 So delighted to welcome back to the University of Chicago, Professor Joel Freider. Joel is the ATOD Davis Professor of Academic General Pediatrics, and is a professor of medical humanities and bioethics at Northwestern University. Joel also is the Chief of the Division of Academic Pediatrics at Northwestern, where he cares for patients at the Ann and Robert H. Lurie Children's Hospital of Chicago. Joel trained at Tufts New England Medical Center and at CHOP in Philadelphia. He's received not just his MD, but a master's degree in sociology. He's written widely on many issues, including transplantation, donation after cardiac death. He's been active in a large number of medical organizations, including the American Society of Bioethics and Humanities. He's chaired the American Academy of Pediatrics Committee on Bioethics and is an elected fellow of the Hastings Center. So it's a delight to welcome Joel back to the University of Chicago. He'll talk to us today on the topic of lung transplantation for children with cystic fibrosis. Can does not mean should. Joel Frater. Thank you. So thank you all for inviting me. Good to see all friends. And at this end of town, it's too bad that we don't get together to talk about ethics more. Couple of preliminary remarks that I think are important. First of all, I don't want to forget to thank a friend and colleague from University of Pittsburgh, David Arnstein. He's a pediatric pulmonologist and now ethicist who reviewed my slides and gave me some helpful feedback and provided a couple of images that I will use and show you. I also want to say that I tried very hard to go over more recent statistics than you will see I have, including a publication from the OPTN regarding 2011 data. The problem with that data, at least with respect to lung transplantation, is that they have a funny definition of children. They define children as 0 through 11 years. And kids 12 and older are included in the adult data. And since I didn't have access to the original data, I couldn't make any heads or tails out of it. So I apologize that I don't have the most recent publicly available data. I could offer you a clearer explanation of that. And maybe it'll be appropriate to talk about that. And the last thing I want to say before we get into this is that I see the role of the ethicist in a clinical context as a necessary skeptic. So I'm very uncomfortable with those ethicists who either choose to, or for one reason or another, become apologists for whatever it is that their clinical colleagues are doing. So this talk is deliberately provocative, as many of my talks are. And I wanted to be taken in that spirit. That is to say, I want people to think seriously about what's going on clinically and to rethink some of the assumptions that go into the clinical thinking. So along those lines, this session is not an attack on lung transplantation. It is certainly not a denial of progress in lung transplantation, even for children. It's not an attack on clinical innovation in any way. And it's certainly not an attack on surgery. And I hope you will agree with me by the end that it is not the ravings of some sort of lunatic lullite. But I am going to be critical. So what this session is about is the critical importance of considering the context of clinical interventions for children. Let me emphasize, for children, I am not in any way going to discuss lung transplantation for adults, even lung transplantation for adults with cystic fibrosis. I'm only talking about lung transplantation for children with cystic fibrosis, not children with pulmonary hypertension, not children with any other lung disease. We're just talking about children with cystic fibrosis. I think it's important to go beyond the individual lines that we have taken up with regard to our therapies and compare the benefits, risks, and alternatives of available options. And if that phrase, benefits, risks, and alternatives seems familiar, it should, because it's the background of the notion of informed consent. And I think one of the things I'd like you to come away with is that we haven't done a very good job in meeting the requirements for informed consent when we consider sending children for lung transplant for cystic fibrosis. So it's important to remember that we have, in fact, entered the era of comparative effectiveness research. In fact, it's going to be a required element of clinical interventions that get the benefit of federal funding thanks to the Affordable Care Act. So we need to do comparisons of different approaches to similar clinical problems. And part of what I'm going to be doing here is helping people think about it in that way. So the good news with respect to cystic fibrosis, especially for children, is over the last 40 years or so, the life expectancy has increased from the late teens when I was a resident, millions of years ago, then into the early 20s to now in the developed world. So in the United States and North America, in Western Europe, et cetera, the life expectancy is near 40 for patients with cystic fibrosis. And that's an average, folks. So that means that the sickest kids who are dying clearly are lowering that average, and many are surviving well beyond that without transplantation. It's also really useful, I think, to remember that we have had an enormous increase in our understanding of the genetic and molecular defects in cystic fibrosis, and that that understanding has finally begun to lead to really revolutionary interventions to correct some of the cellular dysfunction that occurs. And at least in one case, where there is now a drug available labeled for that particular mutation for kids with cystic fibrosis, it has begun to make a real clinical difference for those patients. Now, that particular mutation is a relatively rare one among the many hundreds that have been identified as part of the CF gene. It's also the case that that particular intervention costs upwards of $350,000 a year, so that's a challenge. Nonetheless, the kind of thinking that went into that is a model for what I think are going to be further medical treatments for cystic fibrosis. And we're going to need to take that into account as we think about the medical versus the surgical interventions that are possible for this disorder. So over the last half century or so, the five-year survival of children with acute lymphocytic leukemia, this is a bit of an aside. You'll see why I'm making this, I hope, has gone from around 15% or 20% when I was a resident in the mid-1970s to over 90% for the garden variety kid with ALL, that is no high-risk markers of one sort or another. There have been similar sorts of progress, not perhaps quite so good in other childhood cancers. We haven't had comparable progress in cancer survival that affects adults with cancer. Now, part of the reason for that I would like to maintain, and I think most people would agree with this statement, is that in developed countries, over 70% of children with cancer have been treated in the context of controlled clinical trials. Now, I want to be careful here because it may well be the case that childhood cancer has quite different biology from adult cancer, and that plays a role here. So I'm not in any way claiming that the only thing that's made a difference is enrolling lots of kids in controlled clinical trials. All I am saying, however, is that the systematic application of comparative trial methods has allowed people to make serious progress and make at least some contribution to an incredible turnaround in the survival of children with cancer. On the other hand, fewer than 15% of adults in the United States are treated in comparable controlled clinical trials, and there hasn't been as much progress. So comparative trials likely explain at least some of the progress in pediatric cancer. So why so few controlled clinical trials in surgery? I'm not going to go into this in great detail. I've done that some in this institution in the past. We're not going to go over all of that. What I do want to say is that it's pretty clear if you look at the history of surgery that when people have gotten around to doing controlled clinical trials, those trials have demonstrated that the surgical interventions that many people thought were terrific turn out not to be so great. So many of the new need operations that people have done have turned out not only not to be any better than what was being done before, but have actually turned out to have higher morbidity and mortality associated with them. The classic example is the use of internal mammary artery ligation to treat coronary artery disease, which it turned out when people finally did a couple of comparative trials, actually had higher mortality than standard medical treatment. It also seems to have been the case, the radical surgical interventions for breast cancer and more recently fetal surgery for diaphragmatic hernia have turned out not to provide the benefit that the surgical innovators thought they would. And let me also add some of that innovation was based on very good laboratory trials with animal models so that it was only when people actually did the clinical test in human beings that they found out that things didn't work so well as they had hoped. So there are lots of reasons why there is opposition to and difficulty conducting clinical trials in surgery. The only message here is when people do get around to doing it, it turns out to provide really useful information in a lot of cases. And I want to point to the work of one particularly courageous pediatric surgeon, Michael Harrison in San Francisco, who was the one who conducted two comparative clinical trials in congenital diaphragmatic hernia for fetuses who demonstrated not that it didn't work, it does work, but that the survival was no better than waiting for the child to be delivered and operating afterwards for a host of reasons. So the only point here is, well, two points. One is you can do successful clinical trials in surgery, it works, and two, you get useful information much of the time when you do it. So there aren't really very good excuses in my view for not doing it. So, back to cystic fibrosis. The early experience in pediatric transplantation for CF was tempered by very high morbidity and mortality that was associated with a number of things, in particular, pre-transplant pseudomonas and fungal colonization on the one hand and post-transplant CMV and EBV infection. On the other hand, a high incidence of post-transplant lymphoproliferative disease compared to other solid organ transplants, so liver and kidney in particular. And then perhaps most distressingly to many patients and their families are very high incidence of bronchiolitis obliterans, which once it occurs, and I think this is still largely the case though, I'm sure the pulmonologists in the room might have some different take on this. Once it occurs, inexorably progresses and causes many, many serious symptomatic problems for those patients who develop it. So in 1999, and remember, we're not talking about that long history here, right? We're talking only about 20, 25 years of lung transplantation for cystic fibrosis in kids or anybody for that matter, but in any case. So an important report published from Case Western Reserve in 1999 said that the typical indication that they had been using for referring patients for transplant, that is an FEV1 of less than 30% of predicted, was actually associated with decreased survival after transplants in patients with CF. Now that paper had both adults and children in it, wasn't exclusively kids, but the finding was true for the children as much as it was for the adults. That made that center wonder about the wisdom at the very least, the criteria they were using for referring patients for transplantation, but also they were very concerned that there might not be a survivor benefit from transplantation itself. So the median survival in the low FEV1 transplant patients was not any better than similar patients who did not have a transplant when they did follow-up. And in addition, those authors noted, well maybe part of the reason for this is the fact that we're doing a lot more now, we're more aggressive in our medical management, we've learned how to do it better, so maybe the transplant option isn't as necessary as we used to think it was. Same year, 1999, a more hopeful report from the Hospital for Sick Children in London, Great Ormond Street, the largest pediatric institution in that country. They used a particular statistical method called proportional hazards analysis to create a model to predict survival benefit after transplant in their own patients. And by the way, just to be clear, I'm sure you've all recognized this, but just to be clear, both of these analyses were retrospective analysis. No prospective studies, in fact, no prospective studies to date that do comparative analysis here. So in their analysis, using their model, the transplant risk of death was 0.41 compared to those who were listed for transplant but died before transplant occurred. So in this particular case, there was a clear survival benefit from transplantation different from the Cleveland report. They also noted that survival after transplant was about a third of the patients at five years. That's pretty much consistent with the data from the time. It's substantially better now. Just so I'm not pretending it's not better, it is better now. Lots of reasons for that probably. Same year, another cautious note from St. Louis, St. Louis being one of the two largest long transplant centers, generally but in particular for kids in the United States. They noted in a review of their patients and unusually large incidents of post-transplant lymphoproliferative disease in the patients who had been transplanted who had CF. So of their kids, this is just kids, who developed PTLD, 16 of them in this review, 13 came from the cystic fibrosis population. And the only clear risk factor that they could identify in their analysis was two or more episodes of acute rejection. No particular explanation offered, but again, and remember this is 1999, so PTLD had very grave implications for survival then. It probably still has pretty grave implications for survival, but to be fair, I'm not denying progress has been made there. Either it's not as bad now as it was then. It's not terrific. Nobody wants. I have a question because I think if I recall from this publication that the population, the percentage of patients who had CF who underwent transplant compared to other diseases was about 70%. So that's not too far off than a percentage back there. You're right, it occurred in all the CF patients. So a couple years later, a report from Israel. They echoed basically the same finding as the Cleveland study did. This is a quote, CF patients with an FEV won less than 30% of predicted and who did not receive a lung transplant had survived longer than CF patients who did receive a lung transplant. And the median survival was 7.33 years versus 3.49 years in the CF versus non-CF. I mean in the transplant versus non-transplant population, five-year survival, 73% versus 29%. So again, transplant did not confer the benefit that people had hoped that it would. A 2006 review from the St. Louis group says, post-transplant lympho-perliferative disorders, growth retardation, respiratory tract infections and medical non-adherence appear to be more common in pediatric lung transplant recipients. They're just identifying here a group of problems in this population of patients. Again, children, now this happens to be all their transplant patients, not just CF. But since CF, as we just heard, represents the major indication for lung transplant in the childhood population, it's mostly kids with CF in the first place. So what I think is important about this report is where it comes from. It comes from a group of people who are major transplant enthusiasts. That's what they do. They're really interested in it. They want to push it forward. What they're doing is acknowledging that there is a particular population, that is children. And CF is the major indication for transplant in children and that there are special problems associated with transplantation for children. Then a particularly stinging report from the folks in Utah. And let me be clear, and just so everybody understands, Utah is the beehive state. That's why it says what it says. This group, this group in Utah, which is a health services research group has done a number of analyses like the one that I'm telling you about here. They've come to very similar conclusions in each of their papers. They're not popular in the CF world, but I think most people, even the St. Louis folks, agree that their statistics are actually pretty darn good. So this was a 2007 New England Journal of Medicine article by this group. The lead author pronounces his name Lil, I learned from my friend David in Pittsburgh. So I'm going to pronounce it that way. They use data from the U.S. Cystic Fibrosis Foundation Patient Registry and the OPTN. They identified children with CF on waiting lists for transplant in the United States between 1992 and 2002. They also used a proportional hazards model, so the same sort of model that the Grand Ormond Street group had used. And they concluded, quote, our analysis estimated clearly improves survival for only five of 514 patients on the waiting list. Prolongation of life by means of transplantation should not be expected in children with cystic fibrosis. So two reports, this one from Utah, earlier one from Cleveland, that raised serious questions about a survival benefit in kids with CF transplanted in the United States. There was an accompanying editorial regarding this quite controversial paper, which again, 103 or four that they published with similar kinds of analysis and similar conclusions. And the author of the editorial says that the key issue here was that we appear to be at a point of equipoise in this situation regarding whether in fact there is a survival benefit to transplantation in kids with CF. So the key question, according to the writer of the editorial, is when is predictive life expectancy with medical management less than predicted survival after transplantation? Now, in commenting on the article, he notes that in the Lil article, the median survival after lung transplant in children with CF was 2.85 with a five year survival of 33% nationally in 2007, and that they talked about a predicted five year survival in the analysis in the New England Journal paper of children on the waiting list of 57%, which was higher than other people were reporting. So they wondered about what that meant. Nobody doubted the source of the data, but nobody could explain what appeared to be a somewhat anomalous finding of medical survival in that population. And the editorial and many others have also pointed out that in 2005, there was a major change in the lung allocation system. So the way lungs are allocated for kids in particular, the kids got a earlier shot at getting transplant after this change in the way lungs were allocated, and that that probably resulted in earlier transplantation and better outcomes for kids and that Lil's paper couldn't have taken that into account. So this is one of the images from my friend David in Pittsburgh. It's simply here to point out that when you're doing statistics, you need to compare apples to apples. And this speaks for itself, I think. While some people leveled serious criticisms about Lil and his analysis, in general most people agree that the paper was pretty solid from an analytic perspective. So Lil and company didn't do what this roadside sign does. Well, as you might imagine, a lot of prominent people, Nabob's, chimed in on Lil's analysis or analyses because there were a group of papers and protested rather prodigiously about it. Now I think it's important that many of the people who were critical on the one hand acknowledged that there weren't actually prospective comparative trials that one could examine and that that was too bad. On the other hand, they weren't willing themselves to engage in prospective comparative trials. So I'm not sure how fair it is to be critical of these kinds of post hoc analyses or retrospective studies when people aren't really willing to do what needs to be done, which is to do prospective comparative trials. And it seems to me very important to understand that these positivistic assertions about the value of transplantation are just that. They don't constitute proof. They're just assertions that this works and we should use it. And I'm not saying we shouldn't use it. I'm not even saying it doesn't work. The key question is, does it work better than not doing a transplant? And that hasn't been proven. So as Lill and his co-authors have responded, only a prospective trial could provide clearer answers. And the reason I say clearer rather than clear is we all know about the hazards that could be part of any kind of forward moving prospective trial. We can talk about that in discussion if you want to. So up till now we've just been talking about survival benefit or lack thereof with transplantation, what about quality of life? Well, as most of the papers acknowledge, most of the studies really hadn't looked at it. They were rather quite inadequate with respect to this. And they used surrogate markers such as number of days hospitalized either in the medically managed patients or the post-transplant patients or a number of complications. But that doesn't really answer very many questions about quality of life. And importantly, among those who are long-term survivors, in this case seven years or more, most of those patients had little or no activity restrictions following their transplant. Now there's an obvious ascertainment bias here, right? Those people who are really sick and didn't do well don't survive till seven years. This is a selected population. It's terrific that those who survived this far appear to be doing really well, but it doesn't really address the problem of what happens in the seven years before you get to this point. And there had been some data published from St. Louis and elsewhere that suggested that there were deficits in cognition and academic performance and an increased number of patients with behavioral problems following transplantation. Everybody agreed that teens and they're the ones who represent the largest group who are being referred for transplant, for CF, have challenges with adherence for all sorts of reasons. And then other people have suggested in their analysis that there seem to be a decrease in survival benefit for people who come from lower socioeconomic statuses. Well, one can certainly understand that that might be the case because the amount of support necessary to keep somebody going post-transplant, both economically and psychosocially, is indeed prodigious. On the other hand, it doesn't seem fair, this is an ethics talk after all, to say on the basis of the poor outcomes in that group we're just not gonna transplant them. Nobody's really gone any further in commenting about that, but I do think it's something that those of us in the ethics world need to be thinking about. So this image again from David is here to remind me, to remind you that clearly some people do terribly well following transplant. The girl in the middle here is holding her ex-planted lungs following her lung transplant for cystic fibrosis and she's thriving. And again, I really don't wanna come across here as saying this is the worst thing since whatever, it's not terrible, it's clearly beneficial for some patients. The issue is which patients or, well, that's one issue, another issue is on average, is it better? Not whether particular patients can or do benefit. So let's talk a little bit more about quality of life and in particular about the symptom burdens of patients with cystic fibrosis. So among medically managed patients, it's clearly very problematic as well as those who have transplantation. So those who are medically managed to report routinely pain, excessive problems related to coughing, including sleep loss, shortness of breath, low physical energy and fatigue, sadness, depression, irritability, and just being consumed, having their lives consumed by the treatment regimen. So having to get up two hours earlier than their friends before they go to school in order to do their pulmonary toilet and on and on and on. So there's an enormous amount that needs to be done to care for patients with cystic fibrosis and that's true regardless of when, but obviously as they get sicker, it's more and more true. The key point here is that many of these issues persist following transplantation and some of the post-transplant symptoms may actually be part, be induced by some of the things that we do. So many of the psychiatric symptoms that are reported may be related to Casinure inhibitors or other drugs that seem to have a high incidence of neuropsychiatric complications. And we shouldn't forget about that or dismiss that and in fact in one report, over half of the adolescents were clinically depressed in following their lung transplant. And that's a larger number than the between 20 and 30 or 35% of pre-transplant patients who report depression. Not only that, for those who develop bronchiolitis obliterans, many of the patients say that that disorder is basically like having CF all over again. The symptoms are the same, the treatment is very similar. They're not any better off once that disease takes over. So now the question is, now what? So this is from an article by a pediatric pulmonologist, not my friend David in Pittsburgh. This is from somebody at Vanderbilt. He said, in 2009, a palliative approach to cystic fibrosis should focus on improving assessment and treatment of bothersome symptoms, better understanding of the factors that enhance or restrict adherence to the daily regimen, and improve support for the inevitable and difficult decisions about transplantation and end of life care. Now I might have phrased that slightly differently. I might have said transplantation or end of life care. But I think the point's clear. Walter Robinson here is referring to the fact that people do have choices, and we need to help patients and families make choices. And in order to do that, we need to provide them with the support necessary for making good informed decisions. So helping patients and families with CF, who face possible transplantation, means that we have to have data that people can understand and use if they're going to make good decisions about whether to accept or forego listing for transplantation. A 2009 study, one just this issue concluded that those considering lung transplantation for CF failed to understand why they had been referred for transplant in the first place. They didn't appreciate the risk of transplant or that they had an option to refuse transplantation. Now, those of us who've been looking at the empirical literature and ethics for a long time shouldn't be surprised by this. This is the same thing that everybody else who's ever studied informed consent has ever found, whether it's in a clinical context or a research context. People don't get it. Now, one of the things that's different in what we've been talking about is not only do people not get it because perhaps we don't do such a great job of explaining it, but because the data don't help us very much. There isn't a good information base on which we can provide good information and counseling about what to do. So, After Lil's article or articles were published and there was this big storm in the community about what all this meant. The American Thoracic Society and other people put together a roundtable discussion so it was both an in-person and then published group of discussions about what to do. And in this discussion, one of the major advocates from St. Louis for pediatric lung transplantation said that he was worried about doing prospective studies because there was a risk for a lot of variability in the populations. Now, that's true. The United States, unlike, say, England, which has two places that do pediatric lung transplantation, we have a bunch of different places with enormous variation in the number of procedures they do and their protocols they use. There's not very much uniformity and there may very well be not only differences in how patients are treated or listed or whatever, but there may be different populations that are accepted for referral in the first place so their population biases. And in order to overcome this, there would need to be uniform protocols for listing for the details of the transplant process, for donor criteria and on and on, and that any such studies that people would undertake would need to look at quality of life, costs and palliative care. Now, it's important to understand why it would be so difficult to do a comparative trial here. One piece of it is that worldwide, there are only 50 to 60 pediatric CF lung transplants being done. Now, the major rate-limiting factor here is donor lungs. It's not that people don't want to do more procedures, but with such a small population of patients, it's pretty hard to figure out how you could do some of the statistical analyses that you would need to do. There'd be sample size issues in particular. And again, just to reiterate, I already mentioned this, the decision-making process in the United States is literally all over the map. There are too many centers, they're competing for patients. It would be hard for them to come to agreement. Now, having said that, it would be hard, but it might not be impossible. I want to remind people in the room or tell people who might not know that we have just seen the publication in the last couple of years of a comparative clinical trial of fetal surgery for meningomylosil that was pushed on the centers that were doing this by the federal government. There had been as many as six centers, six or seven with two others who had begun to consider doing fetal surgery for meningomylosil at the time. And the Fed said, wait a second, this doesn't make any sense, this is very controversial. We will fund a comparative clinical trial, but we're only going to do it if we can restrict the number of centers who are doing the surgery to three, San Francisco, Vanderbilt, and Philadelphia. And everybody else in the country has to agree that they won't undertake the development of a surgical center and that all the potential patients be referred to one of the three centers. Now, I'm not claiming that there weren't all sorts of problems with doing that, and I don't actually think it's the world's greatest study for lots of reasons that we don't need to go into, but it was a very important precedent. And I think in an area where there is as much controversy as there is here, we need to pay attention to such precedent and take the imperative to do comparative trials seriously. Other problems associated with doing it are obviously there are continuous improvement in both the non-transplant and transplant related modes of care that people are employing, so it's to a certain extent a moving target all the time, but there are ways of dealing with that. We have statistical stratification methods that can control for some of that. I personally just am not convinced by arguments that we hear all the time that you can't do comparative trials in settings like this. In fact, I would say, sorry, you have a moral obligation, in fact, to do it. Moreover, these practical barriers to doing things don't seem to deter the people who wanna push on and just do transplantation anyway, so if they're willing to be innovative and do their own thing in the operating room or post-operatively, then why aren't they willing to subject what they're doing to critical analysis by way of comparative trials? So I wanna end with the words of a transplant pioneer, Franny Moore, who in 1989 commenting on the premature application of multivisceral transplantation in an editorial in JAMA, commented on the power of surgical enthusiasm, meaning powerful surgeons, people with lots of charismatic authority to use a sociologic term, can convince people to do a lot of things, whether it's hospital administrators or patients and families, and we need to be a little cautious about that. That's pretty infectious. It may not be warranted at the time. It's important to be ethically skeptical about claims of the value of innovation, and we have an imperative not to employ what Dr. Moore called desperate remedies without appropriate academic restraint. So my ending word to you is don't just do something, study it and study it the right way. Thank you very much. I would say that there would be a lot more lung transplant in children if we had more deceased owners. To what extent are they doing any living donation as they had done earlier on? Since the introduction in 2005 of the lung allocation system that is now used, the use of living donors has fallen precipitously in lung transplantation, and very few people are enthusiastic about it. And we are, I think, correctly hesitant to use living donors in many circumstances, but one of the things that's particularly important to understand is that if you're gonna do bilateral lung transplantation in kids with CF using living donors, we're putting two healthy people at risk for the sake of one sick patient, unlike putting one healthy person at risk in kidney and liver living donors. So if anything, it's more ethically problematic. As you have a point there, there was one living donor lung transplant performed in the United States in 2011. And the places that had been doing them primarily at Washington University of St. Louis and University of Southern California have largely abandoned it because it's just not feasible. And the results of living donor lung transplantation weren't as good as the results from cadaver donors so that you're taking a questionable procedure and doing it in an even more questionable manner. And it's kind of guided some of that. Although I have to say that having looked briefly at that data, the numbers were so small that I'm not sure that the conclusion that they were doing worse after living donor transplantation really held up statistically. They weren't doing any better, that's for sure. Yes, please. My question is, oh okay, my question is, I appreciate the fact that you're so provocative, but I had a question in terms of, because a lot of ethicists, they also wear many different hats and their clinicians, how do you justify being an ethicist and being provocative and bringing to task certain things and also having other clinical hats that you wear? How do you bring that to terms? Because you're an MD. It's a great question. I'm not sure I have a great answer. I can tell you what I do. So I, these days, mostly work clinically as a palliative therapy nutrition. So what's important about that is I don't go out and solicit patients. I'm not competing with anybody for the patients I get, but I do take care of some pulmonology patients in our institution who become candidates for lung transplantation. And I engage along with my colleagues in pediatric pulmonology, in candid conversations with the families about what their options are, and I see it as my obligation to be sure that they understand that they can go to St. Louis because we mostly refer to St. Louis. We occasionally refer to Loyola. But mostly we refer to St. Louis. That that's the group that has the best success that's in the region. And we help them understand as much as we can about what that means. We try to do it in as neutral a fashion as possible. And then I also help them understand what a decision not to do transplant would mean and what palliative care would look like under those circumstances, what sort of supports would be available to them. And I'm the last person to claim that it's possible to be value-neutral in completely in these kinds of clinical encounters. So I don't think that I am. I think I strive to be as neutral as possible. I think I have to rely on the patients and families and my colleagues to judge whether I'm successful at that or not. But I think you raise a good point. We're often wearing multiple hats and that creates complications of all sorts. Yes, as a CF care provider, a pulmonologist, one of the issues to think about in terms of the small numbers of transplants in children is that you have to look at the time span that that data was collected because things are much better and you emphasize this in the way of treatment. And hopefully the individuals that are getting referred to transplant are now 18 to 20 or over. That certainly has been the case here. I think you made the point in your last comment that as a clinician our job is to give families and patients their options and be able to tell them what's involved with transplant, what's involved if you don't do transplant. And hopefully they would not be confused about the fact that they have no choice about transplant. I think you're absolutely right. It's very important to help people understand that they do have choices. But again, I want to emphasize what I said before. It's much harder to help provide counsel about what's a good choice for them when we don't have good data about what the outcomes are likely to be. That just makes it so much harder. Hi, thanks Joel. That was really helpful. I couldn't help, but first of all, on that comment of ethics and being provocative, I mean, some of us could argue that to be an ethicist is to require you to be provocative at least from time to time. I was really interested in your comparing maternal fetal surgery for myeloma and ingesiel with the CF issue because the maternal fetal surgery issue is different partly because it involves two parties and involves maternal risks that are very real, prematurity, for example, in all of the cases. But beyond that, I was somewhat involved in this issue in the past. And what I remember is that one of the arguments against a randomized control trial was that there were patients coming out of the woodwork around the Vanderbilt area and across the country, women and couples who really urged that maternal fetal surgery for their infants, even without data that showed that it was definitive. Now, on the side of lung transplants for CF, it seems as if you don't have anything like that outcry but you have a lot of ambiguity, as a matter of fact, on the part of people regarding whether to go to the transplant route or not. So it's an interesting question, Mary. I think that there is a population of CF families who by virtue of who they talk to in the waiting room when they come to see their pulmonologist, what they read on the internet or whatever, who actually are very much determined to get transplants for their kids, regardless of some of the questions they may hear from their doctors or that may be in the published literature. So I'm not sure in that way that it'll be all that different. And I completely agree with you that the Magnum Isle Trial's raised very different issues. I was mostly referring to the logistical obstacles that people claimed were going to make that impossible that after all turned out not to be true. I wonder, can you expand on that element a little bit more because part of what I feel like it's gone on in the handful of cases around this that I've been involved in, is that waiting of the power of the narratives that they hear about those cases which you referred to with the ascertainment bias against the scientific evidence or lack of scientific evidence that there is. And I wonder if you can comment on that interaction. I wish I had something bright to say about it. I think you're absolutely right to point to the power of narrative. What I think is interesting in some way is the lack of availability of countervailing narratives and negative narratives. One of my colleagues who trained here in neonatology actually, Jessica Fry, is involved in a really interesting project now of looking at NICU parents blogs on the worldwide web. And one of the things that we've found in looking over that data, and she's now looked at, you know, 700, 800 different blogs, not blog postings, but blogs from these families, is that there really is a mix of positive and negative. I'm not sure that's true in the CF world, that there is that availability of negative information either for the medically managed or the transplant population, whereas I do think there are lots of sources whether they're pictures like the one I showed you of the young woman holding her damaged lungs, attesting to how wonderful it is. So it's a great