Transcription:

Bill Klaproth (Host): So what is a clinical trial and why are they important? And how do clinical trials benefit patients, specifically children? And what types of clinical trials are happening at Le Bonheur? Well, let's find out what Dr. Dennis Black, Vice President of Research at Le Bonheur Children's Hospital and Scientific Director of the Children's Foundation Research Institute.

This is the Peds Pod by Le Bonheur Children's Hospital. I'm Bill Klaproth. Dr. Black, thank you so much for your time. We appreciate it. So let's jump right in. So, what is a clinical trial and why are they important?

Dennis Black, MD (Guest): Well, a clinical trial is a formal way to test a new drug or a treatment in humans. They're important because they establish two things for a new drug or treatment. They establish the safety of that drug or treatment in humans. And they establish the efficacy of the drug or treatment. That is how well does that drug or treatment function to treat or improve a disease state. So, obviously because of those reasons, they're extremely important for getting new treatments and new drugs on the market for several diseases, including those in children.

Host: Absolutely. So, you talked about safety and efficacy. So, can you explain more how these clinical trials benefit patients, specifically children?

Dr. Black: Well, children compared to adults are what we call a vulnerable population. We know that children are not small adults. That is, we can't necessarily take data from clinical trials in adults, and then transfer those directly to children. They metabolize drugs differently. They have the different diseases than adults do often. And also we want to make absolutely sure in children that a drug is as safe as it can be. We sometimes have to weigh the safety of the drug versus the efficacy. We try to keep the safety concerns, adverse events associated with the drug to a minimum. And then try to maximize the efficacy or effectiveness of the drug. But obviously before approving drugs for children, we are as careful as we can to make sure that we're doing the least amount of harm and generating the most benefit.

To do that, we're involved with a number of regulatory oversight steps. The FDA, obviously the most important one. But also locally, with the Institutional Review Board. And then studies in children, well all patients, including adults who are involved in clinical trials, there's often an independent data safety monitoring board or DSMB that will monitor the progress of the study, review data periodically, including that for safety and efficacy, to make sure everything's going well.

Host: Right, so safety is of the utmost importance. I was has having a discussion with my wife. She was saying, well, why couldn't. We were talking about the vaccine now for COVID. Why can't they just give it to kids? It's approved for adults? And I said, well, I'm not a doctor, but I think since kids are growing and their bodies are changing, you can't just think that if it works for adults, it works for kids. Is that right?

Dr. Black: That's exactly right. There are a number of considerations for children. As I mentioned before, children metabolize drugs differently. In the case of a vaccine, their immune system may react differently to a drug. As you mentioned, children are continuously developing.

And even within the category of what we call children, you're including adolescents, older school-aged children and then all the way down to toddlers and infants. And actually all those subgroups may have differences again, in drug metabolizing, how they react to the drug. And, and all of those things really have to be carefully considered when doing a trial in a new drug.

Host: Absolutely. So, do you have any antidotes of how a clinical trial has helped a patient population?

Dr. Black: Well, one of the most exciting trials that has come along for us in a while, it's still in progress, but, I think it shows great promise. And it shows how a patient advocacy group can work with a pharmaceutical company and with physicians to affect clinical trial that has really excellent chance for a lot of benefit. Just briefly, there's a disease called Dravet Syndrome. And it's an inherited disease that has a, is characterized by really severe seizures early in life. There's also an impact on mental development, quality of life. Seizures are difficult to control. And, there has been some impact from other treatments on controlling seizures, but the quality of life and the impact on psychomotor development, has not really been that great. And it being a genetic disease, it's a type of genetic disease, where one of the two doses of the affected gene has a mutation. So that means one of the genes you have is abnormal. And the other one is normal. But the effect of the abnormal gene overshadows, the normal one and causes that disease. So, the strategy here is very innovative in that they're using a technology call antisense oligonucleotide to actually genetically enhance the normal gene so that its effect can over shadow the abnormal gene and actually result in a significant clinical improvement in these patients.

That is getting underway here in our Neuroscience Center. And again, very innovative and novel therapy. Great potential for helping this group of patients. And it's the kind of thing that really keeps us excited in the field of clinical trials in children.

Host: Well, you can see the importance of clinical trials in the story you just told us in trying to figure out and overcome this Dravet Syndrome. So that's a great example. So, for a parent listening to this, they might understand the benefits of clinical trials and you've stressed safety and efficacy. But how does a parent know if a clinical trial is safe?

