ones that died on me
> because they stunned you. You went out and talked to a mother, said we
> are going to do an exchange, and there is a very low risk, and then,
> boom, the baby\'s heart stopped during the thing and they couldn\'t
> get it started. So, that is still there, and I think there aren\'t a
> lot of people who are very adept at doing exchange transfusions
> anymore.
>
> So, that is an effective therapy all right, but it has with it a
> little risk.
>
> Now, the first time I met Dr. Kappas was when he presented his first
> paper on hemoxygenase inhibitor and right away I knew the days of
> phototherapy were limited, because here was something that you look
> forward to, a shot that you could give.
>
> I have been responsible for the introduction of phototherapy in the
> United States, doing a randomized trial in the late 1960s, and, first
> of all, people didn\'t believe it. I started out thinking light would
> never work myself, as a matter of fact.
>
> It was done because I had a Chilean research fellow who they were
> doing it using it all over in South America and Italy and France, but
> I am monolingual and I never read any of these articles. When my
> research fellow came to me, he said why aren\'t you doing
> phototherapy, I said, oh, it doesn\'t work.
>
> If you look at the early papers as far as evidence is concerned, that
> first paper didn\'t convince very many people. It came out in \'58 and
> nobody in the United States started using it until after we at least
> did a randomized trial in \'68.
>
> Then, there was 10 years, you know, phototherapy would never pass the
> FDA regulations, I think, at this point, or take years to do it. In
> those days, all you had to do was prove that the therapy was
> effective, and people started using it because it was a device, and
> obviously, the device was safe, nobody ever got too hurt by a light
> bulb unless they touched it or something.
>
> So, there was a therapy that came in and then there was just an
> academic debate that went on for a decade because actually there
> wasn\'t a way of telling where did the bilirubin go, where did the
> yellow go. That took about 11 years to be worked out, and there is
> still people who worry about phototherapy.
>
> You will be presented tomorrow, I gather, when you are making your
> deliberations on tin mesoporphyrin about what are the long-term
> effects. Well, to get long-term effects, it takes a long time. Bill Oh
> summarized all the limitations of phototherapy. There is certainly
> several of them. They can be handled, but if you wanted to be a
> purist, you could say, well, nobody has ever followed those people for
> 30 or 40 years.
>
> Well, please remember that very few, I don\'t know of any drugs that
> have been followed where somebody who introduced and then followed the
> people for 30 years. That is just not possible. So, I think you are
> going to have to take a chance.
>
> When I got interested in light and realized it worked, my idea was
> that we give it to everybody, because I had the idea that if you
> walked around on the outside and didn\'t get hurt, and that was 10,000
> times more radiant energy than you got from the light therapy, then,
> this is probably going to turn out to be safe.
>
> So, if you read the little paper carefully, you will see it was
> proposed as a way of preventing jaundice in newborn infants. It
> hasn\'t been used that way anymore because people got worried about
> separation from mothers and the effect of blinders, and everything,
> and we backed off, and that may be one of the reasons why you are
> seeing more\--I mean as phototherapy went down, maybe the incidence of
> kernicterus went up, but we started seeing more anyway.
>
> Then, I got really disenchanted with the field because I didn\'t see
> any way out how you could ever do a study in which you would allow a
> level to go up to something that was toxic and then have a control
> group, so there aren\'t any real possibilities for much of a control
> study with a high risk group out there.
>
> I wrote a thing called, The Bilirubin Mess. There never was a level,
> there never will be a level, which I still believe. Judging the
> toxicity of a certain level versus the baby in the situation, I just
> don\'t think is a practical approach.
>
> Other people have held onto the idea that maybe you should do unbound
> bilirubin, scientifically, quite sound, practically, not apt to be
> very practical.
>
> So, I would urge you to look at new proposal before you as far as the
> treatment is concerned and that we proceed on two levels. One is use
> the new treatment, approve the new treatment, use it and then start
> doing some other studies with it, and try to selectively treat as few
> babies as you can by using some variation of Dr. Bhutani\'s graph for
> picking out babies.
>
> Thank you very much.
>
> DR. CHESNEY: We have two more speakers, Dr. Timos Valaes, a clinical
> instructor in the Pediatric Program at Boston University.
>
> DR. VALAES: It is an advantage and a disadvantage to be one of the
> last speakers. The advantage is that you know, you have heard what
> everybody else has said. The disadvantage is that you cannot have
> prepared slides of anything because then you will repeat what some of
> more eloquent people have already said.
>
> First of all, I guess I have to do my disclosure part, and I am
> Professor Emeritus at the Tufts University School of Medicine in
> Boston, and I have been involves with the tin mesoporphyrin studies in
> Greece from 1988 to the year 2000.
>
> During this 12-year period, I spent 50 percent of my professional time
> doing the studies. The studies were, as you heard, supported by
> National Institute of Child Health and Human Development and when the
> contract was over, the WellSpring Pharmaceutical Corporation became
> the custodian of the computerized database and also paid for the last
> months the nurse practitioners that was involved with the five-year
> follow-up. So, that is my contact with the company.
>
> When they asked me while I was traveling if I am interested in
> attending this meeting, they volunteered to pay my travel expenses
> from Boston to here.
>
> Having said that, I must say that I have not yet recovered from the
> emotional impacts on me from the speech, the presentation rather than
> the speech, of Mrs. Sheridan. The reason I am so involved and impacted
> by her presentation, that in my earlier professional life, I had the
> bad luck of having seen more than 300 cases of kernicterus.
>
> This was after my training in England where I was part of the
> revolution there in taking care of the Rh disease babies and see the
> marvelous disappearance of kernicterus from this cause by the timely
> use of exchange transfusion.
>
> Then, in \'59, I went to Greece, established an exchange transfusion
> service at the State and University Maternity Hospital in Athens, and
> we eliminated kernicterus in that institution, but this left the rest
> of Greece without the help of phototherapy, sending us very late, as I
> said, hundreds of babies and where we could do nothing to save them or
> alleviate their condition.
>
> Then, phototherapy came and the problem was no longer there, and then
> I decided to come to Boston, not because I was looking for the
> problem, no, I was looking to get away from it.
>
> Having said that, I think I need to iterate a few things. Neonatal
> jaundice is a self-resolving condition and all we do with whatever
> measure we take is to buy time for the small minority of babies that
> are going to develop kernicterus.
>
> Kernicterus can be prevented, but cannot be treated, and every
> epidemiologist knows that if it is prevention, you have to treat many
> more patients that will eventually develop the condition, if not for
> the preventive measure.
>
> It is also very well established that if a preventive measure succeeds
> in eliminating the disease, then, the medical profession and the
> public start questioning whether really the preventive measure is
> necessary. This is exactly what happened with kernicterus. We have
> been trapped by our own success in eliminating kernicterus.
>
> What happened, we allowed, or as pediatricians, for a drastic
> reduction of the in-hospital observation of babies, and we are now
> experiencing another thing again. The safety margins for exchange
> transfusion or for phototherapy or for tin mesoporphyrin for
> intervening have been compressed, and this compression means that it
> is not only the levels of bilirubin between these different things
> that are reduced, but is also the time available for us to make the
> intervention, particularly if the baby is already home and there is no
> beeper in the baby\'s system to tell the physician when the target
> call for action has been reached, and there is a lot of delay, and
> that is really what is happening everywhere.
>
> I have produced a mathematical model to show how really bilirubin
> level, a time key anytime during the first week of life has been
> reached. As you see there, there is a cumulative rate of bilirubin
> production involved. It is not one rate, it is a cumulative, because
> this rate changes, it decreases throughout this period of time.
>
> The cumulative intrahepatic circulation of bilirubin is one side and
> then the cumulative rate of bilirubin elimination, and that again is
> not one rate, it is a continuously changing, fortunately increasing
> rate of elimination.
>
> Phototherapy intervenes in this process by increasing elimination. Tin
> mesoporphyrin is acting on the other side by decreasing production,
> and it does it very efficiently and for enough time, at least 7 to 10
> days, so that you only have to give it once.
>
> There is an historical paradigm available to us, how you react to a
> situation like this. There is a condition known to all the
> pediatricians known as hemorrhagic disease of the newborn. It is a
> developmental situation. The baby is born with a low level of vitamin
> K dependent clotting factors. They go further down, particularly in
> breast-fed babies, and this tendency can be reversed by a single dose
> of vitamin K.
>
> In the \'40s, there was a lot of discussion, the commonality is, first
> of all, that there is not one level of clotting\--low level of
> clotting factors that will be for certainly related with clinical
> manifestations, and there is a continuous change of these factors
> different from one baby to another, similar to what is happening with
> bilirubin, and there was a lot of discussion in the \'40s and \'50s
> whether you should be giving vitamin K, which corrected the
> abnormality definitely well proven, to the mother, so that the baby is
> protected during a traumatic delivery, to the baby orally, and the
> problem there was that there was not an oral preparation, but who
> cares, you open the ampule of the intramuscular preparation and you
> pour it into the baby\'s mouth.
>
> But then in 1961, the American Academy of Pediatrics stepped in and
> pushed aside all this controversy, and without any single sort of new
> study that was reported as pushing them in this decision, decided that
> every baby should get an intramuscular injection of vitamin K, and
> this was enough and sufficient to make the complete disappearance and
> make early and classical analytic \[?\] decision of the newborn
> eliminated, and it is a historical sort of condition for most of the
> pediatricians.
>
> Now, what I said had happened, with the British and some other people
> first, questioning why should every baby get an injection. They
> started saying it is not necessary and they stopped giving it, but to
> cut the story short, the American Academy of Pediatrics again
> intervened, I think it was two or three years ago, and said no, let\'s
> forget about all this discussion and go back to the intramuscular
> injection and continue the practice that was there.
>
> Now, of course, this is a different situation we are talking about
> because now we have to introduce a new practice, and not really stick
> with the old one.
>
> Thank you. I didn\'t see any light, sorry.
>
> DR. CHESNEY: We don\'t have a light. That would be an excellent
> suggestion. I don\'t think they anticipated quite so many people for
> the open session. I thought you made some very excellent points.
>
> Our last speaker is Dr. Murray Goldstein, who is the Medical Director
> of the United Cerebral Palsy Research and Education Foundation and
> former Director of the National Institutes of Neurological Disorders
> and Stroke, and a former Assistant Surgeon General.
>
> DR. GOLDSTEIN: Madam Chairman, I apologize for being late. I
> apparently misunderstood the time frame of your agenda. You have
> already introduced me, so I shan\'t introduce myself.
>
> I guess I need to say I have no personal social, working, or other
> relationships with any industrial organization relevant to this
> discussion.
>
> First, I would like to take a moment to congratulate the staff of the
> subcommittee. The thoroughness of its concise staff paper of May 14,
> summarizing the state of present knowledge on hyperbilirubinemia of
> the newborn, and, two, the significance and specificity of Dr.
> Cummins\' charge to the subcommittee.
>
> Having been in government for a number of years, I appreciate both the
> technical excellence of these documents and the sensitivity with which
> they were written. Great staff work.
>
> I have already submitted a brief document on kernicterus for this
> committee\'s consideration and on the role of hyperbilirubinemia of
> the newborn as an important etiologic factor in athetoid cerebral
> palsy. This information is in your folder, and so I won\'t spend time
> repeating it. However, I do need to point out that athetoid cerebral
> palsy is one of the severest forms of cerebral palsy and is
> characterized by a serious lifelong interference with activities of
> daily living.
>
> Also, in the past, it was one of the more common manifestations of
> cerebral palsy. The important findings of a generation ago in early
> diagnosis and therapy essentially removed kernicterus from the screen
> of medical attention.
>
> I daresay there are very few medical house officers today who have
> ever seen a case of kernicterus. Also, I would guess they probably
> will have difficulty recognizing it if it was presented. In essence,
> as a medical research and public health community, we have assigned
> kernicterus and its consequences to the category of benign neglect.
>
> As presented here by previous speakers, the reasons for this benign
> neglect may no longer be appropriate. Although kernicterus is still a
> rare disorder, it appears to threaten to re-emerge.
>
> As my paper indicates, there are a number of clinical care, medical
> research, and public health measures that now demand additional
> attention from both government and nongovernment sources.
>
> To be specific about the role of the FDA in this new agenda, first, I
> urge the subcommittee to advise the FDA to give targeted and priority
> attention to the use of its authority to meet its agency-designated
> responsibilities under the Orphan Drug Act.
>
> This Act was passed to stimulate and support needed research
> development on (a) improvement in the diagnostic criteria and
> methodologies for early identification of hyperbilirubinemia in the
> newborn; and (b) the development of more definitive clinical
> interventions for the treatment of this disorder.
>
> I had the privilege of being one of the people who helped design the
> Orphan Drug Act and was a member of the Assistant Secretary of
> Health\'s subcommittee that designed the specifics of it. Unless that
> Act has been changed, and I don\'t think it has been, I believe the
> need for its use as an instrument of the FDA is imperative, and it was
> designed to do such.
>
> I also suggest that the subcommittee recommend that the FDA use its
> administrative procedures for expedited review to evaluate the results
> of this research and development activities.
>
> These actions on the part of the FDA would meet its unique
> responsibilities for addressing this potentially serious problem of
> infancy. Although kernicterus is not a public health problem of the
> size of SARS or AIDS, to the parents of infants and children with
> athetoid cerebral palsy, one case of kernicterus is one case too many.
>
> Madam Chairman, thank you for your attention and I would be pleased to
> attempt to respond to any questions the subcommittee may have.
>
> Thank you.
>
> DR. CHESNEY: Thank you very much.
>
> We need to move on to Dr. Nelson\'s presentation next and then we will
> be addressing Questions 2, 3, and 4. As a personal favor, in order to
> reinstate my credibility as somebody who sticks to the time, which I
> have lost already, I am going to ask Skip if he could shorten his
> presentation by some amount of time.
>
> Thank you.
