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Choosing a Study Design — Transcript · YTtoTranscript

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Choosing a Study Design

NIH VideoCast · 2,432 words · 12 min read · EN

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Below is the complete, readable transcript of Choosing a Study Design by NIH VideoCast on YouTube. Read the full text, copy any part you need, or generate a transcript for any video with our free tool.

>> Danny Benjamin: Hey, I'm Danny Benjamin. I'm distinguished professor of pediatrics at Duke University, and I've had the privilege of having some of my research funded by the National Institutes of Health and by U.S. taxpayers since the late 1990's. And I want to talk with you today about trial design to improve trial feasibility,

and I'll touch some on the Pediatric Trials Network which is sponsored and supported by the National Institute of Child Health and Human Development. And I'm the chair of that particular network. Now before we get too far into this, I'd like to get some common understanding of some terms that we use in traditional trial design.

When we talk about phase one trials, those are first in human. And there, we are giving the molecule to about 10 to 20 people, and we're trying to determine the exposure; that is the pharmacokinetics, what the body does to the drug. Does it eliminate the drug unchanged from the kidney? Does it metabolize the drug to eliminate it

by a drug metabolizing enzyme in the liver? And from this information, we determine what might be an appropriate dose; whether it's one milligram per kilogram or a hundred micrograms per kilogram. We then go on to phase two, which is proof of concept where we give the molecule to somewhere between 20 and 100 people.

And there, we are looking for some estimate of effect; that is the pharmacodynamics of the drug. Maybe we want to see if the antibiotic kills the bacteria, or we want to see if the antihypertensive actually lowers the blood pressure of a few people. And we want to see safety. Now, in phase three trials,

these are pivotal trials where they are blinded. People are randomized, and we give the product to several hundred to several thousand people. And we want to see does the molecule work, and does it work safely? Now, other common terms are repurposing of drugs. And there, we might look at drugs where we give it to one population,

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say 20- to 50-year-olds. We know it works. We might want to look at it in children, or the elderly, or people who are pregnant. We also might want to look at a different but perhaps anticipated indication. So, the drug might have been originally studied for people with heart disease in adults, say atherosclerosis,

and we want to look at it in heart disease in children. So that is congenital heart disease. Or we could look at an entirely different and wholly unexpected indication. So, sildenafil had an original indication that might be familiar to you if you knew the trade name of Viagra. And years after development, we realized that it might work,

actually, for pulmonary hypertension in premature infants. There, we are repurposing the drug in an entirely different patient population for an entirely different medical indication. These types of repurposing go on with older molecules all the time. And in FDA compliant trials, that is trials conducted under the supervision of the Food and Drug Administration, these are the highest hurdle,

and they give the most reproducible data. And these types of trials are done by the Pediatric Trials Network sponsored by the National Institute of Child Health and Human Development. We repurpose drugs in different patient populations, children, for different indications. Now, in doing trials in children, one of the big challenges, comparing doing trials in children versus adults,

is the feasibility. And really, it's all about enrollment. So, here's a hypothetical example from a drug where our goal is to enroll 240 people into a randomized trial of bloodstream infection, and we're going to compare a hypothetical example from a healthcare facility where we're looking to enroll adults versus children. Now at this particular healthcare facility for adults,

there might be 100 cases per year, but really when you look at the inclusion/exclusion criteria for the trial, only about 25 percent meet those. Only about half of those who are eligible consent. And you get about 10 or 12 patients per site per year enrolled in this trial. And in reality, you miss some of the patients

because they come on nights or weekends, et cetera, when staff are not available to enroll them. And so, you can get this trial done in about two years at about 50 different sites to enroll your 240 patients. And in order to activate those 50 sites, you need to approach 250 sites. In children, it's much, much, much more challenging.

So here, you've got maybe only 20 cases a year because children have a lower healthcare burden than adults. Children tend to be healthier, and they have less morbidity and mortality. Some of those adult -- children who are eligible, however, are too old. They're older than 17. They typically are enrolled in adult trials.

Some are too young; they're neonates. Often, the physiology there is so different, that they are excluded from trials. Really, again, only a small percentage meet criteria for inclusion/exclusion. And now all the sudden, when you take into account consent and missed participants due to weekends and nights, you really have a trial that's not at all feasible at all.

And even if you would approach a thousand sites, you simply cannot get your trial done under traditional trial design. Now, a bit of history about drug development in children. In the 20th century, in older therapeutics, these drugs are now off-patent. Generics can make them, but when they were developed in the 20th century,

drug companies were not ever required to study the drugs in children, and so drug companies typically just put into the label, "Not for use in children." And we didn't study 90, 95 percent of the molecules that we used in the 20th century. Due to the Best Pharmaceuticals for Children Act and the Pediatric Research Equity Act,

and other legislation that was bipartisan and signed in the 21st century, we now have legislation that requires for new drugs dosing, safety, and efficacy trials for children, but old, off-patent drugs need their own special mechanism, and from that, Congress supports the Pediatric Trials Network. And our job is to repurpose molecules, these older molecules that are very,

very commonly used in children and were never appropriately studied in the 20th century. And we study them in a different patient population for a different indication. And the reason that we have to do all of these studies in that even if we were to just use them, our estimates of dosing, even if we use older patient models

and animal models and computer models, we have disastrous errors in drug dosing because pediatric physiology is so different from adult physiology. So, because of this public health imperative of we really need to figure out the right dose, and are these molecules safe? And we need to do these through taxpayer dollars and do this in a most parsimonious way,

and trial feasibility is so challenging. We really do need new trial design and 15 years ago, we started with the first major step forward here, which was the Pediatric Opportunistic PK Study, or the POPs design, which has now been throughout the world by dozens and dozens of other investigators that have used our methods.

And the summary of this approach is to say, "Look, your child is receiving a therapeutic per the standard of care. They're getting this medicine. We don't have an opinion as to whether or not they should get this medicine, but please consent to provide some blood samples so that the next child can get the right dose.

We will examine your child's blood for levels of the drug, and we'll know the right dose 12 months or 24 months from now." We've now done this in POPs. It's the longest running, extramurally funded, continuously enrolling master protocol at the NIH. We're also using it for breast milk, and we use this for feasibility around molecules.

We actually get these studies done. We also see how good investigators are at enrolling, how sites are at quality of data, et cetera. The next study design is Choose Your Own Adventure. That's how we call it. And here, dosing and exposure might differ based on what is happening to the patient. So, we have a study called the staff trio,

and it's drugs used to treat staph aureus, which is a serious infection. And we pick several different drugs that the clinicians might use, and each group of clinicians at different hospitals choose different things as their first line go-to agent. We also use this in a trial called SCAMP for complicated intra-abdominal infections in neonates where clinicians choose

lots of different types of pathways to go, and it's not clear which is the best pathway. And what we do is we tell the families, "Look, we don't have an opinion as to what might be best, but please consent your child for this, what we call, open label dosing, safety, and proof of concept on efficacy study

as to where adverse events might be different or where might dosing might be different." So, we study the safety in dosing and pharmacodynamics from multiple different therapeutics at the same time for big cost savings and finding out maximally for patients what happens to their children when they're on these drugs. Still, we wanted to do more. We've now moved to doing

what we call decentralized outpatient studies of reasonably well children. Now, the decentralized -- sometimes people call these virtual trials, sometimes folks call them direct to patient, or direct to participant, or direct to family. We like to call them direct to family, or decentralized. And I want to give you an example. This is a 16-year-old.

He's previously enrolled in the Pfizer study for SARS-CoV-2 vaccine, and he's asked to enroll in the booster study. And his first question is, "How much do I get paid?" and his parents' primary question is, when approached for consent, "Will he miss school?" And upon hearing his father's concern about missing school, the 16-year-old blurts out that no study

is worth missing baseball practice. In the middle here is this child's daily schedule. It's basically locked up from 7:00 a.m. to 10:00 p.m. at night, and even though the clinic is open from 8:00 a.m. to 4:00 p.m., the clinic is a 45-minute drive one way from the high school, and it's only open during class time.

Now he could leave school early, but he doesn't want to do that because history is seventh period, and it's his favorite class. Now, why do I know all of these details about this particular child? Because I'm his father. He's the one there on the pitching mound. He's also in the picture below with his younger brother

as they were waiting for their doses of study drug. He did end up consenting, by the way. And part of what helps is doing decentralized trials, so centralized meaning I'm enrolled at a site. I do traditional enrollment, consent. All of my study procedures are at the clinic or at the hospital. The decentralized model is everything is done entirely

at home, or virtually, and then a hybrid model combines those two. And, again, we call these either direct to family or decentralized trials. And pre-pandemic, it was very difficult to get folks to do this. The pandemic made a lot of this much more feasible, and now in the post-pandemic era, we're now doing quite a bit of electronic consent,

and you can see this very busy chart here. The point is not for you to absorb all of this information, but to know that you can pick and choose between e-consent and whether or not you get remote data collection, whether or not you do telehealth visits, whether or not you do home visits, home medicine delivery,

do you enroll or collect information via social media, and do you maybe use the electronic health record for recruitment. And you can do a mix and match based on the study of what might work for you. We've now done about 40 trials at Duke that we've led at the Duke Clinical Research Institute that are either fully decentralized or hybrid models.

Now, this trial design really has helped us in the Pediatric Trials Network. We've enrolled over 12,000 patients -- 12,000 children, excuse me, at over 300 sites; 26 molecules that we've submitted data to the FDA for indication; over 100 publications; over a couple hundred molecules that we've developed or found information about in some way

which is a resounding public health success. And if you look at productivity across the BPCA Mechanism, this is the mechanism that funds the Pediatric Trials Network, in 2002 to 2010, that was the original Best Pharmaceuticals for Children Act era that's prior to the NIH's creation of the PTN. There was -- in that eight-year period,

there was one label change that was ultimately derived. There were no direct to FDA submissions of data. They studied molecules across four therapeutic areas. One of the trials was completed. About 700 children were enrolled. Five molecules were studied. Now in the first iteration of the Peds Trial Network, we got the network off the ground

and then those next eight years, we had seven labeling changes, ten molecule submissions to Food and Drug Administration, 18 different therapeutic areas studied, a total of 38 studies, 33 of which were completed, 38 were started. We had to finish enrollment for the other five in the next eight-year cycle. Over 7,000 children were enrolled

and over 40 molecules studied. And now that we're in the third iteration, this is now 2018 to present day. Keep in mind that over that five-year period, we did have to deal with the pandemic like other networks. Nonetheless, we still see a substantial amount of success. We've got 10 additional label changes. We've got 16 additional submissions.

We've got another 20 therapeutic areas were under study, 10 trials started, six of them completed, which is really very impressive, especially because most of this is being conducted under the pandemic. Over 5,000 children were enrolled in this five-year period. Remember, it's -- the PTN 1.0 is over eight years. This is now over five years here

because we're halfway through the mechanism, and over a hundred molecules studied. And you can see the totals in the last column. With that, I want to thank you for your time.