Jaztime is allowed for track сколькоphone is I'm not going to be there. I'm not going to be there. I'm not going to be there. This night's a big fall night. I'm not going to be there. I'm not going to be there. I'm not going to be there. I'm not going to be there. I'm not going to be there. I'm not going to be there. I'm not going to be there. I'm not going to be there. I'm not going to be there. I'm not going to be there. I'm not going to be there. I'm not going to be there. I'm not going to be there. I'm not going to be there. I'm not going to be there. I'm not going to be there. I'm not going to be there. I'm not going to be there. I'm not going to be there. I'm not going to be there. I'm not going to be there. I'm not going to be there. I'm not going to be there. I'm not going to be there. I'm not going to be there. I'm not going to be there. Good morning. It's an absolute pleasure to introduce our grand round speaker today. Dr. Thomas Minkuso. I'm going to talk to us about one of his other roles in the hospital. He's been the vice chair of the IRB committee since 2013. He's going to enlighten us a little bit on how we protect our pediatric human research subjects today. Thank you, Dr. Minkuso. Thank you, Prathima. I was a very good student at the IRB committee. I was looking at the pulmonary artery. I didn't want to upset her in the least because I want my surgeon to be happy. I immediately said yes. The title was chosen with particular care because there seems to be a trend now to call people who are being used by researchers participants. I was on the phone with Dr. Thomas Minkuso. I was in the hospital at the time. I was with Dr. Thomas Minkuso. I was with Dr. Thomas Minkuso. I was with Dr. Thomas Minkuso. I was with Dr. Thomas Minkuso. I was with Dr. Thomas Minkuso. I was with Dr. Thomas Minkuso. I had an appointment with Dr. Thomas Minkuso. It was in our hospital at the time. I was with Dr. Thomas Minkuso. Because if you're sure, treatment A is better, you really don't have equi-poise. And if you're not so sure, the treatment B might be risky, maybe you shouldn't undertake this. So it is a difficult balance and there's attention there. And the placebo group is always a problem for us, or the washout of a current therapy group is always a problem. Particularly for children, because adults can understand the risk to which they're being exposed and accept them or not, but for children it's more challenging. So here's some quotes from some people that I've actually heard these are pretty funny. The RB1, as long as you promise not to learn anything. I can give this drug all my patients. Why can't I give it to have my patients? This happens so often with the new therapy we as clinicians can do whatever we think is best. But if you want to study it, it's a whole different level of critique. And then an investigation of drug is a subject that when given to a rap, research subject produces a paper. So these are the things in the hand I'm going to give you a little tease of what they are. Here's a study using electrodes placed during brain surgery to study epilepsy. They have absolutely no benefit to the child whatsoever, but they're going to have brain surgery and have electrodes placed. Anyway, while we're there, can I use these smaller finer electrodes to learn about epilepsy? It will never help the child, nor will it hurt the child. Another one, we're curious if our bad diet leads to diabetes and use and it's less common in Asians. We're wondering if Asians who've moved to America and have our bad diet are more likely to get diabetes than kids who stay back home and have their healthier diet in Japan. So we want to study these kids. Here's what we want to do with them. There's the cohort and we'll do these study procedures. Is this acceptable or not? Here's one where we want to know what Dexidine really does to kids with ADD. So let's get an FMRI. We'll give it to kids who don't have ADD and see if the MRI gives us an indication of where the drugs are working in a child without that condition and maybe we'll learn more about the drugs activity. It's some surveys, one or two MRIs, and there's compensation of the $570. Here's a study of lead abatement done in Baltimore where first was described when I was a pediatric resident. They're curious about different levels of abatement, different costs to remove lead from homes and they want to study these three things. They'll get, but the parents know about it, five groups of children, hundred eight houses. And finally, the study of occipital readings to see about red and off of the prematurely. It's a bane of the preterm. Some nurseries, their policy is to keep the staff between 85 and 89. Some nurseries, it's 91.95. It's a clinical practice. This study purports to randomize your hospitals at the 85 and 89 group. Your hospital, flip of the coin is 91.95. Let's see if the intensive ROP changes between these two groups. So now we'll get to some, are you kidding me, stories about studies done in human beings by investigators? These are adults and here's a recent study in Europe of this new CD-20 super agonist antibody for maybe use in some cancers and immune diseases. There's some animal data that it looks like it works. It's just mice, but it looks and monkeys that looks pretty effective. So the investigators want to study it first in human trial. All adults. So yeah, it's an IV infusion. Each subject, ten minutes, ten minutes, ten minutes. We got to move along here. This is very expensive. So the first subject, five minutes after he got the drug, completely headache, pain, fever, ripped off the shirt because he complained of burning. So of course, at the ten minute mark, they started subject number two because it's every ten minutes. Well, it was severe cytokine release syndrome, multi organ dysfunction. The study was stopped. They went to the hospital. One lost fingers and toes. One may never fully recover a long term disruptor of his immune system and one was in the hospital for three months. But there was good monkey data and we had to do it every ten minutes. So we had to move along here. Another one of a fatty acid amythodrolase, which has got many possible uses as an analgesic for asthma seizures. It's got a, this molecule has early effects on many, many of our pathways. Looks like it'd be great for immunomodulation. There's no study in humans again and I'll introduce a concept to use in drug studies. The mabel and the no well. So this is the dose where you'll get some effect. It's very low. And the dose, the highest dose, as far as we can tell, there's no biological adverse effects. So reasonable index of safety here between five milligrams and 96. But they want to study this new drug. Again, it's in Europe, first in human studies. So it's a big trial. 