Pediatric Clinical Trials Must Approach Research With Today's And Tomorrow's Kids In Mind
A conversation with Stewart Goldman, MD, SVP of research at Phoenix Children’s, and chair, Department of Child Health at the University of Arizona College of Medicine – Phoenix
Phoenix Children’s conducts research in more than a dozen therapeutic areas and currently offers more than 700 clinical trials. It’s no wonder that the health system SVP of research, Stewart Goldman, MD, excitedly and without pause can share all the good work they’re doing — from the development of a transgenic lung models for treating BPD to a dermatologist studying a JAK one inhibitor cream for vitiligo and a trial studying the efficacy and safety of a spray to treat Prader-Willi syndrome.
And with each of those trials, investigators are caring not only for the current patients but those who have yet to come. Because, as Dr. Goldman puts it, “Every child and family can become research subjects. The only way we know how to treat kids correctly now is because of research that was done in the past. And what we learn from a child today can potentially benefit children in the future. And so, as an oncologist, I feel this really strong responsibility that when I'm taking care of a patient with a terrible disease, I make sure that not only are we giving that kid the very best care, but we can offer hope for the future.”
In this Q&A, Goldman describes their patient-centric approach, offering insights into patient selection and education, as well as trial design.
Clinical Leader: What's happening at Phoenix Children's now, and what types of trials are you working on?
Stewart Goldman, MD: I have a long history of doing quality of life and Phase 1 studies. And you may say, “Aren't those two pretty disparate?” But I don't think so. Not only are we pushing the envelope for a cure, but we're looking at how we're impacting the life of that child and a family.
We have recently been performing a two-arm trial using the Optune device, which is an FDA-approved device with pulsating electromagnetic fields for use in adults with malignant gliomas as a frontline therapy with temozolomide and radiation.
Remember that dreaded biology class where we all saw this movie of a cell becoming two cells when it goes through mitosis? You can see the cell pinching off, and then you can see the chromosomes lining up, and then the cells pull apart, and they duplicate the genetic material and become two cells. Well, the electric fields make it so mitotic spindles can't line up, and then the cell can't pull apart or pulls apart abnormally.
The Optune device has been a great additional tool in the tool belt for treating adults with glioblastoma, but it only works if you wear it. In adult trials, this means wearing the device more than 75% of the day, which improves efficacy and outcomes. To use this in pediatrics, we had to think about whether a 5-year-old could or would actually wear this.
In the beginning, the device was plugged into the wall, or you had a battery pack, which originally weighed 6 pounds. So, we had to consider how that was going to impact the quality of life of a 5-year-old or a 7-year-old who might have limited time left, and they now have less ability to go outside and play. Recently, the device battery pack has been scaled down to two pounds. Yet it is still important to study not just how efficacious the device is, but does it impact the quality of a child’s life.
For the second arm of the trial, we are treating children newly diagnosed with diffuse intrinsic pontine glioma (DIPG). These kids already receive daily radiation therapy ( Monday-Friday), and we are adding Optune therapy. Taking the arrays on and off the scalp for radiation could cause skin toxicity, so we collaborated with Dr. Tinkle and colleagues at St. Jude Children’s Research Hospital to determine how we could safely keep the arrays on, without negatively impacting the way the radiation affected the tumor, and without giving extra radiation to the skin.
We were able to show with high-grade malignancy that the Optune device was well tolerated and did not adversely affect the quality of life of the kids and their families. Now, we have started the second part of the study combining the wearable device with standard of care radiation, which will include up to 30 kids nationally with diffuse intrinsic pontine glioma tumor which has an extremely poor prognosis needing novel new treatments to be investigated.
It's obvious that you’re thinking about these kids' experience during clinical trials. Is that because you have proximity to the patients and the families? Or are there more formal ways to gather patient input and work that into the trial design?
Goldman: There's great science and there's great medical care, and then there's great doctoring. And being a great doctor means knowing it's about the patient and their families, not just about what the monitor says and what the blood test says. About 20 years ago, at Northwestern University’s Feinberg School of Medicine’s Center for Health Services & Outcomes Research, the team developed brain tumor quality of life tools and a study on fatigue that we validated with multiple families. There are also questionnaires where we use the parent as a proxy, depending on the age.
Are there any particular challenges in educating families and recruiting patients?