>
> **Ethical Issues**
>
> DR. NELSON: What I would like to present today is four sets of
> reflections on four different issues. It is not meant to be a complete
> presentation of the ethical issues in drug development in this area,
> but to stimulate our conversation. I think they have been touched on
> at different points in time.
>
> You have the complete slides, so I will sort of, in the interests of
> time, move through them rather quickly.
>
> \[Slide.\]
>
> The first point I want to make is on surrogate endpoints, but for
> those of you in the audience, I don\'t have a biochemical pathway, but
> this is a regulatory pathway which, in your handout, is presented as a
> full page document as the last page of the handout, and it shows you
> how you move through 21 CFR 50 and 56 in the case of the FDA, or 45
> CFR 46, and to orient my remarks according to this regulatory pathway,
> the first question being sound research design.
>
> \[Slide.\]
>
> The first point we need to ask, as we are looking at drug development
> is sound research design, and the issue I want to raise if the choice
> of endpoint, surrogate endpoint.
>
> \[Slide.\]
>
> The primary goal for the treatment or in fact prevention, since I will
> have some reflections on prevention, of hyperbilirubinemia is to
> prevent kernicterus and other irreversible neurodevelopmental
> impairment in case some of the concerns about other impairments at
> lower levels of total bilirubin are confirmed.
>
> The association with total bilirubin level suggests that the control
> of this level may be an appropriate surrogate endpoint, but even
> within that, we still have other possible surrogate endpoints -
> bilirubin above 20, bilirubin above 25, bilirubin above 30, maybe
> something lower, peak or maximum bilirubin comparing two interventions
> or an intervention against a non-intervention control, or decrease in
> the use of other treatments, such as exchange transfusion and/or
> phototherapy. All of those are surrogate endpoints.
>
> \[Slide.\]
>
> A set of quotations from an article by Fleming and DeMets in the 1996
> Journal of Annals of Internal Medicine where they looked at surrogate
> endpoints, and these are several points they made about the use of
> surrogates:
>
> \"The surrogate must be a correlate of the true clinical outcome and
> fully capture the net effect of treatment on the clinical outcome;
>
> \"To be a valid replacement endpoint, a surrogate must provide a high
> level of accuracy in predicting the intervention\'s effect on the true
> clinical endpoint;
>
> \"The primary goal (in these definitive phase 3 trials that they were
> discussing) should be to obtain direct evidence about the
> intervention\'s effect on safety measures and true clinical
> outcomes.\"
>
> So, I am not going to answer the question, but the question is what is
> the appropriate endpoint to use in some of these studies. I think it
> is fairly clear it is not kernicterus. The question then is what is
> it.
>
> \[Slide.\]
>
> So, now some reflections about the justice of healthcare distribution,
> and I am going to actually present some data from California. I think
> it might even be Southern California, but I am not sure.
>
> \[Slide.\]
>
> But the point is raised by this notion of equitable selection. Now,
> usually, equitable selection means if you have a research trial, that
> you equitably select those who go into the trial, so I am using this,
> though, to raise some more general questions about equitability.
>
> \[Slide.\]
>
> What struck me in looking at the AAP\'s document on neonatal
> hyperbilirubinemia, which looks like it was also reflected in the same
> list that Dr. Bhutani put up, is that the root causes of kernicterus,
> if you look at them all, early discharge with no early follow-up,
> failure to check, failure to recognize, underestimating, lack of
> concern, delay, failure to respond, all of these are behavioral
> aspects, all of these are systems issues that appear to be totally
> unrelated to phototherapy, unrelated to the giving of a medication.
>
> Now, I am not presuming to say what the answer is to correct the
> deficiencies, and I also agree with the comments that you don\'t look
> for a behavioral solution. Practicing in an intensive care unit, we
> need systems to correct this, but question is what is the best system
> for correcting these root causes - is it drug development, is it
> universal screening, is it some other process.
>
> \[Slide.\]
>
> Now, the issue of equitability was raised for me in looking at an
> article that came out in Pediatrics just recently, again based on data
> from the 1999 California Maternal and Infant Health Assessment.
>
> In looking at the adjusted odds ratios for either early discharge or
> for inadequate follow-up with early discharge described as less than
> two days after vaginal delivery or less than four days after cesarean
> section, and the particular question was, in spite of the fact that we
> had a federal law stipulating that they had to be provided, who
> didn\'t get it.
>
> \[Slide.\]
>
> At least for early discharge, the only variables that fell out as
> important was maternal income, and that was the adjusted odds that you
> see there in terms of predicting who got discharged early, odds ratios
> for untimely follow, and I see the formatting here didn\'t work quite
> perfectly, but basically, maternal race or ethnicity, Latina, maternal
> income again, Medicaid insurance, or the primary home language being
> non-English, those were the predictors of untimely follow-up. So,
> those infants who were born to mothers that had these criteria were
> those that were at risk for not having appropriate follow-up.
>
> Now, that may reflect a number of different factors that were outlined
> by our speaker from Southern California, but this is the population
> that, in fact, is at risk. So, it would also be the population that is
> at risk for whatever intervention we decide to design.
>
> \[Slide.\]
>
> The authors point out that this is an inequitable pattern.
>
> \[Slide.\]
>
> Now, what is interesting to me is if you rely on the IRB system to
> help with these kind of public policy decisions, you will be sorely
> disappointed because actually in the regulations, the IRBs are told
> that they shouldn\'t pay attention to the impact of research on public
> policy, and this is a direct quote from both FDA and it also is
> mirrored in the HHS regulations:
>
> \"The IRB should not consider possible long-range effects of applying
> knowledge gained in the research (for example, the possible effects of
> the research on public policy) as among those research risks that fall
> within the purview of its responsibility.\"
>
> But the question before us is, does that fall under the FDA\'s mandate
> in terms of promote and protect the public health.
>
> \[Slide.\]
>
> Let\'s talk a little bit about treatment versus prevention. In
> reflecting on this, it struck me that the paradigm has always been one
> of prevention. It was mentioned by a number of speakers. There is no
> treatment for kernicterus.
>
> So, the choice of total bilirubin of 20, I was taught, and it was, of
> course, in Boston in the early \'80s that part of the reason for this
> number of 20 was the balance between the risks of kernicterus and the
> risks of exchange transfusion. Now, whether or not that was ever
> carried out in a systematic way, who knows, but that at least was the
> argument for picking 20, that if you did it at a lower level, you are
> exposing an inappropriate number of infants to the risk of mortality
> and morbidity from the exchange transfusion.
>
> Now, the choice of the lower level for phototherapy reflects a
> judgment of the greater safety of phototherapy versus exchange
> transfusion, and it had the particular therapeutic goal of preventing
> the need for exchange transfusion, again, a surrogate outcome.
>
> The intervention then, in reflecting on this, is designed to prevent
> the need for phototherapy, if you chose that as a surrogate outcome,
> should prove at least as safe as phototherapy, assuming equal efficacy
> in limiting peak bilirubin level.
>
> \[Slide.\]
>
> So, the risk-benefit that we need to look at depends very much on the
> endpoint that we select, whether we pick preventing kernicterus,
> preventing the need for exchange transfusion, some maximum bilirubin
> level whether it is 20, 19, 18, 17, 16, 15, whatever number we pick is
> going to mandate then a different balancing of the risks and benefits
> for each endpoint.
>
> The safe and efficacy tradeoff, nothing is ever perfectly safe and 100
> percent effective. There is going to be a balancing.
>
> The risks of developing kernicterus and/or other irreversible
> neurodevelopmental impairment should be at least equal to the risks of
> an intervention at any given bilirubin level, again assuming that
> it\'s 100 percent effective. If it\'s less effective, then, of course,
> perhaps the risks of the intervention need to be even less.
>
> \[Slide.\]
>
> Now, this reflects to some extent the notion of equipoise, the
> position within which we are truly uncertain whether we are uncertain
> as an individual or at least uncertain as a community of experts about
> the comparative merits of the two different interventions.
>
> \[Slide.\]
>
> In trying to take this notion of equipoise into this setting, I tried
> to ask myself what does it mean to say I am in equipoise or we are in
> equipoise in this setting. It is that level of bilirubin at which the
> risks of the intervention are comparable to the risks of irreversible
> neurodevelopmental impairment, what are the risks of that bilirubin
> level again assuming effective intervention.
>
> Other ways of stating this is that the risks of whatever intervention
> we are considering using, whether phototherapy, exchange transfusions,
> or medication, to stop the rise in bilirubin needs to be comparable,
> balanced with the risks of the impairment of that bilirubin level,
> below bilirubin at that point, the risks of the intervention exceed
> the risks of the actual condition itself.
>
> \[Slide.\]
>
> Now, the treatment paradigm is perhaps applicable for a subpopulation
> of newborn infants at known risk. It struck me as interesting that
> most of the early studies were done in infants with increased
> production, so I asked myself whether going forward we should begin to
> make distinctions between, if you will, a condition of production
> versus slow elimination and begin to parse out the population of
> infants that are at risk for elevated bilirubin in that manner and
> begin to wonder should there be differential interventions based on
> that.
>
> This, of course, if went that direction, would have a big impact on
> the kinds of target populations that we would select for our
> interventions, whether it is newborn infants with increased production
> or so-called healthy infants who may have an elevated bilirubin due to
> slow elimination.
>
> \[Slide.\]
>
> This has been touched on a bit. One of the major issues that we need
> to talk about is at what risk for what, and, of course, the numbers
> needed to treat for any given intervention at any given bilirubin
> level will impact then on the risk-benefit assessment of that
> particular intervention, and these are just numbers that were taken
> from the reports that were part of today\'s documents.
>
> So, there are really two questions: what is the acceptable false
> positive rate for selecting infants at risk for an elevated bilirubin,
> say, above 10 at any given bilirubin level? Another way of asking
> that, which was an earlier question by Norm Fost is what is the
> acceptable false negative rate, if you will, upon discharge if you are
> trying to exclude infants for coming back for follow-up for bilirubin.
> All of these are questions that we will need to struggle with, the
> answers of which are not, from hearing the discussion, obvious to me.
>
> \[Slide.\]
>
> Finally, what about the ethical and regulatory issues in study design.
> Now, briefly, when we look at pediatric research, if that child is not
> going to have the possibility of direct benefit, there is limits about
> what we can do as far as risk, and even if the child is going to
> benefit, there is limits about the justification for that risk
> exposure.
>
> \[Slide.\]
>
> I am not going to spend a lot of time on the non-therapeutic risk in
> the interests of efficiency, but basically, this notion of minimal
> risk, which is debated about how it should be interpreted, but
> basically, tries to get a handle around the risks that if there is no
> benefit to that infant, we should restrict those risks to no greater
> than minimal risk, of if we consider that infant to have a condition,
> maybe a minor increase over minimal risk.
>
> So, when you look at some of the components of a study, certainly
> blood sampling and PK data, you know, regardless of whether or not a
> parent wants their infant to be stuck with a needle, that\'s a
> separate question, or would consent to that.
>
> I think most IRBs would consider that if the sampling follows closely
> sort of the routine sampling you would have for the following of a
> child with hyperbilirubinemia, that they would consider that sampling
> either no more than minimal risk or even a minor increase over minimal
> risk, but either one would likely be approvable by an IRB if it
> followed kind of what our standard practice is, and generally, blood
> sampling is considered minimal risk even if it went above that to a
> reasonable number and volume and frequency. So, I don\'t think that is
> the issue.
>
> \[Slide.\]
>
> The issue is going to be then judging the intervention itself. The
> regulations, although they predate this notion of equipoise in the
> literature, I think roughly try to capture this notion of equipoise or
> balancing, and this is taken from the regulations themselves and it
> particularly is 21 CFR 50.52, which is the FDA version of the
> pediatric regulations.
>
> The IRB is supposed to allow a trial to go forward if there is two
> things that that trial satisfies under the assumption that that infant
> has the prospect of direct benefit.
>
> The first is that the risks must be justified by anticipated benefits.
> That is within each arm of the trial, so that the risk of the
> intervention and the anticipated benefit of that intervention is
> relatively matched for that particular arm.
>
> So, for example, if there is a placebo intervention, you are going to
> assume then that the risks of the placebo and the benefits to that
> infant are roughly balanced, and that is what I call internal
> equipoise. Each arm of the study has to have that kind of balance.
>
> But then there is another relationship that I call external equipoise
> or even equipoise between the arms, which is this risk-benefit
> relationship needs to be at least as favorable as available
> alternatives, and it is sometimes lost in the discussion of this, that
> it is not only the two arms of the trial itself, but it is also what
> that infant may or may not be getting that they would otherwise
> receive, so that you need to have a sense that there is balance
> between the interventions and the arms. That needs to be the balance
> within this case. I could give examples, but I would probably come up
> with ones that are not pertinent to bilirubin.
>
> So, the question is are the risks of the intervention justified by the
> anticipated benefit. This relates as much on the selection of
> outcome - the risk of a medication to avoid phototherapy, the risk of
> phototherapy to avoid a bilirubin above 20, the risk of a medication
> to avoid kernicterus. Each one of these has a different risk-benefit
> balance, and each one of these, depending on how you designed a trial,
> to put one arm against the other, would have a different sense of
> whether we would be more or less certain about the balancing between
> those interventions.
>
> Then, again, the risk of medication versus the risk of phototherapy at
> any bilirubin level, for example, if you decide to treat at 17 or 16
> or 15, what would you say to a mother who is asking what is the risks
> of phototherapy at this level versus the risks of a medication, and
> could you say that medication in the trial or at least in the trial
> where you are randomized perhaps to phototherapy or medication, is, in
> fact, in equipoise.
>
> That is a question that we would need to ask and answer in the
> affirmative for a trial to be able to go forward.
>
> \[Slide.\]
>
> So, to justify a risky or less safe intervention requires a greater
> anticipated benefit, and not simply the ability to achieve the benefit
> whether achieving that benefit is worthwhile. So, that is a question
> we have to ask.
