ODAC Discusses Dose Optimization of New Drugs for Pediatric Patients With Cancer


The FDA’s Oncologic Drugs Advisory Committee discussed the potential need for interpreting pharmacology data, using trial designs that compare multiple dosages, and safety and tolerability assessments to help determine the optimal doses of oncology drugs for pediatric patients.

The FDA’s Oncologic Drugs Advisory Committee (ODAC) met on June 16, 2023, to discuss considerations for dose optimization of new drug and biological products for pediatric patients with cancer.

The considerations discussed during the meeting include the potential need for collecting and interpreting pharmacology data, using trial designs that compare multiple dosages of drugs, and further safety and tolerability assessments.

Dosage optimization is an integral aspect of oncology drug development as it helps to maximize the safety, efficacy, and tolerability of new drugs, especially when used in pediatric patients with cancer. Currently, the majority of pediatric cancer drug development occurs with drugs being developed for adult patients with cancer.

Due to the rarity of pediatric cancers, unique considerations are associated with dose selection and optimization, including variability in pharmacokinetic (PK) and pharmacodynamic (PD) parameters by age and size, the need for age-appropriate formulations, and the potential for toxicities associated with long-term use.

To address the concerns and considerations of dosage optimization in pediatric oncology, the committee and FDA came together to discuss possible challenges to identifying an optimized dosage for new drugs and potential strategies to address challenges for pediatric patients. Additional discussion topics were on considerations for the timing of dosage selection in adults, impacts on timing of trial initiation and dose optimization in pediatric patients with cancer, and considerations for dosage optimization in pediatric oncology clinical trials investigating combination therapies.

Martha Donoghue, MD

Martha Donoghue, MD

“The goal of today's meeting is not necessarily to come up with a consensus on the best way to optimize the dosage of new biological products to treat pediatric cancers, but rather to have a better understanding of each others perspectives to enhance communication and collaboration in future efforts, understanding that a one-size-fits-all approach is not appropriate or possible,” said Martha Donoghue, MD, associate director for pediatric oncology, oncology center of excellence, office of the commissioner, office of oncologic diseases, and office of new drugs, CDER, FDA, during the meeting.


Historically, dose-finding trials utilizing dose-expansion and -escalation portions have been designed to determine the maximum tolerated dose (MTD) for oncology drugs based on an evaluation of dose-limiting toxicities. Using increasing doses given to patients for a short period of time each, investigators determine MTD. Then, subsequent clinical trials administer the MTD, or a dosage close to the MTD, to further optimize the dosage.

Despite the progress made across cancer types over the past few decades, most advanced cancers remain incurable with high unmet medical needs for effective and tolerable therapies existing.

Kristin Wessel, MD

Kristin Wessel, MD

According to Kristin Wessel, MD, this approach was developed to evaluate cytotoxic chemotherapy. For cytotoxic drugs, there is generally a proportional relationship between the toxicity and efficacy of an agent. However, targeted therapies do not always have a proportional relationship between efficacy and safety. Instead, there can be a range of doses of targeted therapies where increasing the doses does not increase efficacy, but does increase toxicity. Therefore, a lower dose may provide more benefit in pediatric patients by allowing for a good benefit/risk balance.

Because there are differences between cytotoxic chemotherapies and molecularly targeted agents, including their dose response, amount of cycles for treatment to be given to patients, toxicities, and more, the FDA supports modern approaches which can help identify doses of drugs that can be used in later trials.

FDA Perspective

The FDA believes that it is important to discuss dosage optimization, especially at this time in pediatric oncology, as it is essential to prolong life and cure patients, while also decreasing the risks associated with treatment.

“Identifying the optimized dosage is particularly crucial for pediatric patients in order to minimize the risk of incurring late effects of treatment that can adversely impact health and quality-of-life,” said Wessel, division of oncology 2, during the meeting.

Over recent years, there has also been increasing recognition that the more is better paradigm that has been used for decades with cytotoxic regimens is not necessarily the best approach. With this, there has recently been a shift within the pediatric oncology treatment landscape from cytotoxic chemotherapies to more targeted therapies.

