 with a particular focus on hand transplantation and facial transplantation. The first speaker in the afternoon is Warren Breitenback. Dr. Breitenback is Professor and Chief of the Division of Reconstructive and Plastic Surgery at the University of Arizona. Warren is a world leader in hand and composite tissue transplants. In January of 1999, Dr. Breitenback led a team of surgeons who performed this country's first hand transplant. It also, if you think about it, those of you who know about it, it was the world's first successful hand transplant. There had been an earlier one done in Lyon. Since then, Dr. Breitenback has performed more hand transplants than any other surgeon in the world. Additionally, based on his leadership and expertise in the area of hand transplant, he's trained many, if not most, of the United States teams that are currently performing hand transplant. In addition to his leadership role as the head of plastic surgery at Arizona, Dr. Breitenback has established, intends to establish an Institute for Composite Tissue Allotransplantation and Regenerative Surgery that would include hands and legs and feet and perhaps face also, which would be the first of its kind in the country. Today, Dr. Breitenback will present a talk entitled Ethics in Composite Tissue Allotransplantation, what it teaches us about introducing complex investigational surgical procedures. Please join me in welcoming Warren Breitenback. Thank you very much, Dr. Siegler, for the introduction. It's really my pleasure, a little bit daunting to me. I don't get the chance really very often to speak to a number of ethicists. I could have used your help when I went to Arizona because after spending many years in Louisville and working with Dr. Siegler on the ethical issues of hand transplant, I arrived in Arizona and they told me it was unethical. So you have to keep reliving things. So ethics in composite tissue transplantation, what hand transplant teaches us about introducing complex surgical procedures. So defining what we're talking about, composite tissue allotransplantation is taking all of the connective tissue and saying it can be transplanted, whether it's skin, bone, muscle, joint. Now this was considered literally impossible to do because skin was such a difficult hurdle to jump over. It actually was the test of how treatment would work in terms of rejection. So the, it was dogma basically that you couldn't go forward with trying to transplant skin. Now what I'll be talking about, and I want to make this clear from the beginning, I'm not going to be talking about the normal thing that takes place when the debate starts on surgical intervention and surgical procedures that are researched. This is an article which kind of addressed that in medical ethics. And what takes place in those types of procedures is, as you know, sometimes a surgeon will change the way he repairs a tendon, for example. He'll add two more strands to the repair. Instead of two, he does four, he does six. And then can he publish it, not publish it? Is that research? Is it innovation? That's not the discussion here. So this is not a discussion about the normal surgical intervention. This is a talk about what is standard of care. That's what I want to get to in terms of hand transplant in a paradigm-changing surgical procedure. This is not a talk about technical surgical advances, but it is going to end up being a talk about medical interaction with a surgical procedure. So as I said, hand transplant was considered not possible to do. And it had been attempted, now a leg had been taken off these different animals and attempted both in mice, rats, pigs, non-human primates, and there had been even attempts to transplant a hand on a human, all that were unsuccessful. So it was pretty well accepted that you couldn't transplant skin. Now, amazingly, and it was maybe by luck, in a very rapid period of time, we went from the position that it was not possible to possible, and the sequence went like this. In 1991, Raymond Lule published an article that everybody missed, saying the time had come to do transplant. In this article he had gotten the consensus conference together. And he was from Spain doing the PhD in immunology in California. And what was interesting about the article is although it articulated where he thought we could go, it didn't really articulate the logic behind it. I don't know if you've read articles like that. I mean, you get the feeling that he's saying something, but you can't make A equals B and equals C. And I missed the article, but in 1995 at the Plastic Surgery Research Council, again he stood up from the audience and said, you know, there's enough data to do a hand transplant. So I invited him as a visiting professor to Louisville and we started talking. In 96 we formed an official group. By 97 we had an international conference of which our keynote speaker was none other than Dr. Siegler. He was instrumental in getting us over the hump of going forward with hand transplant. And in 1998, ahead of time, and I'll explain why we did this, it was also at the direction of Dr. Siegler, we made an announcement that we were going to proceed with hand transplant and we felt we had enough scientific evidence to do it. So we made the pre-announcement and immediately I ended up at Time Magazine as being the first person to put my mouth and gear before my knife. Seriously. And in 1999 we did the first hand transplant. We were beaten by three or four months by the French, but that hand didn't last less than two years. So I like to pimp the French. Now I spend a lot of time in France. I speak French, I was at McGill, I know Dubinard very well, but I love to pimp him by telling him we did the first successful one. The critical biologic insights were the fact that there was a publication in 1995 by Ben Hyman Anthony that for the first time