Pediatric Oncology’s Changing Regulatory Landscape and How to Navigate It
Elly Barry, MD, MMSc, CMO of Day One Biopharmaceuticals, discusses regulatory changes in pediatric oncology, differences in adult and pediatric clinical trials and the benefits of early engagement with the pediatric oncology academic community.
Why have pediatric oncology treatments lagged behind those in adult oncology?
The one basic reason is because the size of the population is much smaller. To put this into context, approximately 2 million adults are diagnosed with cancer every year in the US, compared to 15,000 new cases of pediatric cancer. It’s a fraction in terms of the total number of patients available to conduct clinical trials and ultimately for commercial development.
Development of new cancer medicines takes hundreds of millions of dollars and the business case you build around that investment is typically centered on an adult indication, given the size of available population to study. That has traditionally driven the development path for most cancer medicines. As a result, medicines that could have relevance to pediatric cancers are more or less an afterthought. There are a number of examples where relevant medicines have been approved for adult cancers but not in pediatric cancers.
What are some regulatory changes that have happened with respect to pediatric oncology?
Previously under the original version of the Pediatric Research Equity Act (PREA), when a drug company developed a medicine for any indication, including in oncology, there was a pediatric research requirement in the US, but only when that indication was relevant in the pediatric population. For example, if a company was developing a drug for asthma, because asthma is a condition that occurs in children, drug companies would be required to conduct clinical trials to evaluate their medicine in pediatric patients with asthma. However, most adult cancers, such as colorectal cancer, breast cancer and prostate cancer, do not occur in the pediatric population, and in these cases, the pediatric research requirement was waived because the adult condition did not occur in children. This meant that if a company was developing a breast cancer drug, they would not be required to evaluate that drug for breast cancer in children because breast cancer doesn’t occur in children.
Another previous exception to the pediatric research requirement occurred in orphan diseases, which are defined as a rare disease that affects fewer than 200,000 people in the United States. This definition applies to most hematologic malignancies, which are considered rare in adults, but are the most common malignancy in children. For example, acute myeloid leukemia in adults is considered an orphan disease so drugs developed to treat AML in adults were not required to be studied in children with AML even when the underlying biology was relevant to pediatric patients. Essentially under the “old” PREA, there was no requirement for most of the medicines that have been developed in adults to have been studied in pediatric cancer, even when the mechanism of action of the drug was relevant to pediatric cancer. This gap in the requirement for pediatric studies and access to new therapies became increasingly evident in the era of targeted medicines for genomically driven cancers, where we see medicines have profound benefit across tumor types that share a common genetic driver.
As a result of this gap, important regulatory changes have taken place in the US over the last 5-6 years to mandate research in pediatric cancers. The RACE for Children Act, which was enacted in 2017 and went into effect in 2020, resulted in an amendment to FDARA which now requires drug companies to conduct pediatric research based on the mechanism of action of the drug and not just based on the adult indication. The expectation is that this will result in more of these medicines being studied and evaluated in pediatric indications earlier in the course of drug development, and ultimately to become accessible to children with cancer.
"The RACE for Children Act, which was enacted in 2017 and went into effect in 2020, resulted in an amendment to FDARA which now requires drug companies to conduct pediatric research based on the mechanism of action of the drug and not just based on the adult indication."
This sounds like a similar logic that is used in basket trials.
Yes. When you look broadly across the spectrum of adult and pediatric cancer, you’ll see that some genomic alterations occur in a number of adult tumor types and also in a subset of pediatric cancer types. Many genomic or molecular targets are not exclusive to adult cancer only and can have promise in one or more pediatric tumor types. One example is ALK, which is a driver in a subset of adult lung cancer tumors. ALK also turns out to be a relevant target for neuroblastoma, which is a pediatric disease, as well as anaplastic large cell lymphoma, which can occur in pediatric patients. When we think about targeted medicines, we need to think about the breadth of tumor types where a medicine might have some efficacy.
Are we seeing a similar kind of evolution in the regulatory landscape, for ex-US regulators?
