 Megan is the assistant professor of ophthalmology at the Wilmore Institute at Johns Hopkins, and she specializes in pediatric ophthalmology and astrabismus, and her clinical work includes amblyopia, congenital cataracts, and retinopathy of prematurity. Megan received her medical degree from the University of Chicago, where she also completed a fellowship in clinical megalithics. After an internship in internal medicine at the University of Maryland, she returned to the University of Chicago for her residency in ophthalmology, followed by a fellowship in pediatric ophthalmology and adult astrabismus at the University of Toronto's Hospital for Sick Children. For six years, Dr. Collins worked for the Immune Tonus Network as an expert on ethics and conflict of interest, and today, Megan will speak on the topic doctor-patient relationship and technology. This is a lot of pressure, Mark. The last talk of the day. My talk is actually on the utilization of anti-vegetive agents in retinopathy of prematurity, which is a permutation of technology in the doctor-patient relationship, but a little different than my... Oh, can you hear me? Okay. Hi, everybody. Can you hear me now? Wonderful. So my talk today is on a little bit of a permutation of what you have on your agenda. I'm actually talking about some ethical considerations with the use of anti-vegetive agents in retinopathy of prematurity. I just want to say it's an absolute delight to be here and see old friends, and thank you so much to Mark and all the wonderful faculty from the McLean Center. I don't have any financial relationships to disclose, unfortunately, but I will be discussing off-label use of an FDA-approved medication. This may be the first time in the history of the McLean Conference that there's going to be a lot of photos of eyes. But I think in order for me to frame the ethics question for you, I need to give you a little bit of a background of retinopathy of prematurity. So we're going to talk a little bit about some visual things, and then talk about the anti-vegetive story and then ethical considerations moving forward. So I'm sure all of you remember this from your third year or second year of medical school. This is what the inside of the eye looks like. Retinopathy of prematurity is a potentially blinding vitro retinopathy. What that means is the jelly inside the eye and the retina, which is the back layer of the eye, end up undergoing some abnormal development. It primarily occurs in very low birth weight infants, and it's the leading cause of childhood blindness in the United States, as well as the cause of 20% of cases of pediatric blindness worldwide. So that is certainly a significant problem. What happens with retinopathy of prematurity is very low when infants are born prematurely, their retinal vasculature has not developed completely. Do I have a pointer at all? So when they're born prematurely and the vessels have not grown yet, they can go through various stages of what's called ROP, starting with a very early disease stage zero, going all the way to stage five. Majority of cases will resolve without needing any intervention, but there are a subset of cases that will go on to meet what's called threshold disease, which would require treatment. And the different treatment options, primarily historically, have been cryotherapy, which has been largely replaced in the mid to late 90s by laser therapy, and now some discussion of bevacizumab, which is Avastin. If left untreated, the majority of these patients would go blind from what's called a retinal detachment. And just so you have a sense of what this looks like, this is the abnormal retinal vasculature inside the eye, this is the demarcation between the vascular retina and the avascular retina, causing what's called a retinal detachment. And you can appreciate more significantly here, these are eyes that would have a very poor functional outcome. There are screening and treatment guidelines from the American Academy of Pediatrics for retinopathy of prematurity, and I won't belabor sort of the points of when to treat here, but the important thing is laser is considered the standard of care at this moment in time. Although interestingly, new treatment guidelines that came out about two years ago talked about using bevacizumab, specifically off-label for select cases. Why do we talk about using a new treatment option for ROP when we already have a standard of care? The problem is our treatment option has some limitations to it. This is actually my boss at Hopkins treating one of our babies. In order to treat retinopathy of prematurity, it's a little bit archaic, but we actually destroy the avascular retina. So this is the area of the retina that was abnormal and it's treated by applying laser burns and those laser burns will destroy the retina, which as the benefit of destroying the abnormal drive for blood vessel growth, but the unintended consequence of permanently destroying your peripheral vision, as well as causing some children in particular to become profoundly myopic. And looking out across the room, I know there's a lot of you who have myopia, but probably not to the severity of these kids. Some of these kids that I treat, they could be minus 12, minus 13 diopters of myopia. So pretty significant. Number of these kids also have strabismus for which they would require surgical correction within the first couple years of life. And as you can see from this slide here, a number of them have severe visual disability, particularly those ones with the stage four and five disease. This brings us to the question of using a new treatment modality, because we have something that works for a number of cases, but there's also a number of cases it doesn't work well for. And this is where anti-vegeteves come into the picture. Anti-vegeteves, as you might know, down regulates abnormal blood vessel development. It's been used for many years within ophthalmology, particularly as an intravitreal injection, and primarily for age-related macular degeneration, some types of diabetic macular edema, and some other type of vein occlusions. It was originally approved, of course, for the treatment of metastatic colon cancer. Its use in retinopathy or prematurity hit the literature in about 2007. There were a number of case reports coming out about the use of it both concomitantly with laser treatment as well as on its own. And the case reports were varied as far as what dose to use, how to administer it, whether the children were put to sleep to do this, or whether it was done at the bedside in the NICU, what stage of disease to use it in. And to date, and this still holds true, there's only one randomized controlled trial that has been reported comparing bevacizumab to the current standard of care. And that's a, it's called Beetrop. It's a study that was published in the New England Journal in 2011. And this was a study of 220 neonatal infants who were prospectively randomized to either receive bevacizumab versus conventional laser treatment. And the infant had a specific type of ROP, something that's called stage three plus disease. And just for kind of your interest, that's typically the basic threshold of disease when we decide to treat patients. They found that for kids with stage three plus in zone one, which is the center of the back of the eye, they had a superior outcome with bevacizumab. And bevacizumab in addition allowed for continued normal vascularization of the back of the eye. So remember when I showed you those pictures earlier of that retina that had been destroyed by laser, these kids didn't have that problem. So long-term they probably would not become as nearsighted, they would not have as many problems with their side vision. When something like this happens and whenever ophthalmology actually makes it into the New England Journal, we get a lot of media attention. And there was a mixed response within the ophthalmology community. Some heralding that we had cured retinopathy of prematurity and no kids would ever become profoundly myopic or go blind from ROP again. Others heralding more caution as this is an anti-veg F agent that despite the fact that it's administered into the eye could potentially get into the systemic circulation. And this is about a year later, interestingly, the story didn't end. We started learning that a bunch of these kids who'd been treated and who'd had a very good outcome initially three, four, five months later had reactivation of their disease. And then looking back at some of the data from the New England Journal article, they hadn't followed the kids for more than 16 weeks after treatment. And we found that most of the kids who reactivate are 16 weeks and beyond. So this has led to still some significant controversy within the ophthalmology community as to whether to use this or not to use it and how to use it safely. And this has been a wonderful opportunity for me, somebody who's both in pediatric ophthalmology and has an interest in ethics to start thinking about an ethical framework for this. And surprisingly, there was not a lot of talk within the ophthalmology community, particularly when this started talking about the ethics of using anti-vegetarian in babies. The first question that came to my mind is this research, is this innovation and what are we as an ophthalmology community doing? And this is of course from Mark Siegler, one of his papers, research involves a formal protocol, it involves protection of participants in a formalized way through institutional review board oversight mechanism versus innovations of variation in practice conducted on an individual basis and relies on clinicians' judgment and integrity. And my interest was how are anti-vegetarian agents being used in the ophthalmology community? Anecdotally, I can tell you, in this 2007 I've worked at five different hospitals and all of them do something a little bit different with regard to anti-vegetarian agents. Some actually won't let you use it at all versus others have absolutely no regulations whatsoever about whether you use it or not in a research protocol or as part of your clinical practice. I did a survey with my collaborators at University of Toronto to gain an understanding of how people are using anti-vegetarian and we distributed this to pediatric ophthalmologists and retina specialists in both the US and Canada and asked them about their experience treating kids with ROP, whether they were using anti-vegetarian agents and what we really wanted to understand was what was their institutional policy as well as their personal approach to the consent process. We found some interesting results from this survey. This is one of the tables that divides, just for your reference, both pediatric ophthalmologists and vitro retinal specialists treat retinopathy of prematurity. Historically, pediatric ophthalmologists are probably a little bit less aggressive about using anti-vegetarian agents than the vitro retinal surgeons because the vitro retinal surgeons have a ton of experience using this in macular degeneration and other adult diseases. But we asked all the participating doctors when they used it and was at first line all the time, sometimes based on the severity of the disease, which is what the American Academy of Pediatrics recommends, first line only if they couldn't do a laser treatment or salvage therapy if the patient had failed other things. And as you can see here, the majority of respondents in both the pediatric and vitro retinal group were using it in compliance