Discussion
Thoughtful drug development and timely assessment of promising novel agents in pediatric patients is critical to public health. Over the years, pediatric cancer drug development has relied solely on BPCA to advance drug development and inclusion of pediatric information in the drug label. FDA has issued 40 Written Requests for oncology products during the study period. In recent years some of these Written Requests were issued to sponsors early in the drug development timeline and before approval. Since BPCA and the Written Request mechanism was the only legislative initiative available to facilitate pediatric investigations, the FDA has attempted to maximize its authority to issue Written Requests as early as possible in a product’s development when there was interest in the pediatric cancer academic and advocacy communities to evaluate the potential activity of certain promising agents. Nineteen drugs have been granted pediatric exclusivity, and 3 received approval for use in specific age groups with the indication(s) in the drug label. Most oncology pediatric trials have been designed to evaluate optimal dose, PK, and both preliminary safety and efficacy. The majority of pediatric trials in response to WRs included evaluation of dose and dose-limiting toxicities of the agent being studied and monotherapy activity. More recent Written Requests that included studies beyond phase 1or phase 2 evaluations were contingent upon data from initial studies demonstrating safety and signal of activity with plans for definitive studies subject to review of and concurrence with protocols by the Agency prior to study initiation. For this reason, most pediatric trials in the WRs are single arm design, especially for hematologic malignancies. Although controlled trials are preferred, they are not feasible to conduct within the context of a Written Request because of the small number of study subjects and the time to completion of complex, randomized studies. Most efficacy endpoints involved overall response rate as assessed by investigators; some studies required response rates to be determined by an independent review committee (IRC).
More pediatric trials are still urgently needed. Accrual challenges remain. Many of the completed pediatric trials over the past 19 years have led to conclusions that the cancer drugs developed for adult cancer indications have not demonstrated sufficient effectiveness within the context of limited phase 1 and/or 2 studies in heavily pre-treated patients.
Because of many challenges in pediatric cancer drug development, innovative approaches should be explored to improve the efficiency of pediatric trials. Since children are a vulnerable population, it is challenging to enroll them in clinical trials where the potential for beneficial effects of investigational drugs may be unclear. Given the uncertainty in drug efficacy and for the protection of pediatric patients, the implementation of futility criteria in the trial design should be considered in future pediatric trials. Trials should stop early if evidence of no efficacy is observed to minimize the number of patients exposed to ineffective therapies. A Bayesian approach is a flexible tool that could be used in pediatric trials to sequentially monitor efficacy and futility as data accumulate [37]. 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 approaches 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 are 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 safety profiles well characterized in adults.
Under the FDA Reauthorization Act (FDARA) of 2017 which incorporates the RACE for Children Act [35], pediatric trials for oncology products will no longer be exempt based on infeasibility related to the adult indication for which the drug is being developed or orphan designation. Early pediatric assessment of dose, tolerability and signal of activity will be required for drugs directed at molecular targets observed in pediatric cancers [36]. Original marketing applications in the US for certain adult oncology drugs that are submitted on or after August 18, 2020, will be required to be preceded by plans for pediatric cancer investigations. Thus, pediatric drug development will finally be coordinated with cancer drug development for adults, as part of an overall drug development plan.
We conducted this review prior to the implementation of FDARA Sec. 504 on the Written Requests issued over a 19-year period to demonstrate differences in requirements and the variable response to those requirements. Overall, this report may serve to guide the planning of future cancer drug development for children and adolescents.