>
> I think I am leaving you with my final question, which is sort of a
> whirlwind tour through my remarks, which is I think the important
> question that we need to ask and answer, and I suspect we will not be
> able to answer it today, but whether we end up in the same position
> both looking at the issue of sound research design with respect to
> surrogate endpoints, but also looking at the sort of ethical analysis
> of equipoise, is that really the key issue here is appropriate outcome
> selection to reflect genuine benefit for the selected target
> population, so we need to define in the course of answering that
> question, not only are outcomes that we think are appropriately
> selected for the design of a trial, but what benefit we anticipate
> achieving by having selected that outcome and then what population we
> think that is appropriate to then target out interventions towards in
> order to make a change in that outcome.
>
> Thank you.
>
> DR. CHESNEY: Thank you very much.
>
> I think this is such an important issue, are there any questions? We
> could probably entertain a small number of questions for Dr. Nelson
> before we go on with the official questions.
>
> DR. FREEMAN: May I ask a question of Dr. Nelson? If the FDA is not to
> be involved in policy, in social policy questions, and the IRBs are
> not to consider social policy questions, then, if you are going to use
> a medical intervention to avoid phototherapy and the consequences of
> hyperbilirubinemia, and since as the problem has been presented to us
> with phototherapy, it\'s the women getting discharged early and the
> difficulties coming back, how do you factor that into the equipoise?
>
> DR. NELSON: Maybe I stated it too quickly. I think the IRBs are
> directed not to look at issues of public policy, but personally, I
> think that although FDA may or may not agree, I think is within the
> purview of this notion of promoting the public health, and where that
> comes in is trying to decide what\'s the appropriate safety and
> efficacy profile since, you know, what does safe enough and what does
> effective enough mean in the context.
>
> As I recall that first slide that went up, that Dianne Murphy showed
> where the different balancing is, where do you balance that relative
> to the volume of individuals that a certain drug would be targeted for
> and the indications. So, I do think that is within the purview of
> trying to decide from a public policy perspective what is the
> appropriate intervention.
>
> The only question I am raising is when a lot of the root causes for
> this are systems issues that are unrelated to the drug. Maybe a drug
> development program would answer that, maybe it wouldn\'t, maybe
> universal screening would answer that, which is what I heard a number
> of our speakers argue for, maybe some other systems approach within
> the healthcare setting would begin to address that.
>
> I was simply raising that question for our consideration.
>
> **Discussion of Questions 2, 3, and 4**
>
> DR. CUMMINS: First, I want to thank everyone for sitting through quite
> a complex series of presentations and also comments during our public
> hearing.
>
> We don\'t have our questions available to you as PowerPoint files, but
> you do have a handout in front of you in the packet that was set out
> in front of you today, that have all the questions on them in the
> second page following the agenda. Tom is trying to load them now, but
> we can also start to walk through them.
>
> We actually decided to skip Question 1 and go straight to Question 2,
> and we reordered the agenda today because we felt it was important
> that Dr. Nelson\'s talk go before Question 2, and I will read that to
> you now. It\'s a multi-part question and we would like you to really
> discuss the various issues that are raised in this question.
>
> Question 2. In the context of current medical practice, including
> phototherapy, should drugs be developed for an earlier intervention to
> prevent hyperbilirubinemia in newborn infants?
>
> In answering this question, we would like you to please discuss the
> following:
>
> Your understanding of the relationship between bilirubin toxicity and
> neurodevelopmental outcome;
>
> How you define the population at risk for complications of
> hyperbilirubinemia;
>
> The intervention sequence and what that might be, should it be more
> screening\--and these are just examples, there might be other
> interventions that we have not mentioned\--but examples might include
> more screening, additional monitoring and assessments, phototherapy,
> hydration, pharmacotherapy, cessation of breast feeding, changes in
> infant nutrition, home nursing visits, and why would you propose that
> intervention sequence.
>
> Let me just also say for those of you that are new to this process,
> what we will do is we will discuss each of these questions for about
> 15 to 20 minutes, and then we will move on to the next one. That is
> how the question process works.
>
> With that, I will turn to Dr. Chesney and open the committee up for
> discussion.
>
> DR. CHESNEY: So, we are being asked the question of should drugs be
> developed for an earlier intervention and to take into consideration
> our understanding of bilirubin toxicity and neurodevelopmental
> outcome, who are the high risk populations, and with respect to the
> intervention sequence.
>
> Comments?
>
> I should also tell you that it has been suggested to me that we do a
> round robin after Questions 3 or 4, so that we hear from everybody, so
> everyone will have to come to grips with this issue at some point.
>
> Dr. Mattison.
>
> DR. MATTISON: I guess there is no reason to think that therapeutic
> strategies including medications should be excluded from consideration
> in dealing with strategies to prevent hyperbilirubinemia, but it seems
> to me that the question has behind it a set of qualifiers or steps
> that may need clearer explication, for example, and it has been
> brought up repeatedly in the presentations, one of the areas that
> appears to be missing in terms of thinking through the issue of
> hyperbilirubinemia is the actual strategy for identifying those kids.
>
> So, while drugs might be a good strategy, it seems like the basic
> public health surveillance that we often use to identify our problem
> hasn\'t yet been put in place.
>
> So, I am not answering the question, I am backing away from it
> perhaps.
>
> DR. MURPHY: I think you are giving us the level we are trying to lay
> out of all the issues that you have been presented today - what would
> be the role of drug development in this environment and how do we deal
> with these issues of definitions of occurrences, definitions of when
> we intervene, outcomes, you know, those all are things that you have
> heard about in various forms today, that you would try to synthesize
> that into some thoughts about how one would go about considering
> developing a product in this arena when you have to address some of
> these issues of what is the relationship because we have to be able to
> know what the endpoints are, and to be able to get to the endpoints,
> you have got to know where you are going to intervene.
>
> Again, it is trying to bring back all those issues you heard today to
> an approach developing products in this present environment. So, you
> were right, it is trying to synthesize all that into a few bullets.
>
> DR. CHESNEY: Dr. O\'Fallon and then Dr. Danford and Dr. Hudak.
>
> DR. O\'FALLON: The question here is really a mixture of a whole lot of
> stuff and I think we have to sort out what the major themes really
> are. I think the very first theme is a matter of, as you said,
> identifying the patients, the babes, the children that are truly at
> risk.
>
> So, there is a whole diagnostic issue that needs to be dealt with, and
> it has nothing to do with treatment, it has to do with diagnosing and
> characterizing that.
>
> The second part is okay, if we are going to treat, it sounds like
> there are only two treatments right now, the treatment quiver has only
> two arrows in it, and a third one sounds like it would be very
> appropriate to have a third one, so, yeah, go ahead and develop it for
> something, but how to do that and how to test it brings up all the
> issues that Dr. Nelson was bringing up, all of the design issues,
> choosing an endpoint, you know, and what you are going to buy by it,
> and another thing that was brought up earlier this morning and has
> just been sitting there, but the negative predictive value of these
> treatments.
>
> It is very important, it seems to me, when you have a rare disease, a
> rare condition, that the testing be capable, it is very important to
> prevent a lot of kids that don\'t need it from getting something.
>
> The other part of it is, that has to be dealt with, are the long-term
> effects. I think those of us with more gray hair in this room, the
> problem is that we have been around and we have seen, I can name you
> several treatments that I was told at the beginning, oh, this is
> wonderful, there are no long bad effects at all to it. Yeah, sure.
> They do show up and so there are issues here that have to be dealt
> with.
>
> So, it seems to me there are basically four things going on here, and
> we have got to sort them out and get answers for each one of them.
>
> DR. CHESNEY: Dr. Danford.
>
> DR. DANFORD: I would like to address the first bullet point under
> Question 2, my understanding of the relationship between bilirubin
> toxicity and neurodevelopmental outcome.
>
> Despite the wonderful presentations of a large volume of information
> today, I would characterize my understanding of that relationship as
> poor. I would point to the large numbers of children in Northern
> California presented to us with bilirubin levels in the classically
> scary ranges who seem to be neurodevelopmentally fine.
>
> I would also point to the allusions that our speakers made to perhaps
> some neurodevelopmental issues of more minor importance occurring in
> children whose bilirubin levels were well within the ranges we would
> accept as safe.
>
> I don\'t know what the relationship of that is, and the implication of
> that, as I looked at Dr. Nelson\'s slide, bilirubin levels are not
> necessarily a very good surrogate for kernicterus as he laid out what
> makes a good surrogate. That is a very difficult point for me right
> now.
>
> DR. CHESNEY: Dr. Hudak.
>
> DR. HUDAK: I guess I will make some relatively simplistic answers
> here. I think the first question about the relationship between
> toxicity and bilirubin and outcome is there is apparently a lot of
> biological variability. Some babies can sustain a higher bilirubin
> level than others without damage, others wind up apparently having
> some toxic effects at lower levels, and there is no way of knowing
> ahead of time how a baby is going to behave in that setting.
>
> I think the evidence is persuasive and undeniable that babies don\'t
> get kernicterus without having bilirubin levels that are higher than
> we like to see in most cases with the exception of certain babies with
> comorbid conditions like sepsis where they might get effects that
> lower levels or the blood-brain barrier perhaps is impaired.
>
> So, I think that we have to grant from all the evidence we are not
> going to get any better knowledge about this issue at any time in the
> future, that, yes, there is a relationship between high bilirubins and
> the risk of kernicterus, and it is very variable and it is very
> unpredictable.
>
> The issue of should there be drug development, I think the answer to
> that is yes. I think we are all struggling with how to sort of phase
> that into testing and what are the study designs, but the basic answer
> is yes. If we had a drug that had no side effects whatsoever, I think
> that would be\--and we knew that for a fact\--that would be a
> no-brainer. I think every baby in the country would get a drug to
> prevent hyperbilirubinemia at birth, just like they get vitamin K and
> erythromycin ointment for the eyes, and things like that.
>
> The question is understanding what the level of acceptability of risk
> is with that sort of intervention, and that\'s a big question. If you
> consider we don\'t know how many cases of kernicterus there are in
> this country out of 4 million babies every year, but if it is 1 in
> 200,000, that is 20, if it is 1 in 100,000, it is 40, if it is 1 in
> 50,000, it is 80, so even if you say that it is 100 babies a year, and
> think of that, that is a very, very small percentage.
>
> So, if you say all right, what happens if there is a complication from
> your treatment, that is on the order of 100 out of 4 million, you will
> never find that in a randomized placebo-controlled study. You will
> have to wait and hope and pray that you do not experience that once
> you go to the route of having prophylaxis in every baby. There will be
> no way of knowing until you do that.
>
> But we do need a treatment. Exchange transfusions are not nice, they
> are complex, the expertise is deluded, there are neonatologists out
> there practicing who have never done an exchange transfusion, I
> daresay.
>
> There is a mortality, there are other morbidities, and exchange
> transfusions do not necessarily prevent kernicterus either. I just
> reviewed a legal case from a very well respected busy tertiary nursery
> where a baby came back at two or three years of age with sort of what
> you would call I guess, not the full-blown kernicterus, but a little
> bit of choreoathetoid CP and hearing deficit, and this baby was
> sitting in an intensive care nursery getting bilirubins monitored
> every 4 to 6 hours, and because people were reluctant to do exchange
> transfusions, the bilirubin went up to 32, and this kid had an
> exchange transfusion, but then did have the clinical sequelae.
>
> So, I think that certainly if there had been a drug available to
> prevent kernicterus in that baby, it might have been used at an
> earlier point in time, that baby might have done much better, and that
> would be a relatively limited population.
>
> But I think yes, we do need a drug, we do need some development. The
> real hard questions are who do we treat, when do we treat them, and
> what are the ways that we can develop to sort of improve the system,
> so a lot of these babies don\'t slip through the cracks.
>
> DR. CHESNEY: Yes, Dr. Oh.
>
> DR. OH: I am willing to stick my neck out and say that the answer to
> the question should be yes, and I tell you the following reasons. One
> is that although we don\'t know the exact incidence of kernicterus,
> the fact that we do see them, particularly with the data, in the
> population-based data from New Jersey, suggests that we do have a
> problem, and we also don\'t know what the threshold number is for the
> bilirubin that will cause kernicterus.
>
> On the other hand, understanding the pathophysiology of kernicterus,
> we know that although there is no threshold number that we are worried
> about in terms of producing kernicterus, we do know that the higher it
> is, that might exceed the so-called binding capacity of albumin for
> bilirubin, the more risk you are taking.
>
> So, anything that we can do\--and we also know that phototherapy
> itself has some problem in terms of keeping the levels at a certain
> range on the basis of perhaps, not so much the effect of the therapy
> itself, but the behavior and system involved that might cause problems
> in terms of allowing the bilirubin to a certain level\--and that
> anything that we can do to try and keep the bilirubin level down as
> low as we can will be I think a benefit.
>
> I think it will be a good surrogate, not so much a surrogate for the
> outcome, but in terms of keeping it low enough, so that we are in the
> comfort zone, so to speak. But I hasten to add that any kind of drug
> trial, any development of the drug should be very well designed to not
> only look at the acute, but also the long-term potential side effects
> of a drug that may have some problem that we don\'t know about.
>
> Right now we don\'t know what the potential complication is for this
> particular drug we are talking about, and any drug trial should have
> the safety aspect looked at very carefully before, you know, so that
> we will come out with data will show that, not only that it has some
> benefit, but the side effect is minimal, going to the point about
> balancing the risks versus benefits.
>
> So, that is my comment on the issue. I think the important thing is
> that despite the guideline and maybe because the guideline being too
> gentle in terms of managing the bilirubin, in spite of the
> phototherapy that we use, we are seeing kernicterus in our population,
> and I think that we need to develop another intervention to try and
> improve our ability to handle the bilirubin in the newborn period.
>
> DR. CHESNEY: Thank you.
>
> Dr. Lau.
>
> DR. LAU: I think there is still quite a bit of debate as to whether
> bilirubin is a neurotoxin, but I think in terms of causality, but I
> think the evidence for association is fairly strong.