Dr. Black: I would say probably the most important thing, if you hear about or are approached about a clinical trial, probably the best thing to do is talk to your pediatrician. They would certainly be well-qualified to do a little bit of investigation into that trial, potentially even talk to the investigators who are conducting it. And can probably give you very accurate and informed information on again, the risk and benefit of your child participating in that trial. The investigators, the principal investigators, the physicians generally, who are conducting the trial can provide information as well; detailed information on the trial. BUt I think that contact with the pediatrician is probably the best place to start.

Host: Right. And so then what is the process of bringing a new medication to a clinical trial? How does that work?

Dr. Black: It is a complicated process. One that is expensive and also takes time, with a new drug, for example. And I keep in mind, for children, a trial may involve a drug that's already being used in adults. And then you want to do research to test that drug in children, so it can also be labeled by the FDA for children.

Well, the first step is called discovery and development. And that means that a new drug or treatment, it could be a device for example, there are hardware devices used to treat scoliosis and other diseases. So it doesn't necessarily have to be a drug. But it's usually developed first, in the laboratory, for example, a problem is identified. There may be way to molecularly screen a drug. There may be what are called small molecules that they can conduct high throughput screening to screen thousands of these small molecules to see if in the laboratory, they seem to have an effect that might be beneficial for disease. So, that's the first step. If they discover such a molecule, that may become an effective drug; then they have to do what's called preclinical research. And this is also in the laboratory and involves cultured cells where they work to again establish the efficacy of the drug in those model systems. And also look for, potential safety concerns as well, potential adverse effects of the drugs. So, that has to go through that whole process. And again, the developer of the drug has to register with the FDA.

Because all of the data they collect, has to be reviewed by the FDA to make sure again, that it's reasonably safe and can proceed to the next step, which is actually starting clinical research in humans. And then that goes through phases. Phase one is just to establish the safety of the drug. And even for children, that first phase is often conducted in healthy adults who volunteered to take the medication and then closely be monitored for any side effects or adverse events. And that's generally a small number of healthy adults, it might be a group of children with a disease for which there's no other treatment, and who may be ill from disease, with no currently established treatment, who might be suitable for the phase one. But generally it's in healthy adults. Once that's conducted, then it goes on to phase two.

This may be in adults with the disease. It might be in children, but it generally involves patients with the disease. Generally a small number. And studies are conducted to establish the correct dose by doing experiments where you administer the drug and then draw blood samples and measure the levels to see how fast it's metabolized. Also, you continue to look for adverse events related to the drug, and then you start to look at efficacy. If you're testing it in a patient with the disease, is it having any beneficial effect? And so all that data is collected and very carefully reviewed before you go on to phase three, which is a trial that involves a large number of patients.

It may involve hundreds to thousands of patients. Although pediatric trials tend to be smaller because it's more difficult to recruit. But at this stage, you want to conduct a randomized control trial if possible. That is in addition to having patients who get the drug, you also want to have a control group. And that control group may receive what's called a placebo. It looks dislike the medication and often the people doing the study are blinded as to which is which. But, that's given to the control group or placebo group. It might be a standard treatment, that is a drug that's currently being used. And you want to compare the new drug to the standard of care. But you do have a control group and then patients are randomized into one group or another. That's important because you want to avoid any bias one might have by maybe a physician who's doing the study might think, well, this patient's a little sicker and maybe I want to put them in the drug group or whatever.

So it's all blinded and randomized. And it's prospective that is, being prospective, the patients are going to be followed over a period of time. And this is very carefully conducted. For example, there are strict criteria for who qualifies for the trial. There are also exclusion criteria that is, there could be certain medical conditions or other factors that might make the study inappropriate or more risky for a patient. So again, those are carefully established. And then a protocol has to be written. That is how the study will be conducted.

A lot of work involved. The study and the protocol have to be approved by the Institutional Review Board. For example, here at Le Bonheur, we use the University of Tennessee Health Science Center with which we're affiliated. We use their IRB. And again, the study and the protocol are carefully reviewed and it's evaluated for adherence to federal regulations. If there are issues, they give those back to us and they're addressed. And then, you know, again, it goes through this iterative process of making sure it's in compliance and it's safe and all of those factors.