Due to the rarity and unique considerations needed with pediatric patients with cancer vs adult patients with cancer, the FDA also believes that it is important to create tailored approaches for their patients to best optimize dosages, without impeding drug development.

Some considerations the FDA recommends when identifying the optimal dose in pediatric oncology is to look at pharmacokinetic (PK) and pharmacodynamic (PD) variability by age, organ function, body weight, and body surface area, the formulation of the agent, the long-term effects on growth, cognitive, and sexual development, and to be thoughtful on how dose optimization is implemented into clinical development.

To aid in identifying optimal doses for oncologic drugs, the FDA recommends there be collection and interpretation of clinical PK, PD, and 100 pharmacogenomic data, trials with designs that compare multiple doses of drugs, and the assessment of safety and tolerability.

“The totality of information, including the relationship between dosages, exposure, activity, efficacy, safety, tolerability, pharmacokinetics, and pharmacodynamics should be evaluated throughout drug development,” added Wessel.

Clinical Pharmacology Considerations

According to the FDA, a totality of data is needed to inform dosing in pediatric oncology. First, dose-finding trials should be added to guidelines to include PK sampling and an analysis plan such that PK data are of sufficient quality and quantity to allow an adequate characterization of the PK for a given drug, following the administration of multiple dosages. The PK sampling and analysis plan should also be sufficient and support population PK and dose- and exposure-response analyses for safety and efficacy. Once a dose-finding trial is completed, population PK and exposure-response analyses data should be evaluated along with the anti-tumor activity, safety, and tolerability data to select the dosage(s) that should be used for further evaluation.

When evaluating oral drugs, the FDA notes that the effect of food on PK and safety should be evaluated early in drug development as this can support the relative administration of the dose selected to be evaluated in any given registration trial that may use food.

Within the clinical trials themselves, the FDA explains the importance of enrolling a broad population to allow assessment of the dosage(s) across relevant subpopulations. Then, population PK data should be evaluated to identify specific populations. These specific populations can be defined based on weight, age, sex, race and ethnicity, or organ impairment, and help to show which PK data demonstrate clinically meaningful differences in exposure.

Additionally, there should be relevant covariates incorporated into the exposure-response analyses in order for investigators to identify potential differences in safety or efficacy depending on the subpopulation evaluated. Alternative dosages for relevant subpopulations should also be incorporated into a registration trials when feasible, and sampling and analysis plan for PD and pharmacogenetic data should also be considered. Once completed, the proposed sampling and analysis plans are recommended to be submitted to FDA for review.

Trial Designs

Within clinical trials, the FDA notes that multiple dosages should be compared to assess their activity, safety, and tolerability. Through evaluating multiple dose-levels, it can aid in decreasing uncertainty with identifying an optimal dose for a marketing application. According to the FDA, dosages should be selected based on nonclinical and clinical data which provide an understanding of dose- and exposure-response relationships for activity, safety, and tolerability.

Before a trial is initiated which compares multiple dosages directly, more patients may be added to dose-level cohorts in a dose-finding trial which are being considered for further development to allow for more activity and safety assessments.

It is recommended that the trial be designed to compare these dosages using a randomized, parallel dose-response trial. When it is feasible, the FDA recommends using randomization to ensure that similar patients receive each dosage and interpretability of dose- and exposure-response relationships. Additionally, the size of the trial should allow for sufficient assessment of activity, safety, and tolerability for each dosage, and it is not necessary that the trial be powered to demonstrate statistical superiority of a dosage or statistical non-inferiority among the dosages.

When a registration trial contains multiple dosages and a control arm and is designed to establish superior efficacy of one of the dosages compared to the control arm, the trial design should provide strong control of Type I error. The analysis plan should specify a multiple-testing procedure which accounts for testing multiple treatments versus a control as well as any interim assessments after which an inferior arm is dropped. If safety and efficacy data from multiple dosages will be used to support a marketing application, this approach should be discussed with FDA early in clinical development.