>
> Then, there is also strong evidence to suggest that by lowering
> bilirubin with the treatment of phototherapy, we would reduce the
> incidence of kernicterus.
>
> For the other question about defining the population, my perspective
> is often from the evidence-based approach of reviewing the literature
> is backward, that is, I often end up with studies rather than
> prospectively designing trials, so the approach that we often take in
> looking at the validity of trials would be what is known as the
> peephole process or looking at a patient population, what intervention
> were examined, and what are the comparators, and then what are the
> outcomes.
>
> I think we have discussed a lot of those issues today, and those are
> not easy things to tackle in a population, I think obviously we are
> not thinking of treating millions of babies, and defining the
> population is going to be difficult, but I think we may have some
> tools from some of the work done by various investigators to try to
> define a population.
>
> The intervention, I think that is more well defined and there is only
> one drug being considered. The comparators, that also would be
> somewhat difficult to define exactly what it is being compared with.
>
> The outcomes, this condition is not a disease. I think there is also
> going to be quite a bit of uncertainty, how best to define that.
>
> DR. CHESNEY: Thank you.
>
> Dr. Wilfond, I think was next, and then Dr. Stevenson.
>
> DR. WILFOND: With regard to the question of kernicterus, it is unclear
> to me what is going on with that, however, I am not sure, I feel
> comfortable without even knowing that making some other reflections.
>
> I think that the slides that were presented, that suggest that the
> causes of kernicterus are behavioral make sense, and in that regard,
> it would seem like having a drug wouldn\'t necessarily address that
> problem.
>
> However, I am still in favor of the idea of drug development
> conceptually because if we look at the choices that Skip gave us for
> what we might want to make as a comparison, if we believe at some
> point it is a reasonable thing to do phototherapy on some people, if
> we had a drug that was sufficiently safe and sufficiently expensive to
> reduce the number of individuals who had phototherapy, that would be a
> good thing.
>
> So, I think it is going to depend upon, in the end, its safety and its
> ultimate cost, but I think the objective would be to decrease
> phototherapy.
>
> DR. CHESNEY: Thank you.
>
> I have Dr. Stevenson, Dr. Glodé, and Dr. Fost next.
>
> DR. STEVENSON: I just want to weigh in on the issue of bilirubin
> toxicity although I think that in the human circumstance, it is hard
> to do an experiment that would do prove that causative link
> definitively.
>
> For those of us that work in the animal model, there is no question
> that bilirubin is toxic, and you can create conditions of a variety
> that mimic what we would see clinically and see the impacts of those
> factors like infection, and so forth. There are biological ways in
> which that can be understood.
>
> We haven\'t spent a lot of time talking about those models today, but
> there is a whole area of biology that is focused on that, so I don\'t
> want people to think that there is any doubt about bilirubin as a
> toxin from a biological standpoint under certain conditions and at
> certain levels.
>
> The comment that I would like to make besides that, though, is to sort
> of remind people that there is an undeniable biology here, and part of
> that has been addressed by a drug like phototherapy light, and that
> part of the biology is the limited elimination that the newborn has.
>
> We don\'t use that medicine very well, but we can probably use it
> better and more efficiently. But the other part of the biology is
> really the production of the pigment, and I told you that all newborn
> babies have a higher production compared to adults, about two or three
> times higher, and for many of the individuals who find themselves on
> these unfortunate lists, being near term or individuals that develop
> other conditions, like G6PD, they have very high production rates of
> the pigment.
>
> So, there is an undeniable logic that an additional arrow in the
> quiver is required, which addresses that part of the biology, so as a
> scientist, the logic for that is undeniable.
>
> The issue then becomes one of putting that in the context of your
> other arrows and when do you shoot them, and I think that some of you
> are touching upon those more difficult questions about how best to
> identify the individuals that would be the target of that kind of
> intervention.
>
> I think that the kinds of drugs that are represented by this new class
> of heme analogues, that are competitive inhibitors, suggests that
> there is a way to use them that can target them very precisely. They
> may even work in more precise ways than phototherapy works, and could
> be very, very useful in the circumstance.
>
> So, the last thing I would say, to make this thing come full around
> for you, is that because of the unpredictable nature of the onset of
> this condition, and the fact that when you see it, you are deep into
> it, and unlikely to be able to prevent it, because it is happening.
> There may be some debate about if you get it early enough, you may
> have some reversibility.
>
> Then, you are faced with there being the best quiver solution, the
> best arrow in your quiver, because by that point in time, you are
> already dealing with something that is upon you. It is hard to use as
> a preventive tool because the bilirubin is not there to actually
> undergo the photo isomerizations.
>
> So, the chemical approach is actually a more logical approach if you
> are interested in prevention and avoiding something that is, as you
> have heard, very hard to predict.
>
> So, I would just like to leave you with those thoughts.
>
> DR. CHESNEY: Dr. Glodé.
>
> DR. GLODE: I sort of have two lines of thinking I wanted to bring up.
> The first one would be that at least from my sense of top priority,
> the question would be that the priority is prevention of kernicterus
> and perhaps other subtle forms of neurologic impairment, and the
> question would be do we currently have effective therapies that we
> believe can at least prevent the tip of the iceberg, the kernicterus
> that we recognize.
>
> It seems to me from the discussions today that the phototherapy and
> exchange transfusion are effective therapies. If there were another
> effective therapy that was proven to be more effective or equally safe
> to those two, then, I would certainly favor its development, but I
> would favor that it be studied in selected populations of children
> with hemolytic anemias predominantly.
>
> The second issue has to do with the paradigm that was brought up
> today. The one we heard most often was the vitamin K deficiency
> paradigm, and all babies get an injection of vitamin K. But I would
> like to bring up the other paradigm of the newborn screening, which
> deals with rare conditions, but really does not, except from a public
> health point of view that we can\'t effectively identify and track
> patients, so we have systems set up.
>
> We don\'t say we can\'t prevent cretinism because it is impossible to
> do a newborn screen and follow it up. We say we can do that, and so we
> have systems in place, at least in Colorado, through out state health
> department and through our section of Pediatric Endocrinology, that we
> follow up everybody with an abnormal thyroid screen. We just don\'t
> give all babies thyroid hormone, and we follow up all babies with
> abnormal PKU, et cetera, where we are able to do that effectively and
> prevent those rare but devastating conditions.
>
> So, I just think we should be able, even though again maybe it is not
> within the purview of the FDA, but somehow we should be able to
> develop public health policies that identify high risk children based
> on the nomogram, and they get a letter sent home with them, they are
> reported to the state health department, they are followed up on, they
> get another bilirubin, they get interventions, and we prevent
> kernicterus.
>
> Now, I am again not against developing another drug, but I am really
> worried about giving it to 4 million children and the safety profile
> issue, but I am all in favor of preventing kernicterus by identifying
> babies and treating them early.
>
> DR. CHESNEY: Thank you.
>
> Dr. Fost.
>
> DR. FOST: We are all concerned about studying history so we don\'t
> repeat it, but the question is which historical examples are relevant.
> There are several examples of newborn screening and treatment that I
> worry about, that I am concerned we don\'t repeat.
>
> The first would be PKU screening, the granddaddy of all newborn
> screening and intervention programs, and there are several echoes with
> this story that concern me.
>
> In 1960, we had a rare disease, its biochemistry was very well worked
> out. It was very clear by 1960 that if you reduced exposure to
> phenylalanine, you could ameliorate and even prevent retardation, and
> there was great passion by advocacy groups, including affected
> families and Dr. Guthrie himself, and the president John Kennedy.
>
> So, we mandated PKU screening in every state, and it was 10 years
> before we realized that the screening test was too sensitive, that is,
> that 95 percent of the children with high blood phenylalanines, not
> just Guthrie\'s, but confirmed by whole blood assays, did not have
> PKU, but had a benign form of hyperphenylalaninemia that were destined
> to be normal.
>
> Second, that restriction of diet could be just as harmful as excess,
> that is, the toxicity of the diet was not appropriately anticipated,
> so many of these normal children were not only made retarded by the
> diet, but were killed by severe protein malnutrition.
>
> We don\'t know how many. We know that it took a decade, and it wasn\'t
> until 1972, \'71, \'72, that the Institute of Medicine formed a panel,
> and we now understand it perfectly, and we now know how to identify
> the subset of children with elevated blood phenylalanines who are
> really destined to become retarded, and we now know exactly the right
> dose of the diet.
>
> All this sounds very worrisomely similar to what we have now, that is,
> we have a cohort of children who have an abnormal screen, whether
> it\'s visual or biochemical. We don\'t know exactly what subset of
> them is destined to have anything very bad happen. We know that
> kernicterus is very bad, but I agree with Dr. Danford, it\'s a little
> unclear whether the vast majority of these children are going to have
> anything very bad happening to them.
>
> We have an intervention that looks very promising, whose biochemistry
> is well understood, but we just don\'t have a lot of data on the
> safety of it and maybe not as much as we would like on the efficacy
> either, although that seems a little bit more clear.
>
> There are five other examples. I mean bicarbonate for respiratory
> acidosis, hyaline membrane disease, the biochemistry was well
> understood, the kids were all dying of severe acidosis, just give them
> bicarbonate, the Aschner \[ph\] regimen, it will be fine, and it was
> 10, 15 years before Mike Simmons did a randomized, controlled trial,
> and said it was killing kids, it was causing intracranial hemorrhage
> in some, and now nobody gives it, but there was no prospective,
> careful trial for a decade.
>
> Oxygen. For a century we inspected the kids, these obviously need
> oxygen, then, we got more fancy, we measured it, give them oxygen, it
> can\'t possibly hurt, and look how devastating the consequences of
> hypoxemia are.
>
> Then, finally, we learned that it had a dose-response curve, you could
> give too much, and so on.
>
> Antibiotics. I mean sulfonamides, there are half a dozen examples, and
> the number of normal children who have been killed by these things is
> probably in the tens of thousands.
>
> So, it is not that we don\'t care about the small number of cases of
> kernicterus or PKU, or whatever, the question is how to capture those
> and reduce them even further or eliminate them, and not harm a lot of
> other people in the process.
>
> So, it seems to me doing studies that, as Skip put it, that would
> maximize the benefit-risk ratio for each child in a study, so a child
> who has a discharge bilirubin of 5, I assume has nothing to gain from
> being in a study of a new drug that might prevent kernicterus. One
> that has a discharge bilirubin of whatever the number is, a much
> higher number, 15, obviously has a lot to gain by being in this trial,
> and it might avert something that maybe is more risky, I don\'t know
> if phototherapy is more risky than this drug or not.
>
> It seems to me the first challenge, is drug development good, of
> course, it is good. I mean it is self-evident that if we have a drug
> that is equally effective as phototherapy or exchange transfusion, and
> it is cheaper and safer, of course, it should be preferred, but that
> is what we are trying to find out.
>
> So, in trying to find out, it seems to me we should be as narrow as
> possible in the beginning, so that the children who are entered into
> these studies have the most to gain and the least to lose, we have the
> least number of kids in these studies who are at almost no risk of
> developing a problem.
>
> Those are just some of thoughts about that. I want to say a second
> thing, which is the elephant in the room that we are sort of not
> allowed to talk, which is cost, not an FDA concern, not an IRB
> concern, it is nobody\'s concern in this country, so we have these
> expansive technologies, we have these innumerable examples of drugs
> that are developed for very narrow purposes, in this case, to prevent
> a disorder that affects a mere several hundred children a year,
> terrible for each one obviously, but we know that that is not how it
> is going to be used once it\'s approved, and that the FDA is virtually
> powerless to stop the expansive use of it.
>
> We know how the pharmaceutical companies manage to influence that even
> though they are legally not supposed to be marketing off-label uses,
> but it has happened so over and over and over again that, as the
> background materials suggest, the concern always is that even if we
> were able to reduce the number of children with kernicterus, what will
> the cost be, that is, how many millions of children will get this drug
> who have nothing to gain from it, and what will the toxicity be.
>
> Now, if it\'s like vitamin C, we prevent lots of scurvy with vitamin C
> or like vitamin K, if it\'s virtually riskless, then it won\'t matter.
> If it\'s free, it won\'t matter, like vitamin C or virtually free, but
> if it costs a lot, either in terms of toxicity or in money, then, we
> have a problem.
>
> The cost in terms of toxicity, FDA is authorized to pay attention to
> and will. The cost in terms of money, they are not, so we might have
> another, what, I don\'t know, billion dollar drug on the market that
> does nothing for 99 percent of the people who get it? And we continue
> to have a healthcare system in which 40 million people are insured,
> one-third of them children, and we say we can\'t afford to do anything
> about that, but we can afford to give everybody 10 protoporphyrin.
>
> So, those are the two things that worry me, the one that we can\'t do
> much about. The first one, we can do something about, which is to make
> sure that studies that are designed are done in a way to maximize the
> benefit to the children who are in the study, so that eventually,
> hopefully, the use of the drug could be limited to those children who
> have something to gain from it.
>
> DR. CHESNEY: Thank you.
>
> Dr. Newman and Dr. Freeman.
>
> DR. NEWMAN: I want to comment on these two examples that have been
> used, the vitamin K and the newborn screening. I appreciate Dr.
> Fost\'s PKU example, which I hadn\'t heard before.
>
> It is a little bit misleading to compare, oh, all we need to do is do
> a bilirubin level that costs a dollar or two dollars and ten dollars,
> it could be like newborn screening. If you picture, if your screen for
> hyperthyroidism had a specificity of 40 percent, because the
> recommendations for the systems approach to hyperbilirubinemia
> screening are that the top 60 percent, it is only the bottom 40
> percent we are reassured they don\'t need another bilirubin level, the
> top 60 percent, they all are labeled as having a bilirubin problem and
> need to come back and all need a mandatory second bilirubin test.
>
> So, that is sort of the problem for me, which is that it would be
> wonderful if we could do a test before they left the hospital, that
> said yes, you have a problem, you don\'t need to worry, and it had
> anywhere near the sensitivity and specificity of our newborn screens,
> but they don\'t.