So the study gets under way, again, it's very carefully monitored. Many of our studies, that are involving a pharmaceutical company, we're one of many centers that are involved in the study across the country, in some cases, even the world. And things are carefully monitored by the pharma company.

Again, I mentioned before a data safety monitoring board, that's an independent board, that will carefully monitor the study and periodically review study data to make sure that no patients are being harmed. And will even evaluate, you know, if there is evidence of efficacy. Now that won't be firmly or definitively established until the trial is finished and all the data is analyzed.

But again, focus is on above all in children, is safety, and very carefully monitoring for adverse events. If adverse events, that is a side effect or reaction or any health problem or whatever that the patient develops during the study, those are carefully reported, noted.

Periodically they're reviewed by the IRB, by the DSMB, by the pharma company, again, to see if there are any trends that might indicate that there is a serious problem or a side effect with the drug and the DSMB has the ability to halt the study, if they see a signal that there is some harm potentially being done.

Or even if there's no efficacy, that is, if there are enough data along the way collected to suggest that the drug is not having any beneficial effects; the study can also be halted because of that. So again, a lot of safeguards built in along the way to make sure the drug is again, efficacious and also that it's safe. And when the study is completed and all of the data is submitted and reviewed by the FDA, and they will either not approve or approve the drug. Now if the drug is approved, it can proceed to go on the market. And then there is even a phase four study of drug evaluation, that is there's continue monitoring of patients on the drug after it goes on the market, by making sure that data is collected periodically from patients on the drug in the open market, to see if there are any side effects or issues that might emerge after it's being marketed, youknow thereby being used by a lot more patients.

And sometimes serious side effects only emerge after it's being used by, you know, a whole lot more patients on the open market. So, as you see, there's a, there's a lot of regulation and a lot of monitoring that goes into clinical trials. And because of that, the average time from that very first step in development, to a drug being approved and marketed can run 10 to 12 years. And anywhere along the way, if something goes wrong, then the drug, the study, the process can be terminated and the drug won't be approved.

Host: Well, that is some process involved. No question about that. And it's good for you to explain all the different steps because most people probably don't realize all the different steps that a new medication has to go through to get final FDA approval and how that process works. So, thank you for that thorough answer. That really paints a picture of what these clinical trials are like. So for a parent listening to this, or gets to recruited to participate in a clinical trial, who is eligible to participate then in clinical trials?

Dr. Black: Well, generally in children, it's a patient that is, we call, the patients who are in clinical trials participants in that trial. But generally it's a patient with the disease that the drug or treatment is being targeted to. Again, as I mentioned before, there are inclusion and exclusion criteria. So, the first step in getting involved in a clinical trial is a screening process, where the participant is screened using very strict criteria, that first they meet the inclusion criteria. And then secondly, that they don't meet any of the exclusion criteria.

And then of course, if that all works out, the very first thing that's done, even before that process, is obtaining informed consent. And that is the study personnel have to go over the study with the parent. In the case of pediatric trials, we get consent from the parent. And we talk about the protocol, what the study involves, the risk and possible benefits of being the treatment. Make sure they know that it's a chance the child may be put in a placebo arm or a control arm of the study. We discuss the study procedures, how the drug's administered. If there have to be various tests such as blood test, or maybe an EKG or some type of imaging or x-ray involved in the protocol, they're made aware of all of that. Basically just every aspect of the study. They're encouraged to ask questions and in the case of the child, at age seven and above, we also obtain what's called assent. That is the parent consents, but we try to on a level the child will understand, explain what the study is going to involve for them.

And then, get their assent for the study. And here at Le Bonheur, we've worked a lot with our Child Life folks who in the hospital with patients use games and various activities to engage children in treatments and whatever in the hospital. We've been working with them to develop an assent process for the child that uses images and language level they can understand. And even kind of make it a little bit fun to hear about it, to explain, again, the study and the process to them as well. So that's the first step. And then we go through the inclusion exclusion criteria. Then they're actually entered into the study and the first dose of either the drug or the placebo is administered. And we have specially trained research nurses that conduct the study, along with the physicians and follow the patients, make sure all the procedures are followed. Collect the data. And of course, again, monitor very closely for any adverse effects or side effects of the drugs.

Host: Right. So you kind of were starting to tell us what sounds like the process of participating in a clinical trial. Is there more to it than that?

