FDARA’s Impact on Pediatric Cancer Drugs: Insights From May 2024 ODAC Meeting

On May 22, 2024, the Pediatric Oncology Subcommittee of the Oncologic Drugs Advisory Committee (ODAC) meeting convened to discuss the impact of amendments made by Section 504 of the FDA Reauthorization Act (FDARA) to Section 505B of the Food, Drug, and Cosmetic (FD&C) Act, which was passed in 2017.

Discussion Questions of the Meeting

Please discuss your perspectives on how the 2017 FDA Reauthorization Act (FDARA) is impacting pediatric oncology and development of new molecularly targeted therapies for pediatric patients with cancer. Describe positive effects or challenges associated with the legislation, and thoughts regarding how to improve its implementation.
Please discuss factors that should be considered when determining whether nonclinical proof-of-concept studies should be conducted prior to initiating a molecularly targeted pediatric cancer investigation in pediatric patients with cancer. Also discuss the degree of preclinical antitumor activity that would be considered sufficient to warrant clinical development.
Please discuss the role of pediatric clinical trial networks and international collaboration in efficient development of new medical products for pediatric patients with cancer including identification of relevant molecular targets, specific efforts that have been most valuable, and ideas for improved collaboration. Additionally, please discuss barriers to the conduct of international trials in pediatric oncology and potential ways to address these barriers.

The subcommittee evaluated the implementation of FDARA and how this law affects the need to study certain targeted cancer drugs in children. The law pertains to new drugs with novel ingredients that target cancer on a molecular level, and it only applies to applications submitted after August 18th, 2020. Previously, these drugs were evaluated based on the type of cancer they treated, not necessarily if they would be given to children.

Nicole Drezner, MD, deputy director of the Division of Oncology II at the FDA, noted, "Early indicators suggest that FDARA is positively impacting pediatric oncology drug development. However, challenges remain in leveraging this legislation to enhance efficiency and reduce duplication of studies."

While she acknowledged positive strides, Drezner, as well as other speakers during the meeting, discussed persistent challenges in fully leveraging FDARA to enhance efficiency and minimize study repetition. The need for continued refinement in implementing this legislation emerged as a recurring theme throughout the meeting.

Understanding FDARA and Its Implications

Section 504 of FDARA applies to new drugs and original applications for new active ingredients submitted on or after August 18, 2020. It requires pediatric studies based on the molecular mechanism of a drug rather than the specific type of cancer it targets.

Notably, the FDA determines the relevance of a drug and decides if its target is substantially relevant to pediatric cancer growth. If the target is relevant, a report on the effect of the drug in pediatric cancer is required to be submitted with the marketing application unless waived or deferred by the FDA. This shift aims to address the scarcity of treatments for children under 17 with cancer.

On August 18, 2017, the Research to Accelerate Cures and Equity (RACE) for Children Act was signed into law as Title V of the 2017 FDARA. This law amended the Pediatric Research Equity Act (PREA), Sec. 505B of the FD&C Act, to require molecularly targeted pediatric investigations of certain cancer drugs with new active ingredients.

“[PREA] was enacted to compliment the incentive mechanisms provided by [the Best Pharmaceuticals for Children Act (BPCA)] by requiring sponsors to assess the safety and efficacy of new drugs in pediatric patients prior to the submission of a marketing application seeking a new indication, new active ingredient, new dosage form, new dose regimen, or new route of administration, unless the requirement is waived or deferred,” explained Marjilla Seddiq, MD, Division of Oncology II, Office of Oncologic Diseases, Center for Drug Evaluation and Research, during the meeting.

An initial pediatric study plan (IPSP) is required to be submitted early in development, generally no later than 60 days from the end of a phase 2 meeting. The IPSP should include a description of the planned pediatric studies, pediatric formulations if needed, and a timeline for development. Its goal is to encourage sponsors to identify pediatric studies as early as possible in product development.

Before 2020, PREA had little or no effect in oncology because most applications were either exempt or the pediatric study requirement was due to the adult indication, which did not occur in children. However, FDARA amendments to PREA under the RACE Act were implemented after 2020 to speed up the making of a pediatric development plan, ultimately hoping to lead to the accelerated development of new drugs for pediatric patients with cancer.

Under FDARA Amendments to PREA, reports on a molecularly targeted pediatric cancer investigation are required for drug applications aimed at a molecular target substantially relevant to the growth or progression of a pediatric cancer unless a waiver or deferral is granted.

Deferrals may be granted if adult approval is needed prior to the completion of a pediatric study or if additional safety or efficacy data are required. Full or partial waivers can be granted if studies are impracticable, if the drug is ineffective or unsafe for children, if the drug offers no meaningful benefit over existing therapies, or if pediatric formulation attempts fail. Final decisions on deferrals and waivers are made during new drug or biologics license application approvals.

This requirement applies even if the drug is intended for an adult indication that has received an orphan drug designation. Further, the FDA is required to create, publish, and regularly update a list of molecular targets considered to be relevant and a list of nonrelevant targets to pediatric cancer.

Through the revision, sponsors are now tasked with submitting initial pediatric study plans focused on the drug's mechanism of action and its relevance to pediatric tumors.

"The 2017 revision aimed to address the 2 big challenges in pediatric drug development: firstly, a mechanism of action-based approach for investigating drugs intended for adult cancer treatment, and secondly, focusing on molecular targets relevant to pediatric tumors," said Ruchi Gupta, MS, program director, regulatory affairs, Genentech, a member of the Roche Group, said during the meeting.

While this shift has sparked increased interest in pediatric cancer research, Gupta also discussed the challenges faced by oncologists, including the complexities of study design and the need for clearer regulatory guidance. Furthermore, Gupta and others emphasized the vital role of global collaboration in navigating these challenges and ensuring optimal outcomes for pediatric cancer patients.

