FOCUS In Sound #31: Florence Bourgeois
Welcome to FOCUS In Sound, the podcast series from the FOCUS newsletter published by the Burroughs Wellcome Fund. I’m your host, science writer Ernie Hood.
In this edition of FOCUS In Sound, we meet a Burroughs Wellcome Fund grantee who is researching issues related to the inclusion of children and adolescents in clinical trials. She has also recently published an important international study of pediatric COVID-19 patients.
Dr. Florence Bourgeois is an Associate Professor of Pediatrics at Harvard Medical School and a faculty member in the Division of Emergency Medicine and the Computational Health Informatics Program, or CHIP, at Boston Children’s Hospital. She is a graduate of Yale University and Washington University School of Medicine in St. Louis. She was an NRSA research fellow and earned her Master in Public Health degree from the Harvard School of Public Health.
In 2017, Florence received an Innovation in Regulatory Science grant from the Burroughs Wellcome Fund titled “Pediatric regulatory policy: advancing timely and rigorous evaluation of medicines for children.” The award was for up to $500,000 over five years. She has published several studies in the regulatory policy area, and this year she and her colleagues put out their work using electronic health records to track and analyze international trends in hospitalizations for children and youth with COVID-19.
Florence Bourgeois, welcome to Focus in Sound…
Thank you, thank you for having me. I’m delighted to be able to speak with you today.
Would you sketch the broad outlines of the pediatric COVID-19 study for us?
Absolutely. This study was a product of a large consortium that came together fairly rapidly at the beginning of the pandemic, so last March and April, leveraging existing infrastructure to be able to aggregate electronic health records across institutions. And not just institutions within the U.S., but internationally. And this presented a terrific platform to be able to look at pediatric patients in particular, since COVID-19 fortunately has had much lower morbidity and mortality in children. But this also means that the patient population that is accessible to us for study is much smaller. So we were able to take an international perspective to characterize the clinical presentation of COVID-19 across hospitals in a number of countries, and also demonstrate this type of large-scale, informatics approach to aggregating data in a rapid fashion, which is particularly important during the evolution of a pandemic like COVID-19.
What conclusions did you reach?
So we were able to find certain clinical features that were specific to patients with COVID-19, in terms of complications, as well as certain laboratory abnormalities, and we were also able to find that the data quality that we were able to produce using this approach was quite robust. So we are continuing additional studies now leveraging the same resource to dig into other aspects of COVID-19 specifically for kids.
How did the study advance our understanding of epidemiological and clinical features associated with COVID-19 in children and youth?
One of the findings was that there were abnormalities in coagulation in children. So that is a specific feature that has also been corroborated in other studies. So that would be one specific result. And another one is the complications we saw around cardiac rhythms, disturbances in cardiac rhythms, and also around seizure activity, as an example. So identifying those specific clinical features is another data point to guide further research.
During the pandemic, many of the skeptics have been spreading the misinformation that COVID did not affect young people and children. Although rates and severity of infections have been lower, they are far from immune, aren’t they?
That’s right. And in addition, not only can kids certainly be infected with SARS-CoV-2, so COVID-19, but they also have very specific and unique phenotypes. So for example, multi-system inflammatory syndrome is a phenotype or a disease presentation that we’ve uncovered that is very specific to children and not seen in adults. So understanding those disease presentations and being able to study them is certainly important. And beyond that, we’re concerned not just about kids being infected with COVID-19, but also their role in transmission and as vectors in the population and in the communities. So that’s another important factor to keep in mind, even if fewer kids are actually affected.
So Florence, what are the wider implications of your findings?
From this specific study, I think that one major takeaway is not even the actual clinical results, but really the methods themselves; this informatics approach to creating a network across institutions, across health care systems, and countries even, in order to characterize COVID-19. This could be extended beyond just our research question that we were addressing around COVID-19 to other conditions and diseases. So it really represents a platform of sorts on which we can build future investigations.
Have you been able to use these methods to address vaccination rates?
That’s a great question. That is not something we’ve tackled, and we’re still understanding exactly how we might be able to incorporate vaccination rates, but certainly it’s critical that we understand the importance of vaccination in kids, since there has been quite a delay in terms of vaccinating kids versus adults. So it’s only since March 10 that the FDA approved vaccination for kids down to 12 years of age, so there is a large portion of our children in the U.S. right now who are obviously unvaccinated.
You also assessed laboratory results as part of the EHR work, as you mentioned. What kinds of trends did you see in that data?
The biggest one was around coagulopathies. Those are the laboratory measures we use to measure something like blood clots. And we found abnormalities in those in particular. And again, this has been seen in other reports as well. So it’s a nice confirmation of other studies and provides a basis for future investigation to understand the pathophysiology behind those abnormalities.
Will the methodologies your group used in this study serve as a model for future research efforts?