90 active drug, 30 of placebo. Six were hospitalized. Four had MRI evidence of brain damage and one was declared brain dead. So they stopped it after one sub if you came comatose and the drug goes was 50 milligrams for five to six days. So this was within the past several years in Europe. This is why the IRB might return your protocol to you so they don't get mad at us. So now I'll go back into history. This is one of the first instance of human research protection. Dr. Beaumont, who's the nice guy as a captain there, and Alexis A. Martin, who's got a scar you can see in his abdomen there, had a long and troubled relationship as investigator and research subject. So he was shot at close range and he healed with the gastrocutaneous fistula, which was great for Dr. Beaumont to take advantage of this fact. He's the one who did the first surgery. So Alexis A. Martin was indebted to him. He studied digestion. You ate this fruit. Here's what comes out. I've learned about digestion. He made him sign a contract. He was basically his servant. He did some work around the house. He cleaned the stalls out and he had his diet studied by this Dr. Beaumont for a long time. In some, I don't know the history of this, but in some descriptions, he had him arrested when he escaped and brought back so he could continue his studies. So it wasn't the best thing. He did a lot of experiments. But the funny thing is, at the University of Michigan where Beaumont worked, there's a building with his name on it and there's something called Beaumont's code, which Dr. Beaumont ignored, by the way. There's these things, the voluntary consent, discontinuing when it causes distress. This is the code he developed, he who did not follow it. I'm not trying to build file certainty here. And Alexis A. Martin was his victim, subject, prisoner, new name. Of course, we don't know about Tuskegee, terrible thing in America. So it started in the 30s, but it went to the 50s where black men with syphilis were not treated. When it started, there was no treatment. There was no penicillin effect in this. But it became effective during the study time, however, these men didn't get treated. They got LPs to learn about the disease and they were told, excuse me, it was special for retreatment. And it came to light later, as I say, in the 40s, penicillin became available. They weren't treated. A lot was learned about the disease at the expense of these human beings' lives. And here's some data we know about, the bedblood book and the Nova Special about the deadly deception and the apology by President Clinton. This was a center for the Center for Massachusetts to put forth the National Research Act, which was a foundation of protections nowadays. It's 1974. It's not that long ago. And that led to, well, I'll skip back to the Nuremberg, which happened around that time after the Nazi horror, with the D'Alda Jews, they killed and experimented on. This is the result of that terrible event. Again, voluntary consent is number one, just like Beaumont's code. And risk must be taken into account. And this will come up in our discussion of our actual regulations and protect the subject from harm to the extent possible. And this is for adults again, who, if they're well informed, then adults can take on risk that we wouldn't maybe allow a child to take on. And the person must be prepared to end it when they want, if they decide, I didn't think these models would be so bad, but I'm sick and tired of it. Please stop now. And the scientist also, him or herself, must be prepared to stop. And another one in here is, the qualified person's means is another commentator. A bad study can never be ethical. Even if it's minimal risk and there's no chance you're going to learn anything because it's badly designed, it doesn't make any sense either. As an aside, why we, the RB now insist on scientific review by the Department of Record to be sure it's scientifically sensible, even if it's minimal risk, what's the point if it's not designed to yield useful information. So back to America, after the Tuskegee thing, I'll go over some things we've done before the National Research Act. Here's a study of chlorinventinical toxicity. In Antibiotic, I actually gave as a pediatric resident, well known, the question of bone marrow, they had three groups. Low dose and high dose. And they learned what a surprise that the high dose called toxic bone marrow depression. In the other 60s, military recruits, hello sergeants, I'm Captain Mancuso. I wonder if you'll be in a study for me, read a vulnerable population. They want to see what happens if you don't treat strep throat. Well, we know what happens if you don't treat strep throat. You get the non-sufferative complications and these sergeants got rheumatic fever and the fritis when they weren't treated properly. In anesthesia, cyclopropane was a fantastic anesthetic. Rapid onset, well tolerated, but it caused these arrhythmias. So they allowed people to get a particular ectopete for quite a while. Well, they started it. By the way, the citation, New York Journal is by anesthesia out of the Settomass General, a feature. I'm not sure how he took this on, but his article has lists all these things kind of interesting. In the Jewish chronic disease hospital, people were injected with cancer cells under their skin. They were told it was a skin test. We want to see what happens. Again, these are people who are disabled. They can't complain, can't consent. So let's take advantage of the situation and see what happens if we inject cancer cells here. Here's a great one. This is the beginning of the child, Boston Children's argument. I'm sure. Oh, no, I'm going to go ahead to that one. A Boston pediatrician went to a local medical school, did an LPR, a kid with looking for meningitis because of TB. He thought to himself, you know, this is a pretty useful test. I think I'll do it on my next 50 patients to see how hard it is to do. Just to learn if it's easy to do, he