>
> One of the speakers said prevalence should not be an issue. Prevalence
> is an issue when you have diagnostic tests that aren\'t very good, and
> you have high false positive rates, and the lower the prevalence, the
> higher the number of people you are going to need to treat and the
> more false positives.
>
> The trouble here, the AAP, in their new guidelines, are not
> recommending universal bilirubin screening, and it\'s for this reason,
> the test just does not seem to be that good, it is not clear what to
> do with the result.
>
> DR. FOST: Can I just ask you one question? That is why asked Dr. Ip
> this morning what the negative predictive\--I understood one of his
> graphs to show a negative predictive value of 99.5 percent. That is
> pretty darn good.
>
> DR. NEWMAN: Again, if you are in the 40 percent who have, you know,
> the bottom 40 percent. The trouble is the positive predictive value,
> if you have a bilirubin level that is in the top 60 percent, and
> therefore you are labeled, but, of course, most of those will be the
> false positives.
>
> I think the vitamin K is a really good example because, you know,
> several years ago, many of you know there was an alarm about whether
> vitamin K caused cancer. There were a couple of studies in Bristol, in
> England, that really suggested that intramuscular vitamin K in
> newborns doubled the risk of childhood cancer, and the first one,
> people didn\'t pay that much attention to, it was a data dredging
> thing, and it was appropriately believed that it should be confirmed
> by another study, and the drug company, in fact, funded another study,
> which found the same thing, a more than doubling of the risk of
> childhood cancer after intramuscular vitamin K in Bristol.
>
> Subsequent studies mostly have not confirmed that, but I think that is
> the kind of example, that is the sort of thing that worries me is, you
> know, how are you going to find stuff like that and how many years
> later might it be, and how big a study for how long do you need in
> order to say, oh, yes, this is a drug that we can give to hundreds of
> thousands or millions of children to prevent something which is very
> rare.
>
> DR. CHESNEY: Dr. Freeman.
>
> DR. FREEMAN: Dr. Norm Fost made many of my comments, and I agree with
> him. As a neurologist, I fail to believe that kernicterus is an all or
> none thing. There must be toxicities of bilirubin at lower levels even
> though we do not detect them. So, I don\'t know what level is toxic or
> what level we should treat.
>
> I am also concerned about costs and the cost to society. I am very
> persuaded by Dr. Moosa\'s talking about the number of poor women who
> leave his place with no ability to follow them up and how do we deal
> with that.
>
> Yes, it would be very nice to have a medical treatment that avoided
> phototherapy. I think we can, by and large, we have avoided exchange
> transfusion, but we need something to avoid phototherapy in this
> population.
>
> On the other hand, I am very concerned about the unknown toxicities of
> whatever medication we do, and would like to see any trial, carefully
> monitored, in a high-risk population, so that we can pick up these
> rare toxicities of whatever drug we develop.
>
> DR. CHESNEY: Dr. Fuchs.
>
> DR. FUCHS: I am glad somebody finally mentioned bullet point 3. I
> think that is the hardest thing because as a medical community, we
> don\'t control a lot of that, things you mentioned already, that
> people are not coming back as it is for when you asked them to come
> back for bilirubins, or the other thing about going to Home Nursing
> visits, home nurses will not go into the inner cities to follow up
> these children either.
>
> So, there is a lot of issues that we, as the medical community, can\'t
> control because of the whole system, whether it\'s HMOs or other
> things, that I think it is going to be very hard to answer the
> intervention sequence when we don\'t have a lot of control over that
> until, like you mentioned, the more screening, until there is a better
> test, the same thing. You can ask for additional monitoring, but if
> you can\'t get them back, then, the system has failed.
>
> DR. CHESNEY: Dr. Smith, and then Dr. Ip.
>
> DR. SMITH: I am a chemist, so I believe that chemicals are saving the
> world and will continue to save the world, so, of course, we need as
> many arrows in our quiver as we can possibly get, but two things I
> heard today have me thinking.
>
> One was Ms. Sheridan told us that really the difference between her
> two children was a bilirubin test, and I think it is shocking that
> regular monitoring of Cal didn\'t happen.
>
> Then, Dr. Valaes told us that in Greece, that as soon as they
> discovered phototherapy\--I wrote the words down\--the problem was no
> longer there. I, as a chemist, of course, as many drugs as we can have
> available, the better, but I am kind of wondering if there is a
> problem.
>
> DR. CHESNEY: Dr. Ip, and then Dr. Aschner.
>
> DR. IP: The way I think about the issue is, as a practicing
> pediatrician, without even thinking about your qualifiers to your
> question, if I am presented with a drug that is as safe, as good as
> phototherapy, would I use it over phototherapy, the answer is clearly
> yes.
>
> So, to answer that question, yes, we should develop this drug. Now, I
> don\'t know if you folks, some of you have the FDA background
> document, a thick, thick book, if you turn to page 28, there is a
> graph. It\'s at Tab 6. It is basically an analysis of all the newborns
> who have idiopathic jaundice who develop kernicterus. It\'s the case
> reports, the reviews that we did for the AAP report.
>
> If you look at the distribution, actually, 91 percent of these cases
> had bilirubin 25 or greater. There were three cases between 20 and 25.
> I am just doing some rough calculation. So, if you are going to try to
> capture that particular population, if you are looking at 25 as the
> cutoff, you would be treating about 6,000 kids, but if you are using
> 20 as the cutoff, you would be treating 80,000 kids. That is something
> that we need to decide how many kids are we willing to treat and
> experiment with it.
>
> DR. CHESNEY: Thank you.
>
> Dr. Aschner.
>
> DR. ASCHNER: I am coming from a little bit of a different background.
> I guess my first comment would be that I am almost not sure that I
> have seen enough data to make a good correlation between the level of
> bilirubin and kernicterus. In trying to think more about it, I would
> say that there may be other issues in addition to bilirubin levels
> that might be important in terms of determining whether a neonate
> would go on and develop kernicterus at the molecular levels, cellular
> level, in terms of extrusion of bilirubin from the brain and other
> parameters.
>
> Now, looking at a drug, I think obviously, I would be in favor of
> developing a drug, but thinking again about toxicity and the potential
> that millions of children will be exposed to it, I would like to know
> much more about the safety of the drug, and I am just going to posit a
> simple question for everybody to think.
>
> Let\'s just consider, for example, that a drug has a 5-point IQ
> reduction in the general population, what would that do to our society
> in terms of exposure to a drug in 4 million children over 10, 20
> years, and I am not exactly sure actually how you would go about doing
> a randomized study to pick up the effect.
>
> DR. CHESNEY: Dr. Gorman, Dr. Nelson, Dr. Stevenson, and then maybe we
> will stop at that point and ask the FDA folks if they have enough
> information on this issue, that we can move on.
>
> DR. GORMAN: I am another one who learns well from analogies or at
> least I am impressed by analogies, and the analogy that moved me the
> most today was the lead analogy.
>
> Bilirubin in the blood doesn\'t hurt anybody, bilirubin in the brain
> hurts people. In the procedures of any clinical testing, if there is
> any way to measure the bilirubin in the target organ rather than the
> surrogate marker that we use so poorly, and therefore are troubled
> with our results, would be a big advantage to ongoing studies short of
> brain biopsies or autopsies on clinical subjects or human subjects.
>
> I am convinced that bilirubin is a toxin once it gets in gets in the
> brain.
>
> I will also agree as a practicing pediatrician that if it was shown to
> be as effective and as safe as phototherapy, it would replace
> phototherapy as a terrible, you know, with a great rapidity. The
> practitioners in clinical practice would vote with their feet very
> rapidly and phototherapy would disappear if you could replace that
> with a single shot of any agent, be it this one or another agent.
>
> Having said that, I will address the 600-pound gorilla or the
> 800-pound gorilla, or however big it was, in Dr. Fost\'s opinion,
> there will be therapeutic creep. We will start this with a very small
> group of people. In the clinical trials, it will get tested with
> children with hemolytic disease and then perhaps children as they
> enter phototherapy as an alternative to phototherapy, and then it will
> be used to see if it can prevent phototherapy, and then it will be
> generalized to the population.
>
> That is the therapeutic creep as I predict it if no untoward safety
> data come out shortly, and I would say that this is one of those times
> which is exactly why we need clinical research. I would rather know if
> this drug is unsafe early rather than later, because I see this drug
> potentially being used on 4 million children a year, 4 million
> infants.
>
> The other thing that I think as pediatricians, we all see intuitively,
> there is a therapeutic window which makes this very difficult for this
> drug. It has to be used early, it can\'t be used later. It is again
> like lead, if I ingested lead, there will be those accusing me of that
> around the table, but if I ingest lead now, I will be at less risk
> than if I ingested lead at six months of age, so there is a
> therapeutic window for this drug that is also very important.
>
> Is there an adult equivalent to kernicterus with high bilirubins? I
> think the answer is no.
>
> So, there is another issue about and will that same therapeutic window
> allow us to see toxicities of this drug that we would not otherwise
> see.
>
> DR. CHESNEY: Thank you. Actually, it was an elephant, Dr. Gorman.
>
> Dr. Nelson.
>
> DR. NELSON: I agree, I think it\'s a toxin. I am trying to play with
> some numbers and I am not necessarily facile with them, but I am
> struck by the difference between the numbers that were presented out
> of California and then the numbers, although preliminary, from the New
> Jersey surveillance, having lived in New Jersey. I was born in New
> York, so maybe I am protected from that. But 8 per 100,000 compared to
> a lower number, and the question is if you assume that the bilirubin
> was greater than 20 in all of those that were at risk, I was trying to
> calculate what would be the incidence per 100,000 of those greater
> than 20 for kernicterus, and then add to that the question of
> subclinical or irreversible neurodevelopmental changes that could be
> related to bilirubin.
>
> That would give you a number and then the question is would you
> consider that an appropriate safety profile for any intervention that
> would prevent anyone from getting into that range of 20. You end up
> with a number, such as using New Jersey statistics, 320 per 100,000 if
> you assume all their cases of kernicterus occurred in those who had a
> bilirubin greater than 20.
>
> Then, the question is what kind of trial would you need to see that
> incidence of neurodevelopmental impact, and it would (a) be big, but I
> suspect if we had a drug that we gave to 100,000 newborns and we got
> 320 cases of what looked like kernicterus, we would consider that
> highly unacceptable.
>
> I don\'t really have a conclusion of these reflections, but the
> debilities sort of trade off the interventions. You may end up just in
> a simple situation where you are talking with the parents about the
> relative risks of each intervention, which is what happens now with
> exchange transfusion, phototherapy, and if the trust you, they will
> let it go up into the 25 range, and if they are risk-averse on that,
> they may say exchange at 22 or 23, or 28 these days, so there is some
> variability in practice based on that conversation.
>
> DR. CHESNEY: Skip, I am sorry, maybe it was because I was writing, I
> didn\'t quite get the 300\--I understand the first part of how you
> were approaching this, but\--
>
> DR. NEWMAN: I may have the math wrong. Part of it is coming up with
> assumptions here. If you take the New Jersey statistics, 71/2 per
> 100,000, round it up to 8, then, the question is if you assume that
> all of their cases occurred in infants with bilirubins greater than
> 20, consistent with the report, then, what is the incidence in infants
> greater than 20 of kernicterus based on their statistics, and I get
> 320\--400, so it is reasonably large in that population depending upon
> what you pick.
>
> Then, you go down to 15 or down lower, then, you get obviously lower
> numbers, but the safety profile of any intervention, if the risk is
> 400 per 100,000, I mean I suspect there is a lot of drugs on the
> market that are not considered that safe that might not have that high
> an incidence of serious adverse effects, similar to neurodevelopmental
> changes you see in kernicterus.
>
> So, if the New Jersey numbers are correct as opposed to the California
> numbers\--and that will be a debate I am sure once that comes
> out\--that has a big impact on how you would evaluate the safety of
> any given intervention.
>
> DR. CHESNEY: Dr. Stevenson, then Dr. Newman and Dr. Hudak.
>
> DR. STEVENSON: This is a brief comment again about production. I have
> heard people talk about targeting, and people use categories of
> infants, ABO incompatible, ABO incompatible with a positive Coombs\'
> test, and so forth, and so on.
>
> Those are actually surrogates for actually accurate measurements can
> be made to understand what a production rate is in an individual, so
> if narrowness of targeting is what is going to allow something to be
> introduced, then, you can get that kind of narrowness by actually
> looking at the population from the perspective of the part of the
> biology you want to control with the drug, and that, in fact, improves
> the likelihood of benefit where productions are increased as opposed
> to any risks that might be understood to exist or possibly exist with
> the drug.
>
> The difficulty I have with even I guess making that statement\--coming
> back to what Dr. Fost said\--and that is that if all drugs have to be
> subject to this issue of the creep, which I think is important to
> understand, it makes it very difficult to introduce anything because
> that means that as soon as something is introduced, it will be used if
> it\'s easy to use, and there is not an obvious complication rate or
> it\'s not too expensive.
>
> So, I think you have to be careful not to exclude things that might be
> of considerable value, just to say with appropriate instruction and
> maybe guidelines with respect to use, knowing that there are
> limitations on how you can control behavior.
>
> DR. CHESNEY: Just two more. Dr. Newman and Dr. Hudak. Then, we will
> return to our FDA colleagues.
>
> DR. NEWMAN: Just a quick comment on the data from New Jersey. Those
> are based on discharge abstracts, so it is based on a code, and ICD-9
> code and a discharge abstract, and we use those at Kaiser as sort of a
> screen to see were there any cases of kernicterus, found I think 8 or
> 9 of them, and all of them were false positives.
>
> If you think about if the true frequency of kernicterus as something
> less than 1 in 100,000, even if the specificity of the coding is 99.99
> percent, occasional digits being transposed, and the 773 instead of a
> 776, anything like that will give you a very, very low rate of false
> positive diagnoses.
>
> So, the ICD-9 code discharge abstracts, I think you really can\'t use
> for something as rare as kernicterus. I think that actually the case
> for what the toxicity of bilirubin is, is at least I think clearer
> than has been suggested so far, and that is that really, it looks like
> kernicterus mostly occurs with bilirubin levels over 30, maybe very,
> very rarely over 25, and between 20 and 25, if it occurs at all, it
> would be extraordinarily rare, so I want to correct what one person
> said.
>
> We recommend phototherapy for bilirubins in the 20, 25 range. That is
> not because those bilirubins are dangerous. The whole reason for
> phototherapy in that range is to keep the bilirubin from rising to a
> level where it would be dangerous, where someone would contemplate
> exchange transfusion.
>
> So, if you are thinking about this question, you know, should drugs be
> developed to prevent hyperbilirubinemia, it seems like there are sort
> of three levels at which one might use the drug. One would be actually
> to prevent kernicterus in people who have hyperbilirubinemia, and that
> would be as an alternative to an exchange transfusion, as illustrated
> in the Jehovah\'s Witness child, which I thought looked very
> promising, and I would have no trouble saying this either should be
> used or a randomized trial be done instead of exchange.
>
> The next step would be instead of phototherapy, and still the goal
> here I think is to keep the bilirubin from rising higher, to keep it
> from rising to a dangerous level while the baby\'s liver matures and
> it comes back down.
>
> The number of babies in whom it would be indicated for that would be
> presumably a few percent, the number who get phototherapy.
>
> The last indication would be to prevent the need for phototherapy,
> that is, to give it ahead of time, and, of course, that is so
> attractive because it deals with all the follow-up issues that are
> such a headache for everybody, but then, of course, the potential
> number of people being treated would be way higher, and the number who
> would be treated who otherwise wouldn\'t need any phototherapy would
> be very high.
>
> DR. CHESNEY: Dr. Hudak.
>
> DR. HUDAK: Just a few comments. One is I think that although we
> haven\'t really looked at the evidence, we have been told that there
> have been no complications that have been seen in babies who have
> received this treatment, and there have been several hundred, I
> gather, in a variety of different studies.
>
> I would say right now that given that the risk of exchange transfusion
> is a 1 percent mortality, that the issue of whether or not to do the
> exchange or give this drug if it were available is not an issue, I
> would give the drug based on the available evidence.
>
> The other issue, coming back to Dr. Fost\'s point about screening
> tests, I think maybe just once again to put out something about
> advocacy here, we have in this country a very chaotic system of infant
> screening. Every state goes its own path. There are some states that
> do a lot of screening and do it very well, and other states, such as
> Florida, where we are still back in the prehistoric age, and do about
> five different screens.
>
> There are lots of different metabolic conditions that are amenable to
> treatment in infants that have frequencies on the order of 1 to 2,000,
> to 1 to 10,000, and we do not screen as a society for these conditions
> even though it would require a relatively minimal extra expense in the
> scheme of things, and these are things where babies have long-term
> deficits because they aren\'t identified.
>
> Even if you were to grant that kernicterus has an incidence of 10 per
> 100,000, I mean we have lots of things that are very morbid to
> children that are possibly preventable that we don\'t pay any
> attention to.
>
> The issue of complications, I think clearly I agree with everybody who
> suggests that we need to target a population, but I also agree with
> the issue of creep. If the supposition is that one case of kernicterus
> is too much, by definition, any high-risk group you target to treat,
> even if it\'s only 50 percent in the population, you are going to wind
> up reducing the incidence of kernicterus from whatever it is by 70
> percent, 75 percent, and you are still going to have that registry
> grow every year.
>
> So, for those reasons, I think you would have some creep going on.
>
> DR. CHESNEY: Dr. Cummins and Dr. Murphy, shall we move on to the next
> question, or would you like more input?
>
> DR. MURPHY: I would like to just take that entire conversation and
> pull a few points out that maybe I have selective hearing, but I want
> to make sure that these are some of the main themes that we heard
> here.
>
> People are interested in a therapy, drug therapy, that that therapy
> clearly needs studies, these studies would have to maximize\--the word
> was maximize the study to those who can benefit, and to maximize the
> studies to define the harm, in other words, define the safety profile
> as a theme.
>
> I heard also that surrogate endpoints\--I am just going to say it
> because that is really what it is\--we cannot do a randomized,
> controlled trial for an endpoint for kernicterus, that we have to do a
> randomized, controlled trial with a surrogate; that the committee is I
> think trying to tell us, and this is why I am repeating this, that
> they think that the surrogate is preventing an increase in bilirubin;
> and that the randomized trials would be possibilities, again, I am
> trying to synthesize all this, would be prevention of exchange
> transfusion as an endpoint, or randomization between phototherapy and
> a drug treatment.
>
> The definition of phototherapy intervention somewhere around\--knowing
> all the other things\--around 20, but knowing there is a whole
> nomogram, all that sort of stuff, but that\'s what I think I have
> heard so far. I have heard a concern about defining the trial design
> as a prevention for hyperbilirubinemia.
>
> I mean we need the bilirubin there to work basically, too, in other
> words, not a trial that would be randomized to children who received a
> dose when they left the nursery and those who did not. I didn\'t hear
> a lot of support for that kind of a trial, because I am not sure what
> the endpoints on that would be.
>
> Bob, were there any other points that you thought were coming out of
> this discussion? The definitions of predictability clearly underlie
> the problem here.
>
> DR. JUSTICE: No, I think you summarized it well.
>
> DR. MURPHY: Any comments that I got that wrong, incorrectly? Yes, sir.
>
> DR. OH: I think several of us indicated that a safety feature should
> be incorporated in any drug development. I don\'t think I heard you
> say that.
>
> DR. MURPHY: Oh, absolutely, yes. I was stumbling on it because I wrote
> in shorthand here, but basically, that any trial clearly needs to have
> safety as a major assessment. We do that anyway. I guess what we
> don\'t have enough time to discuss is what is the definition of what
> long-term safety is and how in the world you would do but I think that
> that is a real issue that you all brought up, and I was trying to say
> that, that that is something that we will have to struggle with
> because, in general, long-term safety studies are not usually asked
> for as part of an FDA approval.
>
> You know, there are some exceptions, but it is a very big issue, and
> there is a national study, as you know, ongoing to try to look at how
> to do long-term safety studies.
>
> DR. CHESNEY: Dr. Nelson.
>
> DR. NELSON: A think it is a question for Dr. Stevenson, because I
> heard him say one thing that follows on that slide you showed where
> you show the three black lines going up from the nomogram as to
> whether or not there would be any use for trying to distinguish within
> stratifications of bilirubin at different levels, whether 20, 25, 30,
> or 15, those who are at that level because they have above a certain
> percentile in production versus just above a certain percentile on
> bilirubin as a way of trying to make an additional distinction within
> the nomogram itself using carbon monoxide or some other testing.
>
> DR. STEVENSON: That is a good question. I don\'t know the definitive
> answer yet. Dr. Bhutani is analyzing some of the data from the large
> multiethnic, multinational trial that we did.
>
> As I mentioned briefly in passing, the nomogram seems to be informed
> in part, as would be expected, by production rate, so the higher you
> are up in those percentiles, the higher the average production for the
> individuals in those percentiles.
>
> There are also individuals who seem to be producing bilirubin
> excessively, and what Dr. Bhutani is exploring is whether that
> information is sufficient for identifying or targeting these
> individuals as the individuals that will also jump tracks and proceed
> to leave the nomogram all together.
>
> So, I think the issue you bring up is an important one, that is, that
> it\'s a balance, it\'s a matter of impaired conjugation and
> production, but if you have excessive production and you are already
> behaving in a certain way in terms of your ability to handle the
> pigment, then, you may be self-identifying as a very narrow group of
> individuals who are uniquely disposed to being helped by something to
> control their abnormal production rates.
>
> DR. NELSON: Do you think that when that data is analyzed, that it
> would reduce the false positives and that number needed to treat, that
> is of concern, in other words, those infants who, in retrospect, would
> not have needed an intervention, that if you combined bilirubin plus
> some measure of production, that you might treat three to get one
> instead of five to get one, for example?
>
> DR. STEVENSON: I don\'t know, but my guess is that it would likely
> decrease that number, but I don\'t know for sure.
>
> DR. CHESNEY: Dr. Justice.
>
> DR. JUSTICE: Yes, just one thing to add to what I heard the committee
> say, at least a couple of members of the committee suggested that the
> population be narrowed to a higher risk population, such as hemolytic
> anemias.
>
> DR. CHESNEY: We have a plan for the last two questions, which have to
> do with safety and efficacy. As you know, the FDA has a legal
> responsibility to assure both safety and efficacy, and that is what
> these two questions are about. So, I will read these briefly and then
> we will have 10 to 15 minutes to discuss them.
>
> Then, at the end, we will go all around the table, so everybody can
> have a last comment relative to whatever they feel they need to
> comment about.
>
> Question No. 3. Assuming that hyperbilirubinemia only requires
> therapeutic intervention with phototherapy 3 to 5 percent of the time,
> what safety information would you require from a sponsor for a new
> molecular entity before it could it introduced into the newborn
> population?
>
> Question No. 4. In today\'s healthcare setting, does the benefit of
> drug therapy to prevent hyperbilirubinemia in the newborn population
> as a whole outweigh the risk to individual newborns, the majority of
> whom require no intervention?
>
> Comments? Dr. Freeman.
>
> DR. FREEMAN: I am very concerned about these two questions and about
> any study that you design particularly if it\'s limited to a defined
> population being able to pick up low-risk side effects of your
> medication, and I would urge the FDA to build in long-term studies
> after whatever drug gets marketed presuming that it will get marketed.
>
> DR. WILFOND: I think that these two questions bring us back to the
> comment before about trying to maximize benefit to minimizing risks,
> and the problem with the questions, they are framing it as preventing
> hyperbilirubinemia, whereas, if instead these questions are framed as
> either preventing exchange transfusions, for example, I think the
> questions would be very different, so unless we decide what our goals
> are, and what our population is, these are hard questions to answer.
> The answers are different, I guess.
>
> DR. CHESNEY: Thank you.
>
> Dr. Nelson.
>
> DR. NELSON: I guess a question for those more knowledgeable and
> perhaps Dr. Stevenson, whether you think there would be any possible
> surrogates that could be used to measure risk of certain adverse
> events, such as impact on neurodevelopmental outcome, whether tagged
> drug distribution studies that show none get to the CNS. As I recall,
> there was some of your slides that you went through rather quickly
> showed differential distribution of different drugs and different
> targets. In other words, if it doesn\'t get to the CNS, it would be
> less concerning to me, or maybe that\'s just being naive. So, that\'s
> a question.
>
> DR. STEVENSON: It\'s a good question and obviously a concern. I think
> most of the information is probably known about tin mesoporphyrin, and
> that work has been done by Rockefeller. I don\'t remember the exact
> nature of the experiments that looked for traces of the compound in
> the brain, but my recollection of the report was that none was found.
>
> Our work has been primarily looking for biological effects. We have
> not done labeling studies. So, coming back to your general question, I
> am not sure if that would be possible to do in humans, and in trying
> to get to the issue, understanding what the risk might be or what
> surrogate you might have for looking for that risk, that is very
> difficult. We are learning now something that I think is very
> frustrating to most of us, and that is, when we look at long-term
> neurodevelopmental outcome as a primary outcome for a lot of our large
> trials, in ACC network, oftentimes things which we think are
> appropriate surrogates for long-term neurodevelopmental outcome, turn
> out not to be so.
>
> The most recent example is in the TIP trial, the indomethacin
> prophylaxis trial, where as the smaller studies had suggested, there
> was a marked decrease in Grade 3 and Grade 4 hemorrhages in response
> to that prophylactic treatment, but there was no difference in the
> long-term neurodevelopmental outcome between the two groups.
>
> So, when you try and pick even fairly gross surrogates for
> neurodevelopmental outcome, you may miss the mark, and part of that is
> related to the plasticity of the newborn brain, and there are many
> other things that will impact that brain over the course of the first
> couple of years of life, and that is not just in terms of function,
> that\'s in terms of its anatomy, as well.
>
> DR. CHESNEY: Dr. Mattison.
>
> DR. MATTISON: In terms of the safety information, I guess thinking
> about it from sort of several different levels, I would be interested
> in really very well conducted traditional segment one, segment two,
> segment three FDA animal tox studied.
>
> These are studies that are done to look critically at effects on
> reproductive performance and developmental function, pregnancy
> outcome, and so on.
>
> The problem with the current designs, though, I think for the most
> multi-gen and the three segment tox studies, don\'t get at functional
> endpoints, so I think, you know, careful discussion with any proposed
> sponsor of a molecular entity like this, given that there are a range
> of developmental activities that have to go on in the newborn, I think
> would be really very important.
>
> Having spent a lot of time thinking about developmental toxicity, I am
> also troubled a little bit by the fact that there is kind of the other
> side of the question that we haven\'t addressed, and I am reminded of
> the vitamin A story, which is that no question at high levels, vitamin
> A produces adverse effects, but we also understand that vitamin A
> deficiencies are also associated with adverse neurodevelopmental
> outcomes.
>
> Dr. Stevenson alluded to the fact that he seems a little perplexed by
> is there a level of bilirubin below which we wouldn\'t want to go, and
> from that perspective, then, it is not simply designing a dose that
> lowers the level of circulating bilirubin, it is understanding what
> happens at these lower levels in terms of neurodevelopmental outcome,
> they may not be related to the drug at all, but altered biochemistry
> in the individual, which I think also suggests a different way of
> thinking about the traditional three-segment and multigeneration tox
> studies in animals and might actually suggest the need to look at
> perhaps several different species in the developmental tox studies.
>
> DR. CHESNEY: Thank you.