Part of the underlying informatics infrastructure was already in place, which is what allowed the team to very rapidly repurpose it towards COVID-19. In April already, they had tens of thousands of hospital records already on patients across a network of institutions, which is quite remarkable. So the innovation wasn’t so much maybe in the basic features of the infrastructure, but certainly in the rapid repurposing and then further development specific to COVID-19.
Did the hospitalization rates for children and youth in the 6 countries mirror population-level infection rates?
That is a terrific question, and actually one of the findings that we highlight in our paper is that indeed, with this network we were able to mirror some of the national or population-level disease rates. So what this indicates for us is that using these computational methods we can do some level of surveillance that can in fact complement other types of surveillance that are done, for example through the CDC or other government agencies. So this can be another approach or another tool to monitor population-level infection rates.
What about clinical treatments? Were the approaches used in the pediatric population similar to those in the adults?
They were not, which wasn’t actually a surprise to me. Beginning in the first weeks and months of the pandemic, there was a lot of exploratory use of a number of therapeutics that we saw in adults. And parallel to that, there were a number of therapeutics such as remdesivir that were entering clinical trials and being developed for use in adults. For kids, all of the repurposing of existing drugs and exploratory use would be very much off-label. And so as clinicians we tend to be more hesitant to use drugs in ways that have not been established in terms of safety or efficacy already in adults. So it wasn’t surprising to me that there wasn’t widespread use of a number of those types of exploratory therapeutic approaches. What I think was more remarkable, though, is that there were very few children who for example received remdesivir, which is a drug that was quite promising, or there was a lot of hope that this would be an effective treatment early on. And the reason that kids were not receiving remdesivir was primarily due to the fact that they were not eligible for enrollment in clinical trials. So, many adults had access to remdesivir through clinical trials, but for children, they needed special types of permission in order to be eligible to receive remdesivir.
Florence, that brings us to your long-term work in regulatory issues regarding pediatric populations. I know that was the topic for which you received the Burroughs Wellcome Fund Innovation in Regulatory Science Award in 2017. How has that funding impacted your research?
The Burroughs Wellcome Fund award was really instrumental in allowing me to establish this discipline, or pediatric regulatory science specifically. And it’s allowed me to really dive into this and create a community in empiric research studies around this topic. At Boston Children’s Hospital, I established the Pediatric Therapeutics and Regulatory Science Initiative as a focal point to create a community and to spur research around this specific topic, and then I subsequently also took on a role as co-director of the Harvard/MIT Center for Regulatory Science, where I also work on a focused group of pediatric studies, again around regulatory science.
So are you seeing any movement toward more inclusion of children and young people in clinical trials by pharma?
Absolutely, and I think in large part this is due to two legislations that were passed now almost 20 years ago, the Pediatric Research and Equity Act, which was passed in 2003, and the Best Pharmaceuticals for Children Act, which passed in 2002. Both of these legislations were specifically designed to increase the amount of pediatric research for drugs and biologics. While there have been some limitations to their implementation and to the degree of research and certainly labeling of products that we’ve seen, they have changed the entire approach taken in term of how pharma thinks of and plans and times their pediatric studies. So I think that there has been substantial change related to those legislations, but I would say there is still a lot of room for improvement.
What has made the industry and FDA so reluctant up to this point?
Historically, the attitude really has been that we should be protecting children from research, as opposed to using research to support their care and to benefit them. So I think it’s taken a long time to reverse that attitude and to design approaches that are safe and are maximizing the benefits of any research for children. Of course we don’t want to start any product development in pediatric populations. Typically, we want some safety and maybe even some efficacy data from adult populations, but the exact timing of when the benefit/risk balance points towards inclusion of children, that’s where there’s still some room to move, and where there is still some debate.
What is the current regulatory situation?
We’re still largely dependent on these two legislations that I mentioned, and they haven’t evolved too much. So unfortunately one of them has a lot of carve-outs or exceptions and delays, which limits its impact a little bit. And the other one, the BPCA, the Best Pharmaceuticals for Children Act, is limited because it’s only an incentive mechanism, so pharmaceutical companies can choose whether or not to respond to a request. So I would say that we have two good legislations in place, but what we really need is ongoing, data-driven approaches or assessments for how they can be strengthened. So where there are still gaps, where there are loopholes, if you want to use that term, so that we can better incentivize and also mandate certain types of pediatric studies.
And that’s where you and your colleagues come in, right?
That’s right, exactly. So what we’ve tried to do is take all the data that’s been generated since the implementation of these policies and perform comprehensive analyses of the progress to date to we can try to pinpoint the specific shortcomings and areas where additional efforts are needed.
Florence, thanks for taking the time to speak to us. We wish you the best for continued success.
Thank you so much for having me today, Ernie, it was a pleasure speaking with you.
We hope you’ve enjoyed this edition of the FOCUS In Sound podcast. Until next time, this is Ernie Hood. Thanks for listening!