question, I just don't have anything brilliant to say about it. I would comment on that, saying that the conversation regarding transplantation and cystic fibrosis has changed very dramatically in the 25 years I've been involved in transplantation. The conversation until about 2000 or 2002, maybe 10 years ago I'll say, was let's go get it, this time the family would be pushing for it. The kids would sometimes have a little reticence. The transplant centers who had done transplants in children and adolescents were far more reluctant to sell it because it all had the difficult experiences. But since Lill's paper and since the report from the Cleveland Clinic, the conversation is really much more widespread and broad about the possibilities of what's available and the likelihood of actual benefit. Well, I think you're right. When I talk to my pulmonology colleagues, I have certainly noticed a waning and enthusiasm. Not that they don't refer patients or whatever. I think they take the responsibility to refer patients very seriously, but unlike the way it was five or 10 years ago, there is not fabulous enthusiasm. Joel, great talk, I appreciate it. I have a quick question for you regarding how to move forward. These are expensive interventions in every way and using lots of resources, many of which are scarce and not just financial, but people's time, obviously the organs. Someone's paying for all that. Are those the people, those makers, that those check signers, are those the ones that we need to be talking to? Well, I certainly think somebody needs to pay for the right kind of study. I personally think insurance companies would be doing themselves a favor to fund or take a portion of their profits for the for-profit ones to look seriously at what the comparative benefits and deficits associated with the various modes of treatment are. As I said before, I think we're gonna get into that because we have to now legally because to the extent that these things are paid for by the federal government, Medicaid and Medicare funds, Feds are gonna require comparative effectiveness analysis. So, yep, it's coming exactly how we're gonna pay for it. I don't know, I guess I also think, I'm not sure you were hinting at this, but I'll say it for myself, not put words in your mouth, the company that makes the drug that costs $350,000 a year to provide what seems to be really good treatment for at least one of these mutations, probably ought to be kicking in something too. I'm sure that they're gonna make up for the cost of R&D pretty quickly and they're gonna be able to afford to help out with this effort. Joel, I thought you gave the best arguments in your slides against being able to do a randomized trial in what is a kind of orphan disease. You're talking 50, 60 cases around the world, maybe being operated on at, I don't know what, 10, 15 different centers in the US and Europe and Canada with different protocols, different selection criteria, little uniformity. So are you thinking of a study like Harrison did in San Francisco, a single site study? No, it would clearly have to be a multi-institutional study but like the maternal fetal medicine study for meningomilophil, meningomilophil, it took a lot of work but they did work out protocols that they all agreed on for evaluation of the women, evaluation of the lesions in the fetuses, how they're gonna do the operations, what the follow-up is gonna look like. That's why I bring it up because I think as logistically daunting as it might be, it has to be done. One more question. So you've talked about the need for more comparative effectiveness research and the value of better informed decisions but nationally you're going up against a couple tough trends, one is the for-profit motive and it's not in the interest of device makers or pharmaceutical companies to do a lot of this. On the second is the argument that's used about well-choice, that well, it's things that comes in terms of the patient autonomy and you're taking away my choice if you hit on this road and I actually thought it was a little more, well, not as promising as you mentioned about the Affordable Care Act, the push towards comparative effective research that still the lobbying has been such that you can't do things like cost-efficient analysis or and all so that it isn't as definitive as I think you had talked about. So what you can talk about then how the values you're pushing for, how they then sort of might succeed given these larger societal forces that are pushing first going against this. So it's a great question and you know this area much better than I so I'm not gonna attempt to engage in a detailed argument with you. I guess I think two things, one is that there really is a moral imperative to undertake this kind of analysis but how to do it, who's gonna pay for it and this business of choice, I think it's a really interesting question. We don't in medicine let people make any sorts of choices, we limit all kinds of choices. So really the question is which choices are legitimate ones for transplant teams on the one hand and patients and families on the other. I mean you don't get to walk into your doctor and say I don't like the way my heart feels so give me a new one, at some level it's a straw person argument, right? So you're right, people always put that obstacle up and I hear that from clinicians of any different stripe all the time but you know there are hospitals that impose lots of restrictions on what they can do in the operating room or whether they're even able to do X, Y or Z at all in the operating room or you know there are only certain privileges I have as a medical doctor at Lurie Children's Hospital. This is not a world of perfectly free choice, it's really a bogus argument at some level. Joe, thank you so much for coming. Thank you.