was successfully able to transplant a leg on a rat. Now the way I looked at this was, and this was the argument I used to have with my brother, being somewhat narcissistic as most surgeons, I used to tell my brother I want to be famous or powerful, I don't care if I'm happy. So that shows you my pathology. Now my brother said he wanted to be able to drop a rock and have it fallen to heaven and there would be no reason. So it took me a long time to understand that but what I finally came to understand is to me there always has to be a reason and this was a rock dropping into heaven. And the one thing that they had done that made a difference was they had added mycophenolate moffatil. Now there had been attempts at non-human primates that had not done well, but it did turn out that all tissues in the hand had already been transplanted. And then what we did is what I call the Louisville pig. Now we had a lot of pigs in Kentucky and things weren't as sophisticated that many years ago. We didn't have to get our tissue type. It went out to the farm, got a pig. We devised a flap that we're still using that combines all the different elements. We took it off. It started to reject. You can see over there in the corner, a little hard for me. I don't know if it's coming across to you. No. Is there any way to turn down the lights some? You'll go totally dark? Okay, well, but I want to talk in the dark. But here's a flap that's rejecting. I think you can see some of the dark color there. And there's the little piglet and there's his transplanted leg, a portion of his leg. Now this was the first time that we were able, in a large animal model, to successfully transplant skin. And so I always say the Louisville pig challenged scientific dogma and we were able to do it with kidney-level immunosuppression. And since you can transplant a kidney, it meant you could transplant a hand. Now, if you think about it, so we had a small animal model, a large animal model. We knew that we could use low levels of immunosuppression by low levels, I mean kidney levels. So at the same time, and this was an important objection, there was severe objection about the ethics. So they said, okay, even if you put all this together, it's not ethical. And it's not ethical because you can't subject someone to give them a drug that will be life-shortening for a transplant that will never prolong life. That was the seminal ethical argument. And I didn't have any idea how to grapple with that really. So I wish I could say I was the one who discovered Dr. Siegler, but it was someone on my team who said he's been working with split liver. That was a big ethical issue. He's developed protocols for us. So the next thing I know, we were in a group of about 14 people in 1997 discussing hand transplant from all the different levels and he made the seminal breakthrough which allowed us to go forward. Now, I'm going to go through the five arguments at present that represent why composite tissue can be done. Then I'm going to come back to Dr. Siegler's contribution. So risk-seeking behavior, mountain climbing, scuba diving. The fatality risk is lower than many voluntary risky jobs. Himalayan mountain climbing is not a great one. Combat in Vietnam, long-term smokers. And then finally the myth that we were somehow that transplant always prolonged life just is not true. So kidney transplant for years did not prolong life. Eventually it was able to get. But for the first 20 years it was actually probably life shortening compared to dialysis. And certainly pancreas transplant today still suffers from not actually prolonging life. So these two issues here were ones that actually after we did transplant it proved the critics wrong. There was not high morbidity and mortality and the function of the hand and the complications was nowhere near as high as anticipated. People said that the patients would die within six months and actually right up to the transplant they went after my medical license and I said before you take it just let's see if it works. So this was the meeting we had when Dr. Siegler came and he really gave validity. I don't think without his contribution we could have gone forward. I think having him on the team and I don't know your world well but I know there were people in your world who were critical of hand transplant at the beginning. So it took courage and insight to move forward and I really owe a lot to Dr. Siegler. This was what I considered to be a classic article in transplantation in our field. Now he also came up with the idea I always get the credit for doing the simplest part of it but he came up with an idea that probably many of you who know him are aware of in terms of split liver. I mean how do you ethically ask someone to give part of the liver to a child increasing their mortality by a very small percent in order to save the child there's coercion involved there's all kinds of issues. So what Dr. Siegler had developed this concept of pre-announcement and I think you should all be aware of it that you basically tells the world of society you know before you clone a human being maybe you should tell the bioethicists of the world in the medical community you're going to do it. Not a revolutionary idea but it was revolutionary in terms of bringing it to the proper level in reality if we're going to do things that can change society markedly we should be having these discussions. So my contribution was only to reduce it to simplicity. I remember Dr. Siegler said to me later what was that that you said what I've done how I made it so simple and so it's this simple you think it, you do it and then you announce it's the old paradigm the new paradigm is you think it you do it and then you announce it. That's the one Dr. Siegler that got me in trouble with Time Magazine but I think it's a proper paradigm for us to be using. We also developed