>
> I wanted to ask a question and then I see Dr. Luban. Dr. Stevenson, I
> was struck in your slides by the contrast between the one naturally
> occurring mesoporphyrin, zinc mesoporphyrin\--I hope I have this
> correct\--in almost every instance had the lowest of the effects that
> you were describing as something that we see as maybe good.
>
> Teleologically, that gives me a little anxiety.
>
> DR. STEVENSON: Zinc protoporphyrin is the naturally occurring
> protoporphyrin. Its role is still being investigated. Of course, it\'s
> an indicator of lead toxicity and probably reflects availability of
> iron for incorporation into hemoglobin, and so forth, but I think what
> I describe is simply a compound that has moderate effects and then has
> many of the other desirable features that, in fact, the other
> compounds do have, either at the dose they are being used or by their
> unique synthetic nature.
>
> Those would be besides the efficacy, which can be established at a
> much higher dose, it has the lack of photoreactivity in vivo and other
> things of that sort. But it is a hard compound to work with, and is
> probably at the bottom of the list in terms of one you might pick from
> a drug development perspective because of that property alone.
>
> I am not sure if I answered your question exactly, but I think when
> you engineer the other compounds, you can end up using them at doses
> where you achieve the other desirable features that you see with that
> compound.
>
> DR. CHESNEY: I probably didn\'t express it very well, but it just
> seemed a contrast between a naturally occurring compound and a
> contrived one. In some of the areas, it was so striking that you just
> worry about toxicity issues.
>
> Dr. Luban.
>
> DR. LUBAN: In my review of the two books, there were a few things that
> I was struck with, that I think we need to spend some time talking
> about apropos of Question 3, and the two systems that I think we need
> to send some time looking at in any kind of a long-term safety trial
> are the hematopoietic systems, since this is a hemoxygenase inhibitor,
> and iron metabolism particularly at the nadir of iron absorption could
> be affected.
>
> The second, from a long-term adverse potential, is the RES system.
> Some of the data indicated lymphocytopenia, for example, in some of
> the children that were studied with this class of compound.
>
> So, I am being very specific rather than general, but I think those
> are two areas that we need to concentrate on.
>
> DR. CHESNEY: Thank you. I think those are issues that we probably will
> address tomorrow.
>
> Any other? Dr. O\'Fallon.
>
> DR. O\'FALLON: I think somebody should say at this point the fact that
> we haven\'t\--I mean we have been told that no bad things have been
> found in certain areas\--I think it is very important to point out
> that not finding things in the number of people studied, it doesn\'t
> tell us anything, that in order to find relatively rare events, which
> we would certainly hope most of these long-term toxicities would be,
> or any kind of toxicity, we would have to study a lot in order to be
> finding them.
>
> So, the fact that there is nothing out there yet is somewhat
> comforting, but not completely comforting.
>
> The other thing is we have been listening, we have been told in two or
> three different ways that there are parents who simply are not able to
> even come back for a follow-up bilirubin test within a week after the
> baby was born. If we are going to be putting kids into long-term
> studies where they are going to have to be coming back at year 1, year
> 2, year 5, that type of thing, in order to see what is happening to
> their intelligence levels and their blood counts, and that sort of
> thing, this is going to be difficult.
>
> I think the drug companies have to be prepared to deal with this type
> of thing or we are going to have a problem. Well, I think that our
> results that we have already been told are already biased because
> there was so much missing data on some of the long term, and the
> question is who was missing, who didn\'t get tested, and we can\'t
> have that happen for a good study of these new therapies, because if
> by the treatment creep, we are going to end up treating a whole lot
> more kids that don\'t need it, we have to have a darn good idea of
> what kind of adverse events that are likely to be occurring five year
> hence.
>
> DR. CHESNEY: Dr. Newman.
>
> DR. NEWMAN: I think to answer the question about how much we need to
> know about safety or how big the trials have to be is partly informed
> by biochemistry and understanding these drugs and the biologic
> plausibility that they would have effects on various tissues, and I
> don\'t know that much about that.
>
> My kind of simple-minded thought would be, well, if we are going to
> use it instead of exchange transfusion, we should know that it\'s as
> least as safe as exchange transfusion. If we are going to use it
> instead of phototherapy, we should try to have somewhere around as
> much data that it is as safe as we have for phototherapy. For
> phototherapy, we at least do have the Collaborative Phototherapy
> Study, which was a long-term study following kids up to I think age
> six or seven to look at their neurodevelopmental outcome.
>
> If we were going to try and use it to prevent phototherapy and be
> treating, you know, 5 or 6 or some number of kids for each one who
> otherwise would have gotten phototherapy, then, it seems like we kind
> of need to know that it is at least five times as safe as
> phototherapy, so that would be even a bigger study just to be able to
> reassure ourselves that we are not doing more harm than good.
>
> DR. CHESNEY: Dr. Hudak.
>
> DR. HUDAK: I think in terms of the specific answer to that Question 3,
> I think it is pretty clear that whatever study is done, we need to
> have a minimum of a two-year careful follow-up including the full
> neurodevelopmental exam and assessment. I think that is what is
> standard for the NIH studies where we looked at entities like nitric
> oxide and other things. I think that would be expected.
>
> The difficulty there is, of course, that even in the small networks
> where there is a lot of effort to getting these kids back, we take all
> babies regardless of likelihood that they are going to be coming back
> for follow-up, so we take the poor and the not so poor, and so forth.
> We get about an 80 percent follow-up.
>
> If you wind up spreading this among many centers, we are going to have
> fewer babies at each center, and you don\'t have that sort of network
> to encourage patient capture. It is going to be very hard to get a
> very good follow-up rate, but nonetheless, one has to do the best one
> can do.
>
> The other issue is in terms of the actual study design, we have talked
> about exchange transfusion. I think I would be very worried about
> limiting entry to those babies who are at high risk for getting
> exchange transfusion because if in the control arm you had a lot of
> babies who had exchange transfusion, and if there is some consequence
> to an exchange transfusion in terms of neurodevelopmental outcome, you
> may falsely reassure yourself your drug intervention is reasonable. It
> may even look better than the group that got high incidences of
> exchange, so I think there are caveats there.
>
> DR. CHESNEY: I don\'t think any of us ever want to do an exchange
> transfusion again.
>
> How about if we start going around the table and letting everybody
> address the most compelling issue for them at this point. Dr. Luban,
> you have the good luck of being the first person.
>
> **Committee Final Comments**
>
> DR. LUBAN: Do you want me to go over Questions 2, 3, and 4 or just
> make a general comment?
>
> DR. CHESNEY: I think the idea is more that you maybe address the one
> or two points that are most important to you, most compelling to you,
> that may have to do with any one or all three of the questions.
>
> DR. LUBAN: Well, I think it would be wonderful if we had an absolutely
> safe drug that could stop the need for doing exchange transfusions.
> Since as the director of a blood bank, I can tell you that I don\'t
> sleep at night when those are being done at my institution.
>
> On the other hand, I can also tell you that the number of times that
> we perform exchange transfusions now is lingeringly small.
>
> So, from my perspective, much of the treatment of Rh hemolytic disease
> has taken away exchange and what we are left with are the severe
> G6PDs, the tiny preemies with sepsis and multiple complications,
> metabolic diseases, and then the other class, which nobody has
> mentioned, which are the kids neither with ABO nor Rh, but with other
> antibodies, and those are actually growing in number rather than
> decreasing in number, particularly Kell, so that is a group of
> hemolytic disease of the newborn that no one has mentioned that we
> need to keep in mind.
>
> There is something intrinsically gut-wrenching to consider treating a
> very large number of babies with a treatment modality without a known
> safety record for the prevention of a very limited number of severe
> adverse outcomes.
>
> I will stop there.
>
> DR. CHESNEY: Dr. Stevenson.
>
> DR. STEVENSON: I can be very brief. I think exchange transfusions are
> dangerous, and that is something that needs to be avoided. It may be
> avoided through a whole variety of different ways, some of which
> don\'t have to include novel therapies.
>
> I guess from my perspective, the rationality of the approach that lies
> behind this kind of targeted therapy is best complemented by a
> targeting of the group that might benefit the most.
>
> So, I guess I would weigh in with respect to identifying individuals
> who are at greatest risk and who might benefit from altering this part
> of the biology which is contributing to the problem in their
> particular case, understanding that not everybody who has high
> production has high levels of bilirubin, they would not self-identify
> as being individuals that would require treatment.
>
> A final thing is just that I think that it is important to understand
> that some increased production is a normal part of the transitional
> period after birth, the up-regulation occurs normally, and so it
> becomes a powerful lever if you want to control something that you
> otherwise can\'t control.
>
> So, I understand the interest in getting one\'s hand on that handle,
> but I think it should be done with appropriate respect for the
> complexity of that biochemistry, which I think people have, and try to
> maximize safety with that in mind.
>
> DR. CHESNEY: Dr. Lau.
>
> DR. LAU: My comment will be brief. I think that we need to be very
> precise about our language that is mentioned earlier, that
> hyperbilirubinemia is not a disease, it is a condition, and even in
> Question 4, it is stated as to prevent hyperbilirubinemia treatment,
> so we are not really trying to prevent hyperbilirubinemia, because we
> are already doing intervention on kids with hyperbilirubinemia, so
> what we are trying to do, we are trying to keep them from rising. I
> think we just need to be precise about our language.
>
> DR. CHESNEY: Dr. Newman.
>
> DR. NEWMAN: I have mostly said what I want to say. I just had one
> other thought, which is this whole issue of difficulty with follow-up
> and therefore, you know, patients getting their high bilirubin levels,
> and I totally sympathize with that because we struggle with that, too,
> but I guess it bothers me a little bit that the direction where this
> might head is that if you are caring for a family that is poor and has
> bad access, then, you give them the drug, whereas, the families who
> are better connected with the medical system, you can just follow them
> and have a Home Health nurse go out to their house.
>
> So, I guess there is some sort of troubling ethical issues there about
> who would be the people in the studies and then who would the drug
> actually be given to, and maybe as a society, we really should commit
> that we can do better than just sort of throw up our hands and say we
> can\'t do follow-up a day or two postpartum.
>
> DR. CHESNEY: You articulate that so well.
>
> Dr. Oh.
>
> DR. OH: One final thought I have is issue of powering any of my
> control trial. Very often what happens is particularly using this
> surrogate as an endpoint. The sample size is not powered enough to
> look at long-term outcome, and that needs to be addressed in any kind
> of design in a study.
>
> The other thing that I need to point out is that since we are
> concerned about potential side effect, any trial\--I am probably
> saying something obvious\--should have a data safety monitoring
> committee, independent DSMC monitoring the study to make sure that the
> patients being enrolled are protected during the study period.
>
> DR. CHESNEY: Dr. Smith.
>
> DR. SMITH: I am in favor of development of a new drug. I am more
> concerned about what we are targeting as the endpoints for it. I have
> heard several people say\--and I know nothing about these things\--but
> several people have said exchange transfusion is dangerous. I don\'t
> think that anyone has said that phototherapy is dangerous. It is
> inconvenient, but nobody said it\'s dangerous.
>
> So, I think we should pay particular attention to what we are
> addressing to replace rather than injecting 4 million kids with this.
>
> DR. CHESNEY: Dr. Wilfond.
>
> DR. WILFOND: My comment actually follows on the prior comment. If we
> were to have as an objective trying to prevent exchange transfusions
> using a drug rather than phototherapy, we would not be subjecting 4
> million kids, we would be subjecting that very small number who
> currently gets phototherapy.
>
> I think that really would be the way to go in terms of designing a
> trial that randomized children either to phototherapy or to a drug
> based upon clear criteria when we otherwise think phototherapy is
> appropriate with the objective of trying to avoid exchange
> transfusions and to establish efficacy and safety in that
> subpopulation.
>
> DR. O\'BRIEN: I guess my first comment is I am also struck by the fact
> that our safety systems issues, although not a part of this
> deliberation here, just as a comment, that I would hope that we could
> do a lot better than we are doing, and certainly was very struck by
> Mrs. Sheridan\'s presentation of what happened with her son.
>
> I also would agree that starting certainly with the most at-risk
> infants and any way that we could sort of identify those that may have
> increased production where we know that the drug would be most
> effective presumably would be the way to start.
>
> DR. CHESNEY: Dr. Aschner.
>
> DR. ASCHNER: I like the idea of developing a new drug especially I
> think I have been convinced for those who need it most. What I would
> like to see is much more studies on the distribution of the drug in
> different tissues.
>
> I would like to see proper screening studies done in terms of various
> toxicological endpoints, and to echo what Dr. Mattison said before, I
> think I would like to know much more about what the consequences are
> of reducing bilirubin levels to levels that might be below optimal in
> the newborn.
>
> DR. CHESNEY: Dr. Freeman.
>
> DR. FREEMAN: I think Dr. Newman expressed my opinions. I have concerns
> on two sides. One, I think a drug should be developed, but I am
> concerned about even low incidence of toxicity and the need for these
> long-term studies in large numbers of patients, but I also am
> concerned about the way we treat the poor, the difficulties in
> follow-up, and the need for something to prevent phototherapy or the
> need for phototherapy in this population that is so at high risk.
>
> I am concerned that as we design these studies, that we will be
> targeting a poor indigent population and how do we deal with the
> equities involved in that.
>
> DR. CHESNEY: Dr. Ip.
>
> DR. IP: Am I allowed to comment on the confidential stuff I have been
> reading? I will reserve my comment until tomorrow.
>
> DR. CHESNEY: Dr. Mattison.
>
> DR. MATTISON: I guess I would just reiterate my concerns about
> functional developmental consequences and echo some of the comments
> that others have made with respect to frustration with the current
> system for screening and identification of these infants.
>
> That is not a drug development question, it\'s an entirely different
> kind of system question, but my biggest concern is sort of long-term
> functional developmental impact.
>
> DR. CHESNEY: Dr. Gorman.
>
> DR. GORMAN: A couple of random thoughts. The pursuit of convenience is
> pretty obvious in our healthcare system. We want things that are
> convenient, but sometimes they also simplify, those same pursuits
> simplify the systems for both us and our parents to provide care for
> their children, so I am not sure they are always mutually exclusive.