published that. Someone in Philadelphia, I think I'm not sure if the job wrote a terrible, a natural thing how terrible this was because it was, but this guy in 1896 thought, well, I just learned his test is useful. I think I've contributed to the world. So I'll go back to smallpox. Very long history from the 1700s from Europe and then in America. People learn that people who had cowpox got less severe smallpox. So Jennifer thought, well, let me see if I can deliberately unoccurate someone and maybe they'll do better. Some did, some died, but this is the first one in America. And again, it's just experimenting with no oversight. I wonder if this will work. I'm sure, Sarah Nome's in James Fifstead, note was coming on, but he did it nonetheless. And as research objects, some other things, X-rays for no reason to look at the GI tract anatomy, do adrenal tubes to study digestion again, studying stoverian rickets, protussis and polio vaccine trials. And in Massachusetts, this is New York Willoughbrook. Very famous one, the Willoughbrook Hepatitis Study. This state runs school of kids with terrible developmental disabilities, was always full. Kids require a lot of care, the families couldn't keep up with it. And parents were eager to get their children there because they needed an intensive care at home. But it was full. Everybody got hepatitis. At this period in time, there was just hepatitis. It was an A, B, C, D, no real studies of the different virus. The cause is that it was hepatitis. You got yellow, you got the Renzyme deficiencies. So the saw Krugman, who was the New York State Health person, was told, fix that. We don't have much money, but we need to fix this problem. And he came up with a plan to fix it. He was his plan. So he had a letter to the families. Quite early on, I deliberately was held today, but it's to give them this treatment, this generic protein gamma-globulin that had a lot of immunoglobulins, it's some of which worked against the hepatitis virus, but no one knew how it worked. So he wanted to expose them to hepatitis when he knew they were getting exposed and then treat them to see what was effective. So he asked their permission in 1958. And here's the protocol. At consent, we have a newer, nicer ward. We're full, but this ward over here is open and it's really nice. But if you come here, we have to deliberately infect your child with hepatitis on a certain day and then we'll begin treatment to see if it's more effective than nothing. Because if you go to the other ward, when you get in, they'll get hepatitis because they all do. We're not sure about how that happens. So he picked the older kids, which have a milder degree of hepatitis. And the endemic hepatitis there wasn't fatal, but it was hepatitis. And he followed the course of the illness. And in Massachusetts, the school where the people got radioactive calcium in their food to see what would happen. And at a children's hospital very near us here, some of the cardiac surgeons, when they took out the thymus, put skin grafts on to see if it was rejected differently than kids without it with the thymus, again without parental permission. Here are some other quotes. I'll let you read them about people's comments on why kids are good research subjects. It gives them an opportunity to repay their debt to society. They get feedectric subjects to the goodwill of friends who had an understanding of the circumstances. In conditions insisted upon among laboratory animals, which can rarely be controlled in a study in man. So children clearly are barely human to these investigators. And I got this from a different, a bunch of different studies. So now I hope I convinced you that by and large investigators, let's face it can't be trusted at all. I think goodness we have an IRB to protect the children. Here are the last two. These are from America, rather recently. Jesse Gelsinger, who had one of the teen trans carbamolist efficiency in Philadelphia, was pretty well controlled. He was a heterozygote. So well known, enzyme deficiency leads to liver failure. If it's homozygous, or if not treated properly, protein can't be handled. But although the investigators developed a virus vector for gene therapy, he didn't need it. But he liked his doctors. So he volunteered for the study. And he didn't do well. He died of multi-organ system failure. The virus vector caused ARDS and he didn't survive. I don't think the PI mentioned in the consent document that it was his company that was going to sell this virus vector. Alan Roach worked for the asthma researchers at Hopkins. Again, read vulnerable population. They wondered what she volunteered for study of asthma. But first they had to make her weaves. Hexamethalium causes weezing and they did a brief literature search, but not extensive enough to know how dangerous this is. She died of a straight failure, a healthy adult who worked for the investigators. And again, this wasn't that long ago. So this is the research act that Senator Kennedy sponsored. And it was to identify the basic principles that she'd underlie research on humans. Four things. What's research? What's not research? How do we analyze risk and benefits? How do we pick subjects for this? And what's informed consent? Very logical things. And this is what you'll all be asked to do when you complete the smart forms, which we have for the submission of protocols to the RAB. The Belmont report was what they produced. It's not a long document. It's actually excited on your hand at the bottom. It's very clear, well done. It's not 50 pages of goggalty. Goggalty goggal. It's really done well done. And from that came the principles underlying research. So here are the three principles. Respect for persons. It's quite obvious. And particularly those with diminishing autonomy, whether it's developmental delay, a newborn, a child. It's not a competent adult with agency, as we say in ethics, but diminishing autonomy. Benefits, this means we should do good. We shouldn't just not hurt them and maximize the benefits, minimize the harms. Again, it's quite logical. And finally, the fair distributions of benefits and burdens. We want to decline the study by a very well-meaning drug company. We want to study an asthma drug only in high risk, low income populations. Not the wealthy suburb, where they would sell this drug. They refuse when you ask them, you need a better demographic. They say, well, we want to do that. There's more asthma in the underserved areas where people have little resources. So we didn't approve it as an example. So how do these things get actualized? Respect for persons, turns into proper informed consent or parental permission. Benefits, benefits means a clear definition of risk and benefits, and analysis of risk and benefits. This takes up a lot of the smart form. What are the risks? What are the benefits? And then justice, again, fair selection, distributing the burdens and benefits of research. For example, until a little while ago, we knew a little about heart disease in women, because men had more heart disease, so it was cheaper and easier to study men because you get more subjects more quickly. So women will left out because of, again, financial reasons. We all get consent every day. And to do it well, these are the things that should be included in talking to a research subject. And I think maybe even more care taken than with clinical care where the family thought about it. They know it's coming and they've given it, probably visited the surgeons several times. They're clear on everything. But in research, not the case. And I'll mention it later, but in the revision to the common rule that happened recently, there's an addition to the document. It's a nice front page kind of executive summary. It includes two questions, which I really like. Why would I want to be in this study or my child? Why would I not want to be in this study or have my child in this study? And it's just a quick summary because sometimes, concerns can be 15, 20 pages long. And it's a useful data. We try and streamline it. It's sort of the investigators, but it's hard to make it compact. And the front page is a nice help for families. Here's what you're going to read in the next 10 pages. Look out for these facts and it'll help you make a better decision. In law, there's a reasonable person. So the reasonable volunteer is also part of the consent document. It's just, would somebody actually agree to this? Are you sure that you talk to these people? Because look at all you're doing to them. And risk benefit analysis, all possible harms. And in the days of genetic research now where someone was commented, there's never going to be de-identified data again in the days of polyxyline sequencing. But currently there still is. But that's includes financial, social, it includes the genetic studies. You might be denied life insurance if someone finds out about your genetic background here. You should know this before you agree to this study. You can be denied care. You can be denied some kinds of insurance. And if there's significant risk of impairment, there must be voluntarily agree. And there's got to be a benefit. And again, justice, I think it's really important because so often people with illnesses, and I'll get to this with one of the categories, are coming to us for something because they're ill. Oh, it has to be careful if we just take advantages of the situation that they're here, they're sick. What a great opportunity to study something and learn something. Not a bad thing. But they shouldn't be the victims of research simply because they're sick. That's what already burdened by infirmity means or by their environment. So there's obvious tension if you think about it. Respect for persons means we really should study children because if the drugs we use in the OR are not approved for kids under two because the drug companies are happy we use them. And they're off the hook because they didn't approve it for kids under two. There's some action congress that extend copyright for drug companies that sponsor studies for children under two. But respect for persons would mean we should limit research because we shouldn't hurt these vulnerable children. But justice would tell us what we need to learn about children too. We don't want to hurt them by using some drug or technique that works in adults and we think it'll work in children but maybe it doesn't. So there's attention and it's unavoidable because one principle would lead you to limit research in children, one would promote it, something you have to navigate when you design a study. There's only some definitions. This is my favorite reference here. I think you can find in the library. But we have quite a few definitions and regulations and it's important to keep those in mind. Research, in research, I don't care about you as a person at all. You're number 27 on my spreadsheet. Please sign here. Thank you very much. I'm going to take your blood and I'll learn something about whatever I want to learn about. I am not your doctor in theory almost all the time. In practice, all I care about is you. If I have to transfer you somewhere else or do some innovative therapy or get all the consults, I can think up to the bedside. That's what I'm going to do because I want you to get better. The research is coming on time to go away because you're too sick. So in theory, there's a nice dichotomy but in theory works often but not always. However, it's good to keep these things in mind when you're hearing about therapeutic research. I wonder, what's that mean because I thought they were separate. It'd be nice if they could always be separate. They often are but not always. So you think we'd have to define human subject but we do because there are protocols studying dangerous chemotherapy to occasions with permission of the spouse and adults who are brain dead whether or not a human subject because they're dead or taking samples from again a brain dead individual who has not been withdrawn from life support yet. If the family agrees, I think that's an acceptable thing to do but it's interesting that they're not a human subject in that situation. An interaction means director and director which means your little chart review is an interaction with your subject because you're looking at their private health information. So here's the regulations. The common rule is the rule that describes what the IRB does. There's how it looks and part A just tells you what the regulations cover. Some definitions what the IRB does and the inform consent process. To use some revisions that really wouldn't affect most investigators. There are more things that are exempt, you know educational research. Very non interventional surveys can now be considered exempt from the requirement for parental permission of one consent. If there's NIH fund a research now that's going to be a single IRB not stands for Cincinnati chop and Boston IRB is looking at it separately. One since that's great because each of those IRBs will want to change the consent document in their own way. In one sense it's not great because we get most of them but it's simple for the investigator. One IRB, one inform consent document, one person's report annually etc etc. Minimal risk research which now I have to review every year doesn't have to require annual review because it's minimal risk in the first place. And way of consent has been expanded a little bit and finally that front page I mentioned is one of the requirements you have a brief summary for families to read. So sub part B is for pregnant women, fetuses and newborns. Sub part C is behavioral research and D they finally remember children. So children I think in most states it's 18 but in some states it might be 21 but it varies take by state. Permission means the parents agree and a stand doesn't mean the child sits there like this. It means they look you in the eye, they agree and they put their name on the separate document or the document for the parental consent. The age of consent is quite variable. I think seven or eight most children can understand some things but not everything. And so it's really complicated and maybe it has to be a bit older. In a research that only has a benefit if you're a subject of research they don't get to decline. If it's a cancer study where the two arms are both investigational and they're to treat the cancer the child can't say no thank you but if it's not at benefit only available in the study the children get to ascend and they get to change their mind later. If it's a five year study I'm sick and tired of this MRI stuff I don't want to go anymore. It's their right. So there are four categories that's all 404 or 56 and 7 not involving greater than minimal risk. Greater than minimal risk with potential for benefit so maybe a balancing act here. Greater than minimal risk no benefit. Kind of a problem about that one for me and otherwise not approval which often means well describe more detail. So risk is a potential harm or the potential in action to cause harm harm is any adverse outcome. No life insurance. Anemia from too much philbotomy complications from sedation anything possible trauma from the study itself and then the benefit of course is a positive value. So all these regulations are for health and human services to fund sites. So in theory if you have your own research institute that you fund yourself you could do whatever you want. However most institutions follow these whether they receive federal funding or not. So it's become broadly applicable even though in the government doesn't say you can't do that we will not fund you and if the funding includes the lights in the building it's federal funding. Anyway that's why we start talking about. Who not greater than minimal risk permission of a parent, send the children. Not more than minimal with prospect of a different benefit means to benefit. Corresponds to the risk in some way. The chemotherapy to gauge in might cause a little bit more knowledge and vomiting but it appears we think it's better we don't know yet that's R.B. R.A. is our standard treatment. I'm going to flip a coin and to be cancer therapy and piatrics you got to be in the study and that's how it works. And send the children permission of the parents and the benefits at least is favorable as what is happening now. No prospect of a different benefit. So this is a tough one for me. So we want to enroll your little darling child in this study. You're going to be exposed to risk and you're not going to get any benefit. So here the experience for the child must be something that they're familiar with. So this can almost edge into we're taking advantage of them because they always get bone marrow. We could just do one more. They know what it's like. That's the wrong approach to it but that's how it might be interpreted. And we're going to learn about only their disease. So CF kids get x-rays all the time. They get all sorts of imaging studies of their lungs. Can we get one more CT to learn this fact about them? It's not part of clinical care but they know what they're getting into. They know how much radiation it is. Is this okay or not? But kids off the street just kids with this illness and we're going to learn just about cystic fibrosis. So that's how this one fits. The last category is more broad. We want to learn about the health of children. So now we're not looking at a group with leukemia or an illness or any sort of condition or any sort of social situation. It's we learn about children and maybe there's some risk involved maybe not but that's why it's not otherwise approval. It often does involve some risk but we'll learn about the health of children maybe developed mental milestones. It depends on the details of the study but that's what we're going to learn about and that's these are not that common and this requires quite a bit of review by experts outside the field as well as sound ethical principles. So here they are getting summary for four or five six and seven minimal risk, minimal risk with benefit without benefit and then doesn't fit into the categories. So in a little more detail. So probability and magnitude of harm or discomfort are not greater in and of themselves than those encountered in daily life or doing the performance of routine physical or psychological examinations or tests. Sounds good on paper but what does that really mean? Well these four these organizations I list all have their own opinion about what that means. We don't need to go over all these letters to him but they're all right organizations that look at ethical ethics and research and all that is an absolute standard. What is it a relative standard? Is it a kid living in a wealthy family with three nannies and a boat and an airplane or is it a kid living with a single parent and they're hard to have an hard time getting a job. They expose to different risks. Well thanks for the answers no thank goodness. Healthy children living in a normal environment. But the second part is psychological examinations. I'm a pediatrician. There are no routine psychological examinations in pediatric. So we're not sure what that meant but you can guess. So again it's a normal average healthy child living in a safe environment. That's the standard for minimal risk children not other ones and it's equivalents of risk. So this is really a challenging thing. I'll give you an example. Let's say the cardiac surgeons want to take a small piece of the left age frame during a procedure. That's hardly minimal risk. Well but the intervention is three more minutes to take a piece of the left age frame that will be thrown away anyway. So we translate cardiac surgery bypass all that post-op care. That's going to happen anyway. The additional research endeavor is simply a small piece of left age frame. We can call that minimal risk because if the parents decline they're getting all the same things happening. So even though this doesn't cover that that's what we do. What's going to happen anyway? So what's additional? And sometimes it's a tiny risk for six months. It's a little bit less than six months. My goodness. It's blood draw after blood draw after blood draw. We have regulations how much blood can you draw over a period of time? Because we don't want to tell the Neumann. And if something does happen is it reversible? So this suggests some more textbooks explain if they live in a difficult environment or have difficult circumstances. That's not the standard. The standard is an average healthy child living in a safe environment. And a couple of minutes commented I really like. It's still explaining the obscure with the more obscure. I think that's very accurate. So which of these things are minimal risk? There's some things from the Institute of Medicine's book on this. And I would say we consider most of these if not all minimal risk. But some details matter like the old glucose challenge. Well, who are you doing it to and how much glucose go and will that happen? All those details make a difference. This one graph I think really nails it. The year in collection I think is a nice standard. The bag is minimal. Cather is more than minimal. And a bladder taps. A minor increase of a minimal risk. I think that gives you the sense that one bar function clearly is at least a minor increase. And maybe more it depends on if it's a terrified four-year-old or if it's an 18-year-old. A bone marrow I think is very painful. So this is some of the IOMs book on all these comments. And it varies with the situation in great detail. But that's one sense of what risk can be considered by that. And here's my, this is what we interpret psychological tests to mean. If we do these things which may not be done normally in pediatrics, it's okay. The last one, of course, if you assess sadness or hopelessness, sometimes surveys are the riskiest things that approve. Do you feel sad? Yes. What's your safety plan? How sad does he feel? Is he going to run from a bus right now that you reminded him that he's very sad? So if it's a simple survey among adolescents who might take the survey alone, depending on the situation, you might need a serious safety plan of the investigator knows right away this person said they're very sad. What are you going to do about it? Because now you know something you didn't know before. Whereas the heart surgery left atrium studies improved quickly as minimal risk. So it's interesting how the risk varies sometimes with the context. So prospect of direct benefit, the risk and benefit must be matched. And the details matter so much. It's got to be least as favorable as if you say no thank you to the study. And again, it's hard to discuss this in the abstract. The harms are transient and reversible. The bruising from a phlebotomy, the one x-rays like flying an airplane to Chicago, things like that. And they have support that the people who are going to do this are qualified in safety, radiologists, technicians, the people doing the psychological testing, whatever the details matter again. So if it's very risky, there better be a very big benefit. And if it's the tiny risk, but it lasts for two years, how long does the benefit last? And if it's an interventional study of some kind, and the kids are getting benefit and looks like this investigational drug is very effective, thank you for participating. If you want to continue with $10,000 a month for this new drug, well, maybe there should be some compensation post study for the victims of this research that wouldn't get if you're just a citizen in the community who now knows there's a drug available for your child. And the benefit can't be like in Willow Brook, and if you're in the study, you don't go to that clinic. There's a Starbucks right there. It's a nice quiet room. There's music. You'll get seen right away. That doesn't count. The intervention itself must provide a benefit. And you wonder if it's, I say, really great benefit. Do you have a really bad risk? And anyway, these are what we spend hours working, fighting over at the meetings. And is there echo poise if you think what your studying is actually at least as good as not better than the current therapy? Maybe you can't do it in my trial anymore because I think it's better. I don't feel right in rolling people in the standard therapy. And again, if it is better, if we think it might be better, there's some case where a scent is eliminated because the children should not get the opt out of it. So if it's available outside the study, the family must know that. I want to study these two drugs. You can get this one to CVS if you want, but I want to study them. But I want you to know if you think this is better yourself, you can get it somewhere else. You don't have to be in my study. Just have to inform them. And once it's completed, again, if it's an anthropotensive or any therapy that will then cost the citizens later once it's approved, perhaps the people in it should get the benefit of a year or two of free treatment or something like that. And of course, these get annual reviews, if not more often, if there's adverse events, stopping rules, when do we know? Uh-oh. We didn't realize the rash the kids get as much worse than we thought. We're going to have to stop and publish what we have so far. So no prospect of direct benefit. So here's the one where we're going to use, in quotes, the children who have an illness as our subjects. Because when it's spread of their disease, we're going to do things to them that they probably have had before they're familiar with, but we're going to use it for research only. We're going to do an endoscopy on kids with IBD. And we're getting the usual seven biopsies. We want two more. And these two more are going to be used for the obscure study of the IBD that might be very helpful. Okay. Well, I have an amendment. Can I do six more? Can I do eight more? Can I do 12 more? How many is too many? And what's our institutional experience with perforations during biopsies? Well, we look into this. It's zero. We feel very comfortable allowing at this institution an extra biopsy or two or three. He's going to get an MRI anyway. But if he spends 15 more minutes in the scanner, I can do these other unusual scans we think are going to be groundbreaking for learning about anatomy of kids with brain tumors. Can we get permission for that? They're already anesthetized. So it's just going to be 15 more minutes. We've decided there's a length of time where more anesthesia can be counted as minimal risk or minor increase of minimal risk. We're not sedation for the research only. So this is the things we look over. And again, it's trained in a reversible. It's unlikely to be very serious, but it's all these things are judgments. It depends on the detail of the, reminds me of the answer to every ethical problem, as learned in a fellowship. It depends. So what's in this order of condition, by the way? It isn't being poor. It's sick of selenemia. It's a phyma-tribal disease. It's acute lymphoblastic leukemia. It's appendicitis. It's not living in a single parent home where the parent is in the home much because they have three jobs. So that's a specific medical condition that we can study in greater minimal risk, no prospect for direct benefit. But we can't, should not use, we shouldn't use the fact that if he gets bone marrow as anyway, what's the big deal we can do another one? That's not a good justification. And remember the justice thing in the bone marrow report? I highlighted, we should be careful about people who are burdened by infirmities. That's exactly what they are. They're burdened by infirmities. And we're using them. So they're about, they're disease. But the consent will say, clearly, this will not help you a child. This might help future children with this condition that's in the consent document. So the parents read it and think about it. They at least know that fact. They won't have the therapeutic misconception that this will have my kid. Of course, I'm going to volunteer for this. So why should sick children be exposed to more risks than healthy children? And there's a utilitarian argument or death to society. What about, remember how research is over here and therapy is over here? Well, I'm the oncologist. I'm your oncologist. And this is my study. Oops, now I'm the investigator and your doctor, who the parents really want to keep happy because you're going to save my baby's life. Yes, whatever you ask me, the answer is yes. That's a difficult conflict. Our investigator's navigated beautifully, but in a surgical study is the same thing. I'm the only person who does this operation. It's undue influence unless the person is moral and ethical and they are, but that's something we have to worry about. Remember the research I mentioned, it's research. So over here, therapy is over here. Well, to treating MDs to PI, they're mixed up together again. So not otherwise, approval means, again, learning about children in the world, not about any illness at all. And they're going to be risk involved to a kid who doesn't have any condition and has no real reason to volunteer for this. But is she actually going to be approved by their parents to be in this study as risk to learn about pediatric. Number two, I think I have a slide. It's conducted according to sound ethical principles. Is it a sound ethical principle to expose healthy children to risk? So other kids will benefit or to learn something or get promoted to tough call. So this is a tough one. This requires an expert panel review actually putting something in the newspaper, if people read it, to learn this is a study we're considering undertaking at Boston Children's Hospital. Please send in your comments and the experts have nothing to do with research. They'll comment on whether it's good idea or bad idea, whether it should be approved. So it takes a while to get a 407 approved, but there are some that have been approved. Like this one here, we want to learn about diabetes and Japanese use. These kids have no illnesses whatsoever. So this is clearly in the 407 category. And they want to study eight to 10 year olds, 450 kids, 100 Japanese 150 Caucasian, history and physical, Tanner staging, phlebotomy, glucose tolerance test MRI, DMI, DNA collection for future genetic studies. That's not going to go very far. So who would approve this? Nobody got like now. So it was approved, but the scientific review said there's only barely half a chance that all the kids will reach puberty. And the sample size is so small that one kid might get diabetes. So it's not well designed. It's too small. And, but if it were approved, here's what we would require. Do the glucose tolerance test at a children's hospital? Not at some dock in the box for the ticker of adults and camp with an IVs and get the wrong glucose given. Clearly exclude children from the MR study, enhance privacy for the DNA banking, and repeat a cent because someone who's not thinking about kids, Tanner staging, I would just met, I'm the investigator, take off your clothes. Maybe the 12 years won't do that. They barely want to do with their pediatrician. So they get to say no at the second or third year or second year. I think that's a reasonable thing to do. These are the sorts of things that the IRB might say will conditionally approve it with these conditions. If you don't meet those conditions, we'll have to talk. But it was approved to go to our own. Even though the scientific review was not very favorable. Here's an interesting one. We just want to see what this drug does to normal kids' brains. I thought this was crazy. And my wife was a teacher said, that's just one dose. I said, it's an infetomy. But there are those who said, well, it is one dose. And it might be commenced with risks in counter-indalty life, like playing sports, drinking a lot of caffeinated drinks. So you see