Goldman: Yes. It's my observation that randomized and even placebo-controlled trials pose difficulty for recruiting children. I'm not saying that it's not valid or important to have randomized controlled trials, but think about this in the context of my Optune trial for diffuse intrinsic pontine glioma. I've been personally doing trials in this disease for 35 years, and we still have the same survival rate.
Radiation buys a little bit of time, but ultimately, the cancer comes back. I don’t want to randomize a patient to the radiation-only arm versus radiation plus a new drug, because almost no one's going to buy into that. In pediatrics, there's a demand for crossover trials. So if a child isn't randomized into the potentially better therapy and they participate for X amount of time, then they can get the study drug.
Does trial design play into an investigator's decision to conduct a trial?
Goldman: Of course, it can be a factor, but if the child’s clinical situation or prognosis involves a horrendous outcome and you have no good options, then you accept more difficulties. But if it is a situation in which we have a very good standard of care, why would I or a family want to put their child in a study with extreme demands or risks? I believe it is imperative that investigators and their teams truly review a trial’s design before committing to opening and enrolling children in that trial. We have an ethical and moral imperative to make sure a trial is well designed to answer a question and improve health outcomes for the patient and future patients, while ensuring the trial exposes subjects to the least amount of risk and intrusion in their lives.
When it comes to recruiting and enrolling a patient, what elements can be a roadblock?
Goldman: There are many different areas that we as investigators need to be sensitive to. I've been guilty of this too many times, where I'm writing a study and want every blood test known to mankind every week because I may look back and find some signal somewhere. Well, that might mean a kid has to come to the clinic and get a blood draw weekly instead of every six weeks. There's this balance between gathering as much data as possible so we don't miss an opportunity to learn something new, and the impact the process is having on a child and their family's life. I'm much less likely to have a family enroll in a study where they have to miss school three times a week for a disease that's not impacting their life on a daily basis.
In meeting with these patients and their families, do you find that a particular communication or education method works better than the next?
Goldman: I do think consent forms should be well-written at the third-grade level and be available in people’s native languages, but that is not a replacement for having someone in the room who speaks that language or is a certified translator. The written materials are helpful supplemental materials because we don't remember half of what we hear, but nothing can take away the importance of a conversation between a healthcare provider and a family. It's really important that clinicians and researchers take the time to sit down to ensure patients and their families understand their diagnosis and the risks and benefits of participating in that clinical trial. And this should happen more than once. For example, if a clinician recommends an acne cream a patient applies for a week of course that conversation is going to be shorter than one for a child who has leukemia or a child who needs to try one form of dialysis over another.
If you ever watched the Peanuts cartoons, when the adults are on, it's always “blah, blah, blah.” And I know once I tell families that their child has a brain tumor, everything else for the next hour is muffled. And that’s why we have to take the time to communicate the message several times, along with providing written materials.
Good communication in general is important, but the best and most important is person-to-person communication. Discussions that are not rushed, not rehearsed, and are just an actual honest conversation. I think that's the most effective way to secure enrollment buy-in from families.
From an investigator's perspective, what do pharmaceutical companies do well or could they do better to support investigators?
Goldman: Ensuring clinicians are involved in the development of trials early on is really key to the best outcomes. In defense of the pharmaceutical industry, it's hard to have a Phase 3 trial ready for 12 different sites, and then I come in and say, “Let's change this.” That slows the process down significantly.
For many of the companies, it's during protocol development that clinicians can have the biggest impact. And that happens.
As for the collaboration between investigators and pharma, we are not against each other. The more we work together, the better off everybody's going to be.
About The Expert:
Stewart Goldman, MD, is an internationally renowned pediatric oncologist and physician-researcher. As senior vice president of research at Phoenix Children’s, he continues to grow a robust research and education enterprise, recruits top talent, and oversees a research program with 700 studies, 640 research investigators, and 90 research staff members. He also leads the department of child health at the University of Arizona College of Medicine – Phoenix, focusing on translational research across all aspects of children and family health to innovate clinical care, advance new therapies for common and rare childhood diseases, and improve the emotional, educational, and cognitive well-being of children. A leader in brain tumor research, his contributions to the medical and scientific communities are significant. He's published more than 150 articles in peer-reviewed journals, has held numerous leadership positions, and has been the recipient of dozens of awards acknowledging his tireless work and research.