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.