“One of the major challenges with the implementation of the RACE Act is the prioritization of molecules with similar mechanisms of action, which has led to complex scientific discussions and challenges aligning on rationale and timing," stated Gupta.

Gupta concluded her part of the presentation with a summary of challenges and recommendations for improvement, emphasizing the need for greater FDA involvement in industry prioritization, transparent processes, streamlined review procedures, and realistic targets for pediatric studies.

Despite challenges, the mandated mechanism of action-based pediatric development under FDARA 2017 encourages proactive integration of pediatric considerations, fostering collaboration and innovation in drug development for pediatric oncology.

Molecular Targets

A key aspect of FDARA implementation involves delineating molecular targets relevant to pediatric cancer progression. The FDA defines a molecular target in cancer drug development as a molecule associated with the malignant disease process, including etiology, progression, or drug resistance.

“There should be evidence that addressing the molecule with a drug produces a measurable effect on a cancer, in vivo or in vitro, which may translate clinically to a favorable objective change in the disease process,” added Seddiq.

The National Cancer Institute and the Pediatric Oncology Subcommittee of the ODAC maintain a publicly accessible list of molecular targets that are relevant to pediatric cancer growth or progression. This list may trigger requirements for pediatric investigations.

However, the FDA can require a clinical evaluation of a drug in the pediatric population even if its target is not on the list. Additionally, there is a separate list of molecular targets deemed nonrelevant to pediatric cancer, such as androgen and estrogen receptors.

According to Ramjay Vatsan, PhD, CQA, Office of Gene Therapy, Center of Biologics Evaluation and Research, determining which cell and gene therapies (CGTs) are molecularly targeted therapies is not always straightforward. There is a wide variety of CGT products under development in oncology.

“The complexity of determining which cell and gene therapy products are directed against molecular targets stems from the complexity of the mechanism of action,” explained Vatsan.

CGTs may work through a mechanism of action that is independent of specific targets on tumor cells, and the mechanism of action may depend on the manufacturing process of an agent. Further, Vatsan explained that when the mechanism of action does not rely on specified targets on cancer cells, the determinations of if a CGT is a molecularly targeted therapy is made on a case-by-case basis.

Mesenchymal stem cells, induced pluripotent stem cells, tissue engineered products, and patient-specific neoantigen vaccines are generally not considered molecularly targeted as they interact with at least 1 specific molecule associated with cancer or normal tissue cells or have an interaction that correlates with activity and tumor killing.

Some CGT products are less straightforward and may or may not be considered molecularly targeted therapies, including oncolytics, neoantigen specific T-cells, and tumor infiltrating lymphocytes.

“CGTs may work through mechanisms of actions that are independent of specific targets on tumor cells. The mechanism of action may vary depending on the manufacturing process,” added Vatsan. “Early interactions with FDA can help sponsors design their IPSP’s for cellular and gene therapy products.”

European Perspective

Representatives from the European Medicines Agency (EMA) discussed the complementary nature of US and European Union regulations, stressing the importance of global collaboration to enhance pediatric oncology outcomes. Dominik Karres, MD, highlighted increased voluntary Pediatric Investigation Plans (PIPs) and the necessity for continuous data exchange to avoid redundant studies.

“Pediatric oncology drug development is and has to be conducted globally. This is widely acknowledged. It requires strong national regulatory collaboration also relating to what constitutes relevant mode or mechanism of action, and despite the differences in relations between the US and the European Union…we have observed an increase in voluntary PIPs,” stated Karres, scientific officer of the Pediatrics Medicines Office of the EMA.

Early data indicate that FDARA has significantly increased planned pediatric cancer studies, with a notable rise in targeted therapy approvals requiring pediatric investigations. Ongoing stakeholder engagement and international collaboration remain vital to maximizing FDARA's impact and improving outcomes for pediatric cancer patients.

Discussion Questions

In response to the first discussion question, the committee highlighted several positive effects, as well as challenges associated with the legislation.

"My sense of the data from the presentations and also my anecdotal experience is that FDARA has certainly increased the attention being paid to developing these agents for pediatric patients," stated Theodore Laetsch, MD, attending physician with the Cancer Center at Children's Hospital of Philadelphia, during the meeting.

Positive effects of the FDARA mentioned include increased attention and development of agents for pediatric patients, potentially leading to more available clinical trials. Challenges included the need for greater transparency, depth in measuring impact, and difficulties in recruiting patients for rare diseases.

The panel suggested improving transparency by potentially making IPSPs public and advocating for earlier collaboration among stakeholders before IPSPs are established. Furthermore, there was a call to better define the term "molecularly targeted therapies" for clarity in discussions.

"Ensuring that we continue to understand what is being called the molecularly targeted agent is in line with the current practice and [it is important] that we continue to evolve that definition," Lia Gore, MD, attending physician and director of pediatric experimental therapeutics at University of Colorado Health Sciences Center, shared.

Overall, while the FDARA has raised awareness and initiated positive changes, it may be too early to fully assess its impact, indicating the need for continued evaluation and refinement of the legislation's implementation strategies.

The committee then moved on to discuss the second question on factors for determining nonclinical proof-of-concept studies and the degree of preclinical antitumor activity sufficient to warrant clinical development. Richard Gorlick, MD, Department of Pediatrics, Division of Pediatrics at MD Anderson Cancer center kicked off the conversation by discussing that the adolescent and young adult population's needs are not fully met by pediatric or adult oncology. He suggested that nonclinical toxicology studies might be less necessary for this group since they tolerate chemotