Discussion
Thoughtful drug development and inclusion of pediatric patients in trials is critical to public health. Over the years, because of rarity of pediatric cancer, pediatric cancer drug development has relied on BPCA rather than PREA to promote the development and inclusion of pediatric information into the drug label. Under FDA Reauthorization Act (FDARA) of 2017 and RACE for Children Act [25], pediatric studies for oncology products will no longer be exempt based on orphan designation, and the pediatric studies will be required for drugs directed at molecular targets observed in pediatric cancers [26]. Original marketing applications in the US for certain adult oncology drugs that are submitted on or after August 18, 2020 would be required to be preceded by plans for pediatric cancer investigations. With the change, pediatric oncology drug development should generally be coordinated with oncology drug development for adults, as part of an overall drug development plan.
Before the changes of FDARA and RACE Act take place, we conducted research on the written requests requested through BPCA over 19-year period. This would serve the purposes to study what has been requested over the years and what have been completed in response to the requirements. We consider this to be the anchor of pediatric cancer development for current stage and can potentially provide insight on how pediatric cancer drug development would change for the future years.
Since 2001, FDA has issued 42 written requests in the area of oncology. Among those, 18 drugs have been granted additional pediatric exclusivity, and 4 received approval for use in specific age groups with indication in drug label. Most oncology pediatric trials have been designed to evaluate both safety and efficacy. The majority of pediatric trials in response to WRs included monotherapy activity evaluation. Request over the years has seen that more recent pediatric trials changed to request whether phase 2 studies should be conducted are based on results from the phase 1 study. Most pediatric trials are single arm design, especially for hematology indications. Although controlled trials are preferred, they are difficult to conduct in a pediatric population for ethical reasons. Most efficacy endpoints involved overall response rate and assessed by investigators. Only a few assessed the response rates by an independent review committee (IRC).
More pediatric studies are still in urgent need. Accrual challenge is the main reason for study termination. Many studies terminated because of difficulties with enrollment. On the other hand, many completed trials had the problem of over-accrual. Most of the completed pediatric trials over the past 19 years have led to conclusions that cancer drugs used in adult populations do not work as well in children. Since children are a vulnerable population, it is challenging to enroll them in clinical trials where the effects of these developmental drugs are unclear. Given the uncertainty in drug efficacy and for the protection of pediatric patients, the implementation of futility criteria into the trial design would be recommended in future pediatric trials. Studies should stop early if evidence of no efficacy is observed to minimize the harm to pediatric patients.
Because of many challenges in pediatric cancer drug development, innovative analysis should be explored to improve the efficiency of the pediatric trials. A Bayesian approach is a flexible tool that could be used in pediatric trials to sequentially monitor efficacy and futility as data accumulate [27]. This approach provides an option to stop trials for efficacy or futility if enough evidence is observed, and thus with the advantages of possibly requiring fewer patients and shorter trials. Bayesian approach in pediatric trials can formally incorporate prior information from adults, older age groups, and other external sources if appropriate and quantify the uncertainty. To overcome the limitation of a small population and limited opportunities for extrapolation, an innovative approach using Bayesian strategy to allow more flexibility in statistical design for future pediatric trials should be considered.
Identifying an optimal starting dose remains important for successful pediatric oncology drug development. Modeling and simulation is a powerful tool to inform selection of safe and efficacious doses as early as possible in the drug development process and to avoid overexposing children to subtherapeutic doses. When the disease pathobiology and the mechanism of action for drug would not differ by age, a starting dose may be selected by targeting similar exposure to the adult therapeutic dose without the need to evaluate multiple dose levels. When similarity in disease between pediatric and adults cannot be assumed, a more extensive PK and dose finding study may be required. While traditional designs like the 3+3 and rolling 6 are commonly used for dose escalation, Bayesian designs like the continual reassessment method or adaptive logistic regression design could be preferable, especially for targeted therapies with adult’s safety profile well characterized.
We believe this research provides the sponsors, patient advocate groups, academic groups, and treating physicians on the current landscapes of pediatric studies in support of labeling changes and approved pediatric use of oncology and hematology drugs. Overall, this study will benefit the planning of future drug development in oncology and hematology in the pediatric population.