Flexibility Required: Balancing the Interests of Children and Risk in Drug Development for Rare Pediatric Conditions

There exists a standard approach to developing drugs for adults. The process begins with animal studies focused on toxicity, followed by phase I safety and dosage studies in humans, phase II efficacy and side effect studies, and finally, phase III effectiveness studies, all before a drug can be approved for use (FDA 2018b). Historically, most drugs were only approved in adults, and were used in children “off label.” More recently, a series of laws (Pediatric Research Equity Act and Best Pharmacutical for Children Act) have encouraged researchers and drug manufacturers to study those drugs in children as well (FDA 2018a). For common conditions that can affect both children and adults, such as asthma or hypertentsion, safety, and efficacy studies are first completed in adults and pediatric drug research then begins with efficacy studies. The reason for this is that the FDA regulations require that research on children that is more than minimal risk have the prospect of direct benefit, and phase I/II adult studies can provide evidence of this potential benefit. In general, this process works effectively because of the large number of potential participants, researchers, and drug manufacturers focused on common conditions.

However, there are some diseases that do not appear in the adult population at all, for example medical conditions that are exclusively within the realm of neonatology or pediatric conditions for which life expectancy does not reach adulthood. Drug research does exist in these contexts, taking a modified approach that begins with safety studies involving very small numbers of children and then progressing to efficacy studies. As an example, pre-clinical (animal) evidence suggested that, when started immediately after birth, erythropoietin could have a neuroprotective effect on the cognitive development of infants who are born prematurely. Human research began with a safety study of 30 infants receiving the drug intervention at varying doses, followed by an efficacy study (Juul et al. 2008).

Drug development for rare pediatric diseases frequently struggles to fit into the standard adult-first model. In these cases, there may be justifiable reasons to forgo this adult-first approach and develop a process, similar to that used for conditions that do not appear in adults, that still protects children while simultaneously allowing for a more efficient process to study possible therapeutic drugs. However, this case (Johnson, Duenas, and Wilfond 2020) was reviewed by the FDA with the standard adult-first approach in mind.

The FDA indicated a preference that, rather than conduct a safety study in children, researchers further evaluate the drug in adults, and then, when there is more evidence of efficacy, conduct a phase I/II safety-efficacy study in children. We argue, however, that there are compelling reasons to deviate from this adult-first approach for this drug development study for pediatric-onset lupus. First, for many rare diseases, as with Systemic Lupus Erythematosis (SLE), affected children have limited clinical options. While some rare diseases do not affect adults at all, in others, such as SLE, the biologically-driven adult experience differs significantly from the pediatric experience (i.e. growth, immune developmental stage, genetic load), thereby potentially warranting different interventions and also diminishing the relevance of adult-focused research. Second, even if adult research is warranted and relevant, subjectivity exists in terms of the amount of efficacy evidence from adult studies considered adequate to move forward with pediatric clinical trials. For this particular case, there is evidence of efficacy for low dose IL-2 in adults with SLE and other autoimmune conditions in single-arm studies and case reports (He et al., 2016; Humrich et al., 2015; Humrich et al., 2019; von Spee-Mayer et al., 2016) and yet the FDA did not find it to be sufficient, despite the fact that the adult experience differs from the pediatric experience and therefore may not be as relevant as might be desired. Third, the number of potential research participants is very small and the number of researchers interested and qualified in leading relevant studies is also very limited. For many rare diseases in children, the research is less commonly initiated by large drug manufacturers with exhaustive resources and more frequently by clinician scientists who primarily care for children and work with limited financial research resources. An expectation for these pediatric clinician scientists to conduct adult efficacy studies, for what is essentially a different condition, is likely not practicable.

To be clear, it is necessary for the drug development process to avoid exposing children to unnecessary risk. However, interpretation of the FDA regulations is widely variable across IRBs (Shah et al. 2004). There is subjectivity in the interpretation of relevant terms such as “minimal risk” and “minor increase.” In considering what risk falls within a minor increase over minimal risk, one should consider the perspectives of those with an intimate knowledge of the disease and it’s impact on daily life, such as physicians, patients, and families. This better assures that all risks associated with living with inadequately treated SLE are considered. This is not to say that parents should be making risk determinations, but these parties are all important stakeholders in considering the real-life impacts of the interpretation of regulatory terms.

Because of the subjective nature of what is meant by a minor increase over minimal risk it is possible that some drugs, such as low dose IL-2 where risk appears to be modest, could meet the threshold to permit an initial safety study. Additionally, because of the subjective nature of risk, there is great value in seeking out the views of the families of children living with these conditions. When few good clinical options exist, the priorities of families to find effective treatments should hold some weight. Parents may believe that it is in the long-term interest of their children, as well as other children with the condition, to allow the initiation of safety studies in children for drugs with a reasonable adult safety profile, when there is at least moderate evidence of efficacy in adults, rather than delay research to develop treatment. One of the authors (AS), conducted a focus group of parents and patients with pediatric onset SLE who shared that they supported this view.

Finally, as proposed in this case, a safety study in a small cohort of children exposes fewer children to risk than does beginning with a larger phase II efficacy study, such as was proposed by the FDA. Because the biology of SLE in adults is different from that of children, more adult safety and efficacy data still may not decrease the possibility of unexpected safety signals in either a pediatric safety study or a pediatric efficacy study. Thus, beginning the pediatric research with safety in mind and subjecting a smaller number of children to potential risk has merit.

There are good systems in place for the protection of pediatric human participants in research, but real life situations shed light on the potential limitations that come from strict interpretation of regulations without any flexibility. Sometimes, interpretation should include the intent of the rules and consider what is in the best interest of children struggling with a devastating disease. If the ultimate goal of drug development for pediatric SLE is to help children quickly yet safely, stepping away from the standard adult-first approach and instead modeling a drug development approach on that used for conditions for which there is not a comparable adult counterpart could better facilitate the drug development process for rare pediatric conditions such as pediatric SLE. This pediatric-only approach could be better for children and their families, as well as more feasible for the researchers dedicated to helping these children, while still ensuring adequate safety for the pediatric research participants.