 about parental decision-making and this is a little bit about how parents make decisions and it's a little bit about how the government makes decisions and a little bit about how money plays a role and how a format plays a role. So I don't have any monetary conflicts of interest but in full disclosure I am one I'm currently on the PDRT advisory committee of the FDA and this topic came from a case that we reviewed. So we're going to talk about the challenges of research in orphan diseases and you've just heard from other cases across the world from England and from Italy how desperate parents will go and how far they will go to find a diagnosis and to find a treatment. So we're going to review some specifics about Duchenne's muscular dystrophy some of the components involved in the challenges with these trials and then talk about some of the different ethical principles at play when trying to come up with novel treatments for these diseases. So people in general are aware of what orphan diseases are. So it's less than 200,000 people nationwide but not everybody knows that the FDA has a specific division dedicated just to orphan product development and the whole purpose of this is to expedite things that are potentially promising for these orphan diseases for these families that are so desperate. There's a whole branch of the FDA that's out there just to see how can you fast-track these things to market. So what do we know about Duchenne's muscular dystrophy? People are pretty familiar with it. It's the most common genetic condition. They present between three and five years of age and they often die in their 20s. It's caused by a specific mutation on the dystrophin gene and you need dystrophin to have your cell walls work. So this is a picture take us all back to medical school of the dystrophin gene and then you can see, you can see on here, but the red one is the dystrophin gene. So you've heard a lot about how people are willing to try everything for molecular genetics. So there is millions and millions of dollars looking at that dystrophin gene and how you can fix that exon skipping problem which is the molecular problem that causes to shift. So this is how the children present. Often they start with weakness. It's a clinical diagnosis, but then the parents all want to know what's their gene. Did they skip this exon or that exon? Because if they can quantify what exon was skipped, then they can rebuild the dystrophin and then they can walk and that's the hope of all of the parents. When children have Duchenne's muscular dystrophy, about a third of them also have cognitive impairment which goes into issues of a sentin, unconsent in terms of what their understanding is of what they're signing up for and then their life expectancies even today is in the early 20s and this is just some pictures of what it looks like over time. So what do we have for treatments? We know that steroids slow the progression of disease. We know that there's even more specific steroids that are developed just for this purpose and then it was a Tuplerson that was the first one that was all about the excitement of the exon skipping and so what they found in this trial and it was approved in 2016 and it was approved against the advice of the FDA committees and what it found was that it helps them make a better gene, but it doesn't help them walk. So it makes a better gene, but it doesn't change anything with their function. So when people looked at that, they said why was this approved? So the FDA initially said they were not going to improve it because they said yes, there's an increase in the dystrophin G. So when you look molecularly, there is an improvement, but when you look at the child, there's no difference. There's no change in how far they can walk. So the FDA mandated that there was a random months trial, the FDA expert committee reviewed against it. Big Pharma said to the FDA, no I promise you it's really going to work. Like this is the one that's going to do it so it got approved. And so as you can see, this is troublesome for people. So they say this drug was a worrisome model for the next generation of molecularly targeted therapies because there's a slight difference in the laboratory test. Then you have the community, the patient community is activated, you win approval of your drug, you charge really high prices and it's a win, right? If you're the CEO of SREPTA, you're golden. All you need is one drug. It doesn't matter if you've changed child's life, you can make a ton of money proving that you increased the number of dystrophin genes. So what are people going to do? So they're trying to do bigger studies, looking at a functional outcome. So how far can they walk? So this is a double blind placebo controlled trial of exon skipping treatment. And it's a phase three trial that's an open label and it has to do with which genes the boys have and in terms of whether or not they're eligible for this medication. And so for they get for 96 weeks, they either get a steroid or placebo and then they switch over. But it's important to realize when you look at this, for 96 weeks, which is a long time, they're getting weekly infusions of placebo. So they're going through a lot of harm in terms of needle sticks, in terms of procedures, in terms of all different things. There's also multiple if you look at this slide, muscle biopsies. So they're giving them a placebo, they're taking pieces of their muscle. And it's unclear if this is really making a difference. But what are the families thing? This is like, super exciting. Everybody wants in this trial, people fly all over the country to get to the center that has a trial. People are really, really excited about this drug. Keep in mind, there's no evidence it works. Zero. But everybody wants it. What have the families found? The families who are traveling all of these big distances are finding that our kids are getting stuck with needles again and again and again, because they have to get infusions. And so people are upset because they want this drug, they're getting placebo, but the kids are getting stuck with needles. So families actually brought this and they complained to the UCLA IRB. And then the UCLA IRB brought it to the FDA and said, we want to place central lines for a placebo. And this was specifically because earlier the FDA had said that you were not allowed to use a port in the United States because you cannot place a central line for the purposes of a placebo. In all the European trials, the kids just got central lines. So in March of 2017, that's when they had the complaint. And then it was brought to the FDA with a specific question. Can you place a central line solely for a placebo? And this just shows you that in their other trials that were done, the majority of the children did end up having a port place, which is an implantable central line. And these are just the different types of central lines. People have seen those before. So when the FDA brought everyone together, they said, is it okay? Is it acceptable to place an indwelling venous catheter knowing that for 96 weeks, which is two years, they're going to get a placebo for something that may or may not make a difference? And so that was a specific question for the panel. How much risk can you put a child through? And what are the limits of what people can decide? So central lines, does it matter if you put a central line in? Well, it does. There's up to 25% mortality if you get a central bloodstream infection. Again, this is for a placebo. And then there's also clot risks. And these are kids who have descents muscular dystrophy. So for the lot of the time, they're in wheelchairs part of the time. So they already have higher clot risk because they're not as active as other children. So it's not a benign intervention, again, for the purposes of a placebo. The FDA likes the word ought. So they always use the word ought in all of their