Dr. Black: Well, that's really the main thing. We want to make sure that the patients are followed closely. That there's an open chain of communication between the parents and the study coordinators who are conducting this study, that if there's ever a concern or question on the part of the parent, they need to feel they can call or contact the study personnel, anytime to have them answer a concern or answer a question. That's a really key part of the whole process is open communication. And then, just making sure all the components of the protocol are properly carried out and then, you know, all the way from the beginning to the conclusion of the study.

Host: So let's talk about the kind of clinical trials that Le Bonheur is currently conducting. Can you tell us about those?

Dr. Black: There are a lot. I could talk all but I've narrowed it down to a few that might be of interest. Well, I think probably with our current pandemic, I think folks might be interested to know that we are in involved in a monoclonal antibody study in children, that is currently ongoing. We also have some other studies with COVID that aren't necessarily trials, but for example, a large scale data collection on COVID patients, along with clinical specimens, such as blood samples and sputum and other samples, so we can do studies to learn more about the immunologic reaction to COVID in children, to try to identify factors that may make children more susceptible in some cases. Or factors that might affect how they react to the infection. We have a lot of that going on currently. With our Neuroscience Institute, which I mentioned earlier, there are multiple studies going on involving seizure medications. The Neuroscience Institute has been involved over the years in multiple trials that have resulted in very effective seizure medications becoming available for pediatric patients. We try to tailor a lot of what we do here at Le Bonheur in terms of clinical research with our local patient population. And if you look at the CDC map, you'll see that we're right in the middle of the obesity epidemic.

And not only for adults, but also for pediatric patients. So we have trials, and clinical studies underway for obesity in children. Our Endocrinologists are conducting trials for medications used to treat diabetes in children. And that's not only Type 1 diabetes, but also Type 2, which is often associated with obesity. And, unfortunately as the incidence of Type 2 has really gone up dramatically, with the obesity epidemic. And so we're testing treatments for that. The orthopedic doctors here at Le Bonheur are testing devices. For example, I mentioned a little bit earlier about various devices for helping treat scoliosis in children. We have a Cystic Fibrosis Center here at Le Bonheur. And they participate with a large consortium of other centers to conduct clinical trials in patients with CF. And over the last few years there have been dramatic advancements in the treatment of CF patients and their survival has gone up quite dramatically because of that. We have an immunologist here who's involved in a number of studies in presenting peanut allergy, by using exposure to peanut allergens early in life that actually desensitizes patients to exposure later, because these can be life-threatening reactions that patients can have.

And, another big area is in cardiology. We have a Heart Institute here at Le Bonheur that's very active and we have a very talented investigator here who has developed techniques in collaboration with industry for a device that can close a Patent Ductus Arteriosus. That's called a PDA. It's a blood vessel that is open in the heart in fetal life to allow proper oxygenation of blood using the mom's blood and in utero. But this vessel needs to close at birth. And if it stays open, if this PDA vessel stays open, it can cause all sorts of problems with lung function and other issues and particularly in premature infants, it can be a big problem because it tends to stay open after birth in preemies.

So this investigator has developed a device that can simply and it used to have to be surgically closed. But now he uses heart catheterization to introduce a device into the heart to close that vessel nonsurgically, with just a heart cath. And I'll stop there. I could go on.

Host: Well, it sounds like you could, and it sounds like there are a lot of clinical trials happening at Le Bonheur so, as we look into the future, it looks like clinical trials will be ongoing. And you'll continue to do this type of research and field many types of studies.

Dr. Black: Well, I think it's going to be an ongoing, and I think it's going to be very bright indeed. We are continuously increasing the number of trials that we're involved in.

Host: Right. So ongoing, innovative, effective and as you said, it's a, the outlook is bright for all the clinical research and clinical trials happening at Le Bonheur. Well, Dr. Black, thank you so much for your time today. This has really been informative. We really appreciate your time. Thank you so much again.

Dr. Black: Thank you. My pleasure.

Host: And that was Dr. Dennis Black and visit Le Bonheur.org/research to learn more about clinical trials and other research underway at Le Bonheur. And be sure to subscribe to the Peds Pod on Apple podcasts, Google podcasts, or wherever you listen to your podcasts, you can also check out Le Bonheur.org/podcast to view our full podcast library. And if you found this podcast helpful, please share it on your social channels. This is the Peds Pod by Le Bonheur Children's Hospital. Thanks for listening.