In Europe, there has been a requirement for pediatric research for the last 15 years. That said, even with the European requirement for a Pediatric Investigation Plan, or PIP, to be submitted after completing adult phase one trials, in reality, most PIPs are submitted very late in the life cycle of drug development. This has resulted in a delay in conducting trials in pediatric cancer in Europe. Additionally, the current European requirement for pediatric research is also linked to the adult indication, similar to how it was previously in the United States. This again has resulted in waiving the requirement of studies in children when the indication in adults is not relevant to a pediatric population. The European regulations are also likely to change in the future to follow a mechanism of action based approach as well
How can CMOs better approach regulatory interactions navigating these kinds of changes?
The pediatric oncology academic community is very much tuned in to these regulatory changes and have been working with companies for the last ten years because of these evolving regulations. As companies consider their pediatric oncology development plans, it is important to consult with the academic researchers who not only have access to the patients needed for trials but who are also fairly savvy and have learned a lot about working with industry and regulatory agencies to develop study plans that will fulfill regulatory requirements. I encourage companies to invite investigators to participate in regulatory conversations because they bring a sense about what is feasible and what is the highest priority from a research perspective.
"As companies consider their pediatric oncology development plans, it is important to consult with the academic researchers who not only have access to the patients needed for trials but who are also fairly savvy and have learned a lot about working with industry and regulatory agencies to develop study plans that will fulfill regulatory requirements."
How is the design for pediatric oncology clinical trials different than for adults?
From an ethical standpoint, the trial has to provide a prospect of direct benefit for patients. Because of their age, pediatric patients are not able to provide full informed consent so before you conduct a trial with an experimental medicine, there needs to be evidence to believe that the drug could benefit that patient. This is a different standard than adult Phase 1 trials, where an adult, can provide informed consent for a medicine with unknown benefit that has never been studied before in humans.
Additionally, as I mentioned before, the pediatric cancer patient population is very small. To conduct these trials, especially larger randomized trials, you need a lot of clinical trial sites which in turn require a larger infrastructure to support the study. Working with pediatric oncology consortia and research networks can help expand the footprint of the trial to recruit more patients.
An appropriate pediatric-friendly drug formulation is also an important consideration when planning a trial in children. Not all children can swallow pills. Medicines are generally dosed in children by body-to-surface area, which means the formulation type and dose strengths should be flexible in order to adjust as patients grow over time. Additionally, while children are growing, it is important to consider the potential impact of the medicine on growing bodies, organ systems, and organ function over time. For example, the impact on puberty on drug metabolism or bone development has to be taken into account.
How can biotech companies maximize their chances of developing effective drugs while satisfying new regulations throughout the development process?
Especially with the evolving regulatory landscape, thinking about the pediatric development plan is not something that should be deferred until the last possible moment. If you think about it earlier, there are opportunities to potentially integrate it into the adult development plan or to stage it in a way that de-risks both the chances of success in the pediatric study and also the chances of having an approved pediatric research plan by the regulatory authorities.
Early conversations with both the academic research community and regulators are very helpful. Regulators want to help. They want to eliminate barriers in conducting pediatric research and are willing to have conversations early on. You shouldn’t be afraid to have those early conversations, even before putting pen to paper and coming up with a plan.
"I’ve seen a number of cases where a trial makes sense on paper, but the patient population is so rare as to make the trial unfeasible. That’s why it’s so important to get real data and real conversations from the folks who actually see and treat these patients before you design the trial."
What are some common mistakes made when developing for pediatric oncology?
Not engaging with academic research experts. Designing a trial on paper that you think will meet the regulatory requirements, getting that approved, and then ultimately finding out that no one in the clinical research community will actually support the study is one common mistake. I’ve seen a number of cases where a trial makes sense on paper, but the patient population is so rare as to make the trial unfeasible. That’s why it’s so important to get real data and real conversations from the folks who actually see and treat these patients before you design the trial.
Because the pediatric patient population is relatively small, you have to look at the overall landscape of clinical trials when you’re thinking about a particular study or development plan. You need to think about how your plan might fit into the existing landscape in terms of feasibility and in terms of where this treatment would fit under current paradigms and standards of care.
Anything else?
If you are developing drugs in the oncology space, think about the regulations and plan for pediatric development early on. This can lead to development efficiencies. There is a community of researchers and regulators who are eager to engage early on.