Safety and Tolerability

Across multiple doses, investigators should compare the duration of exposure, proportion of patients able to receive all planned doses, the percentage of patients that require dosage interruptions, dose reductions, and drug discontinuations for adverse events (AEs), and the percentage of patients with serious AEs to help determine the optimal doses of drugs.

Trial designs should include dosages associated with a high percentage of dosage modifications or serious AEs, and protocol should state what action will be taken if the percentage of dosage modifications or serious AEs is too high. These actions may include pausing the trial and allowing the safety monitoring committee to review these AEs, changing the starting dosage for future patients, and/or discontinuing the trial.

To best optimize the dose of therapies for pediatric patients, specific AEs, even those that are low-grade, may still significantly affect a patient’s ability to remain on the drug for extended periods. Furthermore, the frequency and impact of such reactions should be assessed and considered when being selected as a dose for subsequent clinical trials.

Since some drugs may be associated with early-onset, serious, or life-threatening toxicities, there should also be evaluations of alternative dosing strategies, including stepwise dosing to improve tolerability. Patient-reported outcomes (PRO) can also provide an assessment of expected symptomatic AEs, so PROs should be considered to enhance the assessment of tolerability in early phase dosage finding trials.

Drug Formulation

As for the formulation of agents, there should be various dose strengths available and evaluated in clinical trials. Different dosages may be needed in different disease settings or oncologic diseases as there are differences in tumor biology, patient population, treatment setting, and concurrent therapies when the agents are used in combination regimens

Strong rationale for choice of dosage should be provided before initiating a registration trial(s) to support a subsequent indication and usage, especially for oncologic diseases not adequately represented in completed dose-finding trials or for 213 new combination regimens. If sufficient rationale for choice of dosage cannot be 214 provided, additional dose-finding should be conducted.

The FDA also notes that there are unique considerations regarding dosage selection and optimization in pediatric patients with cancer, including variability in PK and PD parameters by age and size, the need for age-appropriate formulations, potential for toxicities associated with long-term use in children across stages of development, and the rarity of pediatric cancers.

There is also an interest in studying new drugs and biological products in combination with treatment regimens that are already established and used as standard of care, or other novel therapies to address potential drug resistance mechanisms and maximize the potential for meaningful antitumor activity.


Some common misconceptions are that the identification of optimized dosages are needed in adults prior to the commencement of studies in pediatric patients. However, this is not the case, and drugs with the potential to benefit pediatric patients with cancer should begin to be studied as early as possible. If there is sufficient information and preclinical data available, first-in-human trials for pediatric patients can occur.

There also is a question of whether a pediatric monotherapy recommended phase 2 dose should be established before evaluated in combination regimens. However, this is not necessary.

“Early data from monotherapy can help support an appropriate starting dosage for combinations taking into account the potential for overlapping toxicities and drug interactions,” added Wessel.

Finally, the FDA acknowledged the concern that dosage optimization may not be feasible in pediatric and rare cancers. However, they believe that it is possible to incorporate the principles of dosage optimization while tailoring to specific development programs. They note that there cannot be a one-size-fits all approach and that dosage optimization may look different based on specific populations and development programs.

"We as a community have mant areas that we agree in respect to dosage optimization for pediatric oncology. Recurring themes include that early initation of clinical trials of drugs that hold promise for pediatric cancers in pediatric patients is very important, and should not wait until the dosage is optimized for adults. What is important is the timing and we have the assurance there is a prospect of clinical benefit in pediatric patients, and we have what we need for possible to identify the starting dose that will be potentially therapeutic in pediatric patients in order to provide that clinical benefit," concluded Donoghue.

Oncologic Drugs Advisory Committee (ODAC) Meeting. FDA website. June 16, 2023. Accessed June 16, 2023. https://www.fda.gov/advisory-committees/advisory-committee-calendar/june-16-2023-pediatric-oncology-subcommittee-oncologic-drugs-advisory-committee-meeting-announcement