how different people can look at, there's no way I would approve that. I would say that's absolutely a non-starter for me to give a kid a drug like that that they don't need even those one dose. And the compensation can be easily considered undue in thoughts. Because there's several visits for surveys. I think it was an artifact to get people to do it. But is this minimal risk? Because it's just one dose. And some kids drink a lot of red bull. They play sports. Or they know. So this is, you'll have to guess who the surgeon is here, who does epilepsy surgery, the moral ethical guy, if ever there was one. And they want to stick these electrodes in your child's brain. What's the big deal? But the electrodes that will be used to study seizures are maybe thinner than a pencil lab, but they're pretty big. And they go in pretty far into the brain. And they're going to get a sense of what part of the brain might be resected at the next surgery later. These electrodes are thinner and shorter. And they're in amongst the others. If you think about it, gee, they're thinner and smaller. The same surgery, we placed the same, they actually know more surgery when it's either time. So it's an interesting problem. We on the RB were having a hard time with us. And we thought, you know, the MD is the PI, of course. We said, this is a device. Maybe we can punt to the FDA because it's the device. We don't have to adjudicate this. So we did. It's manufactured according to that data guidelines in Hungary. All device, all the device are MRI compatible. I think maybe the FDA is going to give a adjudication. Then we can be off the hook here. But they punted back to us because they start, they make determination of things that are intended for human use, not research. So they punted it back to us. But we approved it greater than minimal risk, no potential for direct benefit. And both parents, the reason that's a tough one is both parents have to sign because it's greater than minimal risk, no potential for direct benefit. It is a very minor increase if you think about it. If you do those cases, big electrodes go on. These are tiny, but hardly noticed they were there when the things were removed. So it is quite safe, given that they're going to have the operation and electrodes anyway, that's going to happen no matter what. There's where we, what's different, what's added. You can almost make the argument, this is indeed his minimal risk. So Kennedy Krieger. This was a well-meaning people at Hopkins who want to study, and this is really interesting, because it changed into public health research also. What if they learned that the 1650 abatement was as good as the $6,500 abatement? Well, then six more houses just got abated, and all those children are safer. But what if they learned it wasn't as good? And the kids are living in those homes all this time. And they didn't have a control group, because many homes had led. And there wasn't enough money involved to more city to fix it. So they're in a tough spot. But it's an interesting design. The details would matter so greatly in deciding what this was ethical or not. The consent document, how it happened, how much time they spent with the families and all that sort of thing. But the family sued because they weren't fully informed. And it was dismissed at first by the court. And there's the citation. However, they appealed. And it was upheld dramatically so. The judge compared this to Tuskegee or the Nazi horrors. It said, how could you experiment on these children like this? They were, the judge was terribly critical of this. And he thought that they didn't, again, they took advantage of high where the Hopkins experts. We want to help you. We have a lot of credibility. They thought all this went on. And that it was not done correctly. And this is one commentators. It's easy. We know how to give it a leg. We just don't know how to pay for it. And it's better for a landlord not that to pay money than a kid who's supposed to lead. It's a pretty strong statement. But on the other hand, if they found out the chief of treatment was as effective as the expensive treatment, it's a huge public health advantage. I'm not sure the answer here. But I think the family did receive compensation for this. Support. This must be 10 new and journal editorials here. So here's the study I want to see about ROP and two groups of kids, the Lowes Hat and the Highs Hat. Again, they're nurseries in the country that pick one or the other because that's what they think is better, but no one's compared them. And they could do what they want, at hospital A, hospital B. If you're in this trial of these 23 institutions, you're on the high group. All your kids get the highs Hat and you're in the low group while your kids are the lows Hat. Same newborn care. It seemed like a reasonable study of comparative effectiveness research, which is another different flavor. Well, interesting results. In the high-s Hat group, they had more ROP. And the low-s Hat group had less ROP, but they had more debt. And I think it was one debt shy of statistical significance. So it's pretty troubling. And is this minimal risk? Because if you were born over there, you would have gotten that sad anyway, just because you're born over here, we're using their SAT because that's when we were randomized. We even need to tell the parents. We're just doing clinical care because if you weren't to study, turns out we're in the group that uses a SAT, that we always use anyway. And should they be randomized? Is that allowable? And is this comparative effectiveness research, which is different than randomized controlled trial? Real ethical conundrum. And I think Bob Troug has written editorials in this. As a matter of fact, the NIH and LHRP disagreed on whether this was ethical or not. And there's the two organizations that supervise this sort of thing. So this was a really tough one because it is clinical care that can be delivered to each child, depending where they're born, what they're randomized. And they learned what you'd expect. ROP went down. I think the death shocked everybody. And it wasn't what almost statistically significant. OK, the marathon's over. I can have a few minutes for questions. If you ask about a specific study, my answer is going to be, you can't do that. So thank you very much.
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