>
> It is clear to me that healthcare is not the number one priority of a
> large number of our populations, so that systems we set in place, that
> seem logical to us, don\'t always seem logical to our patients.
>
> I have a comment to follow up on Dr. Luban\'s. I think that I would be
> even more specific in my long-term safety profiling than you were. Who
> knew there were so many ways to make carbon monoxide in the body?
> Certainly not I. But I think that at 18 and 24 months, carbon monoxide
> production, since we are specifically targeting it and changing it,
> should be monitored, and the hemoxygenase system, in whatever way you
> measure it, in 18- and 24-month- olds should also be tested.
>
> I would also like to echo something that Dr. Freeman said, which was
> that he thinks that there is a distribution that does not include only
> kernicterus with bilirubin\'s effect, and I would hope that a gross
> developmental screen, such as the one we do, would pick up a halo
> effect if, by reducing bilirubins, we look at confounding or
> contributing variables to other neurological diseases that we see and
> we can only poorly explain.
>
> DR. CHESNEY: Dr. Ebert.
>
> DR. EBERT: I am in support of the development of drugs for the
> management of hyperbilirubinemia, and I would see the role in therapy
> here being somewhat before exchange transfusion. Where exactly that
> fits, I think certainly that discussion has led us to believe that we
> are not sure exactly where that would be at this point.
>
> I think probably first and foremost, we need to do a better job of
> characterizing patients who are high risk for progression to high
> bilirubin levels and/or kernicterus, whether that be through more
> intensive history taking and sampling of individual or ideally by
> developing a test that can be administered prior to discharge because
> of the concerns about follow-up of patients after they have been
> discharged.
>
> I don\'t think that we can really determine at this point what the
> safety would be of this compound without first testing it in a group
> that is at higher risk for complications, try to at least at that
> point get a risk versus benefit assessment, and perhaps then with
> post-marketing assessments, Phase IV trials, as lower risk populations
> are tested, we can continue to follow up with safety at that point.
>
> DR. CHESNEY: Mine is more reflection. I think it is ironic that the
> healthcare system has put us in this situation because pediatricians,
> I think almost uniformly, decried the move to discharge at 24 or less
> than 48 hours, and it is because of that that we seem to be having a
> problem now, and it is also because our processes are imperfect that
> we don\'t seem to be able to get children back and to monitor what, on
> the face of it, should be a fairly simple thing to monitor, but we
> don\'t have the processes in face, so it is just a reflection.
>
> Dr. Fost.
>
> DR. FOST: I hate to wake anybody up at 10 after 6:00 with a new idea,
> and I also regret disagreeing I think with John Freeman, my teacher,
> and Tom Newman, whose work I admire so much in this area, but it seems
> to me there is something close to consensus developing around the
> table on a general principle that, first of all, that a new drug,
> there seems to be wide agreement that a new drug, if it were safe,
> effective, and reasonably cheap, would be a great help, and that,
> second, it should be tested on children who have the most to gain from
> it.
>
> If that is true, it seems to me that the ideal target population is
> those who are most underserved at the moment, that is, children in a
> developing country, who presently have no access to anything and for
> whom being in a trial of a reasonably promising drug against
> phototherapy would be a boon for the children in the trial, it would
> almost certainly have a benefit if we take high-risk children, that
> is, children with hemolytic disease or at high risk for hemolytic
> disease, that the benefit-risk ratio for that population would exceed
> anything we could do in the United States.
>
> it might also, if the drug were cheap enough, lead to a treatment or a
> preventative for underserved populations since phototherapy is
> extremely unlikely. I am guessing, maybe I am wrong about that,
> certainly, home phototherapy.
>
> So, it seems to me the ideal place to develop, to study this drug is
> in a population that presently has no access to any treatment for
> hyperbilirubinemia and that is at high risk.
>
> DR. CHESNEY: Dr. Hudak.
>
> DR. HUDAK: That\'s a great idea, I just wish it were possible to get
> follow-up on those kids. That is the key. I think everyone is in
> consensus that we need the drug development study. It is just the
> details that are the devil, and the power issues are critical and
> depending upon what you are looking at, the power calculation will be
> different.
>
> I think we do need to look at the high risk group. I have no idea how
> you define that. Anything you do, by definition, is going to be
> somewhat arbitrary because we don\'t know at any given point what the
> exact risk is for getting from bilirubin level X to bilirubin level 30
> without intervention, we just don\'t know.
>
> So, it would be reasonable to pick by the nomogram, for instance, if
> you wanted to get a good number of patients in, you can either pick
> the hemolytic disease patients, who have a high incidence of having
> high levels, or you can sort of by the nomogram pick those who are at
> the 98th percentile anytime within the first 48 hours and assume they
> are the ones who are going to be most at risk for getting the very,
> very high levels, although we don\'t know that. So, there is something
> about the natural history we don\'t know.
>
> In terms of the follow-up, I think the point that was made about is
> there a 5-point difference in IQ that might result from this
> treatment, well, you can put a number on how many babies you need to
> study to reassure yourselves that there in no more than, you know, a
> 1-point difference or whatever. I think that sort of study design
> needs to be done because a 5-point difference in IQ, I think is a
> significant societal issue and needs to be carefully examined what the
> impact on that is.
>
> You know, other outcomes, for instance, like what happens if this drug
> were to double the underlying incidence of aplastic anemia, how many
> patients are you going to need to determine that. I go back to the
> studies that were done on the rotazyme vaccine, and very well done
> studies showed it to be very safe and effective, and within nine
> months of it getting on the market, being used in a lot of patients,
> the issue of intussusception came up, and the drug was withdrawn.
>
> So, I think there are clearly instances where something gets into
> widespread use despite the best study efforts at determining safety
> and efficacy and there are problems that are detected, and I think it
> is just critical as we go along whatever path this goes down, that the
> FDA hopefully has the authority to make sure that there are the
> appropriate large registries once this drug gets outside into open
> clinical use.
>
> DR. CHESNEY: Dr. O\'Fallon.
>
> DR. O\'FALLON: My comments, I keep remembering my dad saying that it
> took a dentist to invent the railroad couple. You know, I am outside
> the medical community, I work with physicians, but I am listening to
> you, and it just seems to me in listening today that it isn\'t that
> hard.
>
> You guys are all talking about eligibility criteria. As a
> statistician, I think that defining the eligibility criteria very
> precisely is an extremely important thing to do in each of these
> studies, and you guys are all talking about levels of hyper\--well, I
> can\'t say it, but the level of bilirubin, you are talking about rates
> of bilirubin rise. There are ways to measure that. You talked about
> that.
>
> So, I think you already know and could define a group that you could
> agree would be at real risk and should be studied first. So, I think
> that can be done, listening to you. Then, the comment about the
> population, about going to Africa and some places like that, come on,
> guys, we have all these Americans sitting in our inner cities that
> have no medical care either, and I think that we should make an effort
> to include those guys in any studies, too, that the companies should
> make sure that they are spreading around the benefits and the
> liabilities.
>
> The endpoint definition is absolutely crucial and again, what I am
> hearing you say, you say, well, should we give exchange transfusion
> when it hits 30 or 28. I think you have got to just define your
> endpoint as being some extreme value, and if the bilirubin hits that
> level in either group, they have failed, that treatment has failed. I
> think you can do that, define it some way like that, but it would not
> be to avoid either of these therapies because the physicians, you
> know, you are kind of a rebellious group, and you tend to say nobody
> is going to make me do anything, and you aren\'t always following the
> guidelines.
>
> But if it comes down to the level itself, understanding the
> variability and the laboratory measurements, and all that, I mean
> there are going to be problems, but that would seem to me as close to
> an objective endpoint as you could have.
>
> The careful follow-up is so important and it has go to be long term,
> and it has to be very vigorous to make sure that everybody comes back,
> that we are not losing a large percentage of the patients out on the
> long-term follow-up, and that is going to be hard.
>
> Then, oh, yeah, the modeling. We keep talking about the modeling, and
> I do a lot of that, I am a statistician. Folks, a model is only as
> good as the items that are in the\--I call them the shopping lists,
> the independent variables, and we are finding out it is very
> humiliating to recognize that we are missing a lot of very important
> variables that nobody ever knew were important, and we all know that
> there are genes that are important, that we don\'t know anything
> about.
>
> So, the modeling we take with a block of salt on each shoulder.
>
> DR. CHESNEY: Dr. Fuchs.
>
> DR. FUCHS: I think I echo a lot of people\'s opinion that this is
> going to be a long-term, several step process. I think the idea about
> comparing drug versus phototherapy to prevent exchange transfusion is
> probably step number one with long-term follow-up, and that group, it
> could be the ABO group, the G6PD group, that is your target population
> as one option.
>
> Then, when that is proven as safe or as effective as phototherapy,
> then, you jump back down and then you can get into your healthy
> newborns with whether you want to use with risk factors or without
> risk factors, it is going to take a long time no matter what you do.
>
> DR. CHESNEY: Dr. Danford.
>
> DR. DANFORD: I think everybody probably agrees that ignoring extreme
> hyperbilirubinemia is dangerous and there are two ways to approach
> that problem to make it go away. One is to make the extreme
> hyperbilirubinemia go away, the other is to tune the system, so that
> we no longer are permitted to ignore it.
>
> I wonder a little bit about the risks of developing a drug that could
> come into common practice that could be perceived as the magic bullet
> that prevents extreme hyperbilirubinemia, you have had your shot, you
> go home, nobody ever worries about hyperbilirubinemia and kernicterus
> anymore, and yet there will be system failures in either the
> administration of the drug or the effectiveness of the drug in certain
> small populations yet to be identified where that drug will be a
> failure and the next generation of patients entering the kernicterus
> registry will be those who have received the magic bullet and the
> medical community has given themselves permission to forget about
> them.
>
> That having been said, I really do think that we need to investigate
> the development of a drug like this. I agree with the remarks that the
> safety data that we need to accumulate will require a large, long-term
> expensive and difficult to interpret studies.
>
> I would like to be assured that the drug that we unleash on society is
> safe as phototherapy.
>
> DR. CHESNEY: Dr. Glodé.
>
> DR. GLODE: Just on a historical note. As you noted, Dr. Chesney, about
> the change in medical practice with early discharge, I do now recall
> that the most common conversations I ever had with mothers during my
> training was the conversation about how your baby could not go home
> because of the yellow jaundice, and, in fact, had that same statement
> made to me with the birth of my first child, staying in the hospital
> because my baby\'s bilirubin was 12 and we need to check it tomorrow.
> So, it is a remarkable effect.
>
> Back to again the priority, prevention of kernicterus, do we currently
> have effective therapies, I would say yes, we just have an inability
> right now to correctly identify and capture who needs those therapies.
>
> I am happy to have a new therapy developed. I think the bar for that
> therapy is very high because it has to be as safe as phototherapy and
> either equally effective because more convenient or more effective
> than phototherapy. So, the bar is very high. I am happy to have it be
> developed.
>
> The last comment I would make is that I think if you had an
> opportunity to read the two statements at the back from people who
> didn\'t present at the open hearings, but the Joint Commission and the
> March of Dimes both had an interesting letter there. Perhaps again
> this is outside the realm of the FDA, but on my desert island, if I
> were advising the FDA on the issue of prevention of kernicterus, I
> would recommend that they send\--I don\'t know if they can do this\--a
> formal letter that would go to NICHD, to the CDC, to the American
> Academy of Pediatrics urging funding of pilot studies concerning the
> efficacy of newborn bilirubin screening to prevent bilirubins of\--and
> then you name it, 22, 25, 27, I don\'t know, I would like to see those
> pilot studies funded, and that would be my recommendation.
>
> DR. CHESNEY: Dr. Nelson.
>
> DR. NELSON: I am still thinking about Norm\'s suggestion. I think an
> active control superiority trial with phototherapy head to head with a
> medication to try and prevent not so much exchange transfusion, but
> perhaps a bilirubin where most people might contemplate an exchange
> transfusion, say, 25, so you could get it at 20 and then you hopefully
> prevent 25, and then you would have to have, if the phototherapy
> fails, some crossover to the drug, but all those kinds of details
> could be worked out.
>
> But then I am not sure what the control group would be in an area of
> underserved, because I would be tempted to want to build up the
> infrastructure to provide phototherapy, and I am not sure that would,
> in fact, be doable, and it would worry me if we then take a drug that
> hasn\'t been used a lot, but we have efficacy here, and then decide,
> well, let\'s just hand it out to a million kids elsewhere and see what
> happens in terms of safety.
>
> I will follow you a ways down that road. I am not sure, though, on the
> details. We would have to work that out.
>
> DR. CHESNEY: Dr. Cummins and Dr. Murphy and Dr. Justice.
>
> DR. JUSTICE: I think I hear a consistent message that the drug should
> be studied in a population that is at higher risk, and there should be
> long-term safety, follow-up particularly neurological, hematopoietic,
> and that the trial design I have heard is a randomized trial of
> phototherapy versus the drug with perhaps an endpoint of a bilirubin
> of a certain value or perhaps an exchange transfusion.
>
> That is what I have heard the committee suggest.
>
> DR. CUMMINS: I would add to that, that there needs to be and I have
> heard very detailed preclinical safety testing because the bar for any
> new intervention is high because of the safety, known safety of
> phototherapy.
>
> DR. MURPHY: I would just like to say thank you and I think we ought to
> let you go because we have got another long day for you tomorrow.
>
> DR. CUMMINS: I could add to that thank you very much. This has been a
> really productive day and we appreciate your time and input.
>
> DR. CHESNEY: Tomorrow morning we start at 8 o\'clock is my
> understanding. Let me also thank everybody for letting us go so far
> over, but I think it has been extremely interesting.
>
> \[Whereupon, the meeting was recessed at 6:30 p.m., to reconvene the
> following day, Thursday, June 12, 2003, at 8:00 a.m.\]
>
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