a patient advocacy program and I know there's been patient advocates before but we changed it a little we had no contact with a patient advocate except to treat them like the patient we gave him the same material the same informed consent and he had no ties to the medical community this was to put a barrier between the fact of the surgeon coercing the patient into accepting something if this procedure hadn't worked it wasn't me who was going to die who was going to be the patient this is the first patient he had blown his hand off in an M80 firecracker which is a small stick of dynamite this is not, here's the concept you need to get around there's nothing shocking about this any good micro surgeon well trained with experience in the United States can put a hand on that's been cut off I'm not saying it's easy it takes years of training but it's what we do you take the hand that's off you get the tendons and nerves you need and you attach it to the other part this is not going to be like what Dr. Semina was going to be telling you about because face transplant went into areas where people had done very little we knew how to do this half asleep sometimes you are half asleep in the middle of the night when someone comes in and the trucks run over them and you're there with two residents trying to get it done and there's the first successful hand transplant on his way this was the picture that was supposed to go on the cover of Time Magazine but it was beat out by Clinton because he was impeached so I just want you to see a little bit I want you to understand that it does work now I will tell you surgeons always show you their best pictures okay and we certainly have worse results than this he's one of the best he has thinner eminence function the nerves have to innervate into the thumb he has almost normal sensation when I say almost normal it's normal on some days and not other days physiologically we can't explain that but it does happen you can see that he can do fine motor motion what you would notice immediately if you met him is that the hands weak he's lost about 70% of his strength the reason for that is because the injury took place here the hand I put on was pretty normal but I had to hook up to blown apart muscles so if you're going to need a hand transplant make it a clean amputation because it gives us a lot more to work with now here's the rub that we need to think about what is hand transplant is it innovation, experimental or research and I think all of you understand is ethicists and I really didn't understand this and I told Dr. Siegler I've actually been preparing for this talk since February it's fortuitous in a way because I've been working on this issue of standard of care but in my reading I realized that you can be innovative and not be research you can be research and not necessarily innovative and you can be experimental which should be research but may not be innovative I would say that hand transplant falls into all of these categories at this particular moment it certainly was experimental it was innovative and it was research but the ethical issues which are facing us now and I'm going to jump from that slide to this slide in the next 20 minutes or 15 minutes are we now standard of care I want to talk about the fact that patients are dying under these protocols there are patients in associated protocols that aren't seeing the intent to treat in other words the results are being hidden that's happening here in Chicago and not at this university but before you throw me out and not reporting complications and results truthfully I don't know if this goes on all the time but I'm going to make a statement which is true in medical school I looked up to doctors and my position where I am now as a professor I can tell you that I'm disgusted with a small segment of and what makes me even more disgusted is it's allowed now this is an ethics conference so you can come up to me afterwards and tell me where I'm wrong it's my contention that hand transplant should be considered standard of care what is the definition of standard of care where you're all aware there's a legal definition of prudent physician but there really is no definition for standard of care when it comes to trying to decide about medical technology there is no now this is my writing here there is no singularly accepted process for how a new and innovative surgery is brought to a standard of care there is no accepted sequence combination of definitive criteria that need to be met before the standard of care threshold is achieved the history of medicine shows that society has required different thresholds at different times for different procedures well that's why I've been working on this since February what I've done is I've broken down my concept of standard of care the majority of the medical community accepts the procedure as medically necessary ethical committees review and scholarly works deem them done so we don't know about society but I think from all the hoop law that's gone on you can see that society accepts it thanks to Dr. Siegler I don't think there's any ethical pushback now that we can't do this and shouldn't go forward a series of institutions have carried out the procedure under IRB review with a record of success there's now four or five I think five that have done it and there's another ten in the wings with IRBs ready to go of which now I'm in that situation because I've left where I did this in Louisville and I'm now in Arizona starting over so I had to go to the IRB and fight off the critics Arizona is kind of like going back to Tombstone that's why Tombstone's right they like hand transplant what's that a majority of the medical community accepts kidney transplant as standard of care that has not taken place I still don't think a majority accept it scholarly work that demonstrates beneficial outcome absolutely no doubt and I'm going to skip forward here to show you this this is the one year survival rate of kidney transplant hand transplants on the far left hand side and this is kidney transplant at different times at the very early stages this was your chance of your kidney surviving look at what we were in our first years far better now of course they caught up to us so now they're roughly about the same as where we are and that makes sense since we learned from their immunosuppression we picked up their immunosuppression what is really surprising is that long term kidney transplant success today has by five years significant majority are gone 40% 50% from chronic rejection where this is not true in hand we're seeing better success than we ever anticipated so to continue with the criteria indications that there is public desire for the surgical procedure I think that's present now what's marked here in red now when I started this project all of that in its criteria literally over the last two weeks preparing for this talk I've changed my mind you know the great saying by Emerson a foolish consistency a foolish consistency is the hobgoblin of little minds I'm really questioning whether quals utility as part of this work over the last year I think we've pretty conclusively proven it's almost impossible to get a true utility if you know what I mean by the standard gamble to get utility to do quals to determine whether something should become standard of care you can't do it we may be able to get there but at this point it's really not valid and I'm not sure that we should be involved in the cost containment element of this so that's where I'm headed for the rest of this there's also really what we're going to be talking about here technology assessment versus standard of care and I want to talk about the ethics of what's called crossover therapy has anyone heard of that that's good because I got it from an ethics article so now I feel maybe I'm telling you something you don't know this came out of ethics and I'm going to try to talk about crossover therapy ethics standard of care and technology assessment and how that plays together so what do we mean by standard of care well as I said no definition the legal definition in this article about the meaning of standard of care they said one of the ways that you can do it is put together a consensus group but the trouble with a consensus group is normally there are people who are experts in the field and what do they push for a consensus what they believe in that hasn't always worked out that well the difficulty inherent is that they're based on part of the consensus that is the bias of the experts and may shape the guidelines and either exclude reasonable choices or incorporate personal favorites now I fully believe that now that I've seen what I've seen over the last number of years in medicine here are a few procedures that were standard of care that failed miserably and I'm not going to go through all of them I mean you know apesiotomy I actually just had not me my wife had a baby I have an 18 month old and I was shocked when they didn't do apesiotomy it shows you how far behind I am gastric bubble hormone replacement here's a good one electronic fetal monitoring it doesn't really do any good society holds it as standard of care by saying they want it but it hasn't been shown to be beneficial necessarily in very high risk it might be my mother got this radiation therapy for acne sleeping face down we don't sleep our babies face down anymore which was standard of care that's where sudden death syndrome came from so my point is this conform getting a consensus together is all fine and dandy but it doesn't always lead to good results and if you were to do a positive predictive value of getting consensus I don't think it would be that high so it leaves us with a problem of where we go so here's an interesting article on the introduction of health technology assessment now I want you all to understand have you heard the word technology assessment anybody okay a couple of people basically technology assessment is a category of policy studies intended to make decisions about information impacts consequences of new technology within medicine now this is information that policy makers need and they need it in the right form and these policy makers cannot judge the merits of consequences of technology they have to do it within a strictly technologic context policy makers a policy maker has to consider social economic legal implications in any course of action now I'm not sure if that's in reference at the bottom there to an actual law but I was kind of unaware of this so here I am listening what I think standard of care should be and I'm actually putting policy issues in of utility you know quals and the policy individual are looking at these things which goes everything from ethics to legal to economics so here's where I start to have problems they're going to be looking at the legal the economics and what we tell them we think is standard of care but they're going to be looking at cost and this is going to get involved with both government and insurers technology assessment should not be part of the process of determining standard of care in my opinion I like all of you if we're doing questions later to tell me why if I'm wrong on this but standard of care should be part of the process of technology assessment we tell them what we think standard of care is the criteria for standard versus experimental therapy was summarized by Reiser and this will tie back now this will tie back to this argument about where standard of care intersects with technology assessment what Reiser said is not all new ideas come necessarily out of something that's completely new you could have used a drug that was used somewhere before so how a therapy defined as standard becomes