with the guidelines. However, somewhat concerning was that about 10% of vitro retinal and pediatric specialists were using it as first line therapy in all cases and actually moreover offering this to patients as the new current standard of care. We asked people about what they were doing in the consent process and what they were telling patients and we gave them a list of options of different things that we thought should be included in the consent and asked both what they were currently doing and what they suggested should be included. The majority were mentioning that this is an off-label use of a medication and that there's an unknown long-term safety profile. Not as many people were talking about their own institutional or personal experience with this medication or the fact that there are risks of systemic complications when both used for other eye diseases as well as systemically. Regarding use of educational material for patients, the majority were not using any educational material to supplement their consent discussion. If they were, however, interestingly, about half of them were giving patients scientific papers and as someone who used to write a lot of consent documents for a living, essentially, this is not what I would call at a sixth grade understandable level for families. Regarding institutional oversight, most institutions don't have a policy on using anti-veg F agents. In fact, only 5.4% of respondents said that they were required to obtain ethics approval for any use of an anti-veg F agent at their institution. And the vast majority didn't have any sort of approval process necessary for off-label drugs at all. So to put this into context, this is a tough disease that sometimes does well with standard of care, but sometimes doesn't. And there are certainly some benefits to consider with anti-veg F agents. One, it's very easy to administer. You use a small vial of the medicine. You do what's called an intravitural injection, which you put a tiny needle into the back of the eye. I know that makes most people cringe, but ophthalmologists are good at it. And it can be administered very quickly versus laser treatment is typically done under general anesthesia with a child asleep. Can take over an hour to do. So there's the risks of the comorbidity of that length of anesthesia. We do know from some of our preliminary data that it has a relatively good safety profile. And there's continued development of normal retinal vessels with the hope of warding off myopia and visual field loss. But we also know that there's a lot we don't know. We don't know whether this gets into the systemic circulation. We don't know if it down regulates anti-veg F both in their kidneys and their lungs. There's the risks of interestingly, if you deliver the drug too late in the process of ROP, they can actually cause them to develop a tractional retinal detachment, which is what you're trying to avoid. And probably the most salient thing is these kids get late recurrences. And speaking as a pediatric specialist, examining a kid who's about 40 weeks of age versus a kid who's 50 weeks of age is a much different exam. And as kids get older and very big, it's very complicated to examine them in clinic. Often you have to put them to sleep for anesthesia, which is one of the things you were trying to avoid in the first place. We don't know much about the risk of death with anti-veg F agents, but certainly it's theoretically possible. My collaborators on this project from University of Toronto and I published a paper recently talking about sort of how to proceed with using anti-veg F agents. The general consensus of the ophthalmology community is to embrace this new innovation. And, but we are really suggesting it needs to be thought about within a very carefully structured ethical framework. One is that it's really more of a medical innovation and can't be offered as a current standard of care, particularly as a standard of care alternative to laser treatment. And it must be held to a higher standard of consent. Premature infants and their parents must be considered a vulnerable population. The unique thing about the ophthalmologist and the relationship with a child in the NICU is we often come in either early morning or late in the day after our surgeries and we often don't meet the families. And the only time we end up meeting the families is when kids require treatment. So they don't have the same day-to-day relationship that they have with their neonatology team. And that's something that we need to work on. And I personally, when I have kids that I think are going in the direction of treatment, I make a point to meet the parents and say over the next few weeks, we're gonna be deciding whether or not your child needs treatment and I'll give you weekly updates. We have published a nine-point checklist of elements to be included in the consent document as well as a template for educational material because we felt that this was so important that the different elements be included all the time rather than practitioners using their template, a consent from their institution. In some of the elements we want included in all the checklist, of course the data from the New England Journal Study, that's the most robust data we have to date. The important emphasis that we just don't know what happens long-term systemically with these medications as well as the limited data we have on how well these kids do visually. The kids who got the drug for the first time are still very young, they're probably three, four, five years old, so we don't have a lot of information about their visual acuity as much as we will when they're eight or nine years old. These kids have the potential for late reactivation of disease, we'll need to undergo exams for a much longer period of time and importantly to mention is that this is an off-label use of medication. Of most medications used in the NICU are used off-label so I don't think that in a loan should be something to eliminate us from considering this but it still needs to be told to families. So moving forward with using anti-veg F agents, so I think it's a viable option for a specific sub-population of patients and certainly not all patients. It must involve a rigorous consent and parental education process as well as cautious long-term monitoring of these kids. This is an idea that Mark and I had talked about a long time ago when I worked with him in the Immune Tolerance Network, this idea of creating a registry of collecting information because it's still institutions may have you know five, six cases over a six month period so they're not building up a huge database quickly. It would be nice for us to pool our resources both from our US and Canadian colleagues to figure out how these kids are doing both short-term and long-term. That is the end of my presentation for today and hopefully I've stayed somewhat on time. Thank you so much for your attention and I'm happy to answer any questions. I thought you was going to use their mic. The question today, if I could plot this in my new name, Dr. Collins, if this was your baby, because this sounds wonderful and exciting but it also sounds scary. You're the expert, I'm gonna throw this on you and say it's only what we should do. So I would say that for a subset of patients that are too unstable for me to do a laser treatment I would use anti-veg F. But the way that we use it at Hopkins is we are doing it under an IRB approved protocol. So it's considered an experimental use of the medication. The parents have to go through the somewhat rigorous consent process of the IRB documentation as well as having a discussion with us. There's a number of kids that I have seen personally that had been treated in the community and they had never been offered laser treatment. This has just sort of been, this is the new hot thing on the market which unfortunately ophthalmology is a little victim too at times of we're great innovators and have a lot of technology and we often want to adopt the latest and greatest. But I urge against offering this to a kid who is gonna do perfectly fine with laser treatment. Just a quick observation. And that's it seems that there seems to be a correlation between the cost of an intervention and how excited we get about the ethics of something. When something is very inexpensive people don't get too excited about it. It's only when things start costing a heck of a lot that a lot of people seem to get very excited about it. So kudos to you to addressing this. Thank you very much. The, I think it's just that anti-veg agents have become so popular within ophthalmology in general and we've had such significant success particularly in the world of macular degeneration with them just being a revolutionary treatment. But our approach to innovating and developing this in kids I don't think has been as well thought out as it could be. For example, the dose we use is half of the dose that you would use for an adult. And I can tell you a 574 gram baby is not half the size of most of our adult patients. So I think it's, again, I think it's something that has a lot of potential and the tide is certainly moving in the direction to embrace it wholeheartedly. But my hope is to add just a little bit of thought and caution to the process before we embrace it wholeheartedly. I should preface this by saying I'm not a physician scientist so I apologize if the answer is obvious. I'm curious first in my nature, I've noticed in the list of items that she'll at first ask about consent, I was curious about the relevance or at least how it got on the list about urine and product products. So that is probably something that is, it's on the list, but it's a fairly low significance for people, but that's where the anti-vegeta is derived from for a vastan. It is around 100%? Most people are. So we asked everybody whether they were mentioning that or not and most people, as you could see, were not. I personally have never mentioned that during any of my consent discussions. Well, I think we wanted to have a somewhat exhaustive list of options for people to tell us what they were doing. My experience with sending out surveys is rather than having people fill in a lot of answers if you give them checkboxes of different options, sometimes they're more likely to respond. Crabbits, thank you. I just have a few concluding remarks. Thank you all for coming to the 27th Annual McLean Conference. I wanna give a special thanks to the 40 or so presenters yesterday and today. Talks were, as always, splendid, magnificent. I know people have come, many of them, from far away and I greatly appreciate that. I wanna thank our moderators, Blaney and Marshall and Monica and Dan. I think I moderated a few and Peter Angelo's for moderating the sessions. I did wanna tell you that this conference and last year and the year before have been video recorded and they will be uploaded for you to look at, if you want, on the McLean Center's YouTube channel. If you're registered for the conference, we will send out an announcement of how you access the YouTube channel in the next two or three weeks. I think Paul takes about two or three weeks to get things pulled together. Let me also tell you the dates of next year's conference. Have I done that yet? Just decided it will be November 11 and 12, again, a Friday and a Saturday of 2016. And the conference, this was supposed to end at 510. I believe we've made our deadline and I wanna thank you all for staying here so late and attending. Thank you.