questions. And the specific question was if it's ought to be allowed, how do you quantify it? Is it if the child's been stuck three times? Is it 30 times? How do you decide? Is it if the child feels that they're a difficult stick? Is it if the best nurse feels they're a difficult stick? How do you quantify these things? We've heard from everybody today that our first job is premium nono cherry first do no harm. So can you place a central line to give someone a placebo knowing that they could get clots, they could get infections and they could potentially die from sepsis. Or is it worse if they're getting the emotional harm because they're developing PTSD from all of the needle sticks. So beneficence is what we say prevails in pediatrics. I think the hard thing for the committee was to know what's really in their best interest. The children themselves, they all want a port. They want a port, they want a central line. They do not want needles. They are unified in that. So for the children that have a scent, they want a lot and the families aren't sure. And a lot of it has to do with how convinced are you that this molecular treatment in the 96 weeks that they get it is going to make a difference. So all of the children enrolled in the study, it goes on for four years, get two years of placebo, then they get two years of active drug or vice versa. But everyone is exposed to active drug over the four year process, which is why people were so motivated to get in the study. So we talk about autonomy. We talk about the children's autonomy. Living with Duchens muscular dystrophy does give these children more maturity than other children in terms of understanding about their body. And they do have extraordinary needle phobia. So what are the limits to this? We've heard a little bit about resources when we heard about how governments make choices for vaccines. And we heard about jockey McMath and how people moved to New Jersey because you can get it paid for in New Jersey. So who's going to pay for the subsist related admission for the central line that was placed for a placebo? When otherwise, the child has no other indication for a line. So I think there's big picture questions in terms of who's going to pay for this, or should surrept the people who are going to make a billion dollars when this gets approved? Should they pay all the hospital costs associated with the study? And how do you determine what's a cost related to a study? And what's a cost related to a complication of a line that was placed for the sole purposes of administration of a placebo? And then if you're going to say this is okay, should the families know? Look, if you get admitted for a blood clot, you're going to have to pay for that admission and your insurance costs could go up. Or if you're in the hospital for a long time with subsist, you're going to have higher co-pays. I think families, I think in medicine we often never want to talk about the pay or piece of it, but it has big implications for families in terms of if they end up having to pay portions of all of these admissions. So what are the rules of government? We already know from our tepsilon that that was fast tracked against the advice of the FDA committee. Should the FDA legislate what kind of central line was indicated? And what are the limits of governmental involvement? We certainly heard this morning about oftentimes that all the governments across the world making very bad choices. We've heard about judges making bad decisions. Who really should be making this decision? So at the end of the day, when we had to vote, I did vote yes, that they could place a central line, that it was permissible. I think one of the things we can talk about, because I was hoping we could have some conversation about this, is really talk about what you think you would have done, and what you think the right way is to approach orphan diseases, where there's no way to get a real outcome of a functional study without subjecting the children to some risk first. So at the end of the day, there are select circumstances where it may be appropriate to have a child undergo risky procedures for research purposes. And how do we move forward with this expedited process for promising treatments, while simultaneously prioritizing patient safety and minimizing the therapeutic misconception? And I've left lots of time for discussion, so we can talk. It was approved at the FDA level that they could place a central line for placebo administration. The reason it was justified was that over the span of the four years, for two of the years they'll get the central line, and for two of the years they'll get placebo, and for two of the years they won't. But for the purposes of the study, based really on the motivation of the family and the people, so it was the family members of the children with Duchenne's who brought it to the UCLA IRB, and it was the UCLA IRB who brought it to the FDA, and it was very much driven by the families of the children with Duchenne's who wanted central lines, and they did not think it was fair that all of the international studies in Europe, the children had central lines, and their children were being stuck 18 times, and all these families came with videos, and all the audio, and how many times they were stuck, and these really extraordinary, you know, this sense from the family that they were participating for the greater good of every child with Duchenne's, but in the interim their child was being tortured by all these needle sticks, so it was very much a family-driven initiative, but it was approved that they could do it, and they are getting ports. Do you have a question with the children knowing they were possibly disabled? Yes. Informed consent. Yes. Controversial. Yes, Dr. Massal. The current state of care is to have all these children on steroids, too, which is non-trivial in a setting of doing these lines, and the data historically for children who like had shortcuts and had lines for four years is everybody's having complications of those lines, not a one percent or a five percent, and those complications are awesome. By that I mean there's stroke, there's clots to kidney. How did the parents treat this as oh, it's just a central line, and I go how were they really informed of what the bad possibilities are? I think that's a great question, and I think people were really swayed by this concept of PTSD, and what are you subjecting the child to? Certainly as an ICU physician, I'm acutely aware of when sepsis goes wrong, when clots go wrong. We deal with this every single day, and it's life-threatening and a horrible thing to have happen. The focus of the conversation really was around the trauma of the needle sticks, and people felt as though the line infection and the risks of sepsis were a lesser concern, but clearly I think it's a huge issue. But there are ways to manage the pain of frequent needle sticks better than doing central lines. That's what's crazy. I agree with you a thousand percent, and that's why at our own hospital there's all sorts of different protocols out there about the freezy spray and the fuzzy, and all these different things you can do, both for guided imagery for needle sticks and for decreasing the pain of needle sticks. Really it became more a fact that it was so repeated, and they were running out of IVE sites because they had to have so many different IVs for placebo, but I think it's very controversial. So they do have a dating safety monitoring board, and they did to say that it was okay. It's complicated, right? Because the FDA told them to do this study. They said we're tired of your head-to-head comparisons, we're tired of your gene thing. The only way you're going to know if this makes a functional difference is to do a placebo control over time. Oh I agree. No argument from the ICU. Okay, well just gives you food for thought, so things to think about. We're going to move on from the topic.