experimental when it was applied to a new area of care so you use something that was already known well if you think about hand transplant that's exactly what happened there's nothing new about hand transplant we put hands on all the time what we did is we took drugs that were already a standard care in transplant and used them now that changes the dynamics of the ethics and also the technologic assessment and failure to see that has prolonged the process towards standard of care in my opinion so what makes something experimental is the fact that it's normally protocol and the outcome is uncertain and yet the outcome of the drugs we're using on hand transplant were already known in terms of kidney transplant heart transplant and everything else so let's look at the total number of hand transplants and I'll try to bring you home on this and let me see there have been 66 hands and 45 patients now the trouble is that some of those were done there's two hands that were done on a patient where they did two legs, he's dead there's been a face done on a patient with two hands he's dead there have been a face and two hands done in Boston two hands are no longer on that patient and the patient almost died, I think you get the picture if you look at just hands, two hands or one hand, all the patients are alive and have done well okay so the first thing to take home is that when I'm talking about standard of care I'm only talking about hands I think people are swinging for the fences your arms and your legs and you realize 40-50% of your total body blood volume and surface area putting them on is no small feet so we now know the complication rates in these patients and we know that these complications are lower than in kidney and heart except for acute rejection and I won't go into all this we can talk about it if you have any for some reason our acute rejection rates are very high it doesn't have any effect it has no major effect avascinocrosis, diabetes, hypertension, hyperlipidemia chronic rejection still up for debate now, my point is that our outcomes in terms of complications is less but because of the confusion about transfer, crossover transfer, people are still looking at the complication rates in heart and kidneys which are higher and I think those are ours it's really that simple the question is with these levels is it worth doing a hand and should that be considered standard of care with the numbers that we have so my position is I change from I to we maybe to be safer but we do not advocate that insurance, government and private coverage should be considered part of the criteria standard of care now I have a contract right now with one of the major insurance companies but my position was I'll bring you the data and then you decide the reason being and I think we all understand this is that insurance companies have problems, this is an interesting article that came out in 94 about bone marrow transplant for women with breast cancer in the conclusion the pre-termination process as applied to patients receiving care in clinical research trials of cancer therapy was arbitrary although most of the patients eventually received financial coverage for entry in the clinical trials the process of pre-determination by insurers did not correlate with the protocol based medical decision making and it was a barrier to a training treatment now who was wrong here I think when you mix research into an insurance company there's an issue now I know what happens all the time we live in a pluralistic society and some but I think it's a danger I think we should define it maybe we'll be flawed but we define it as standard of care and then we hand it off to the technology assessment group and then they make the decisions as to whether it goes forward as a covered transplant both government and private insurers have a conflict of interest we all understand that and believe me I'm a capitalist I mean I'm a card carrying Kato Institute you know kind of civil libertarian I'm not against insurance companies actually I've had nothing really but good relationships when I went to do the first hand transplant I can't tell you how helpful the insurance companies were all the hand transplants done in Louisville including the first when it was totally unknown and everyone said it shouldn't be done was basically 80% covered by insurance they were not boogeymen but they got a job to do they're going to take care of the profit motive they're going to die if they don't make a profit and they've got to have shareholders government they have their own issues now they've got to pursue votes I mean you can't govern if you don't get elected and if you're going to be elected you have to offer people things promise what I cannot deliver we're doing that very well and with medicine right now then you catch up by constraining or limiting access those are the two games these doctors don't want to be in those games I don't think as a physician you should have one job you're a patient advocate you are not a cost control advocate allowing insurance or government to participate in the decision of standard of care is to dilute the physician's role as a patient advocate allowing insurance or government actually participate in the decision of standard of care is to open the doors to the rationing of standard of care with the doctors involved so I think I'll leave it there I've kind of run over my time I will tell you that I've been very disillusioned in medicine with the things people in my field they have complications they don't report them swinging for defenses and killing patients there's all kinds of stuff that goes on that's very disconcerting I'll leave it at that and I hope I'll get some interaction because I don't know where I've gone off the reservation or on the reservation I'm not an ethicist but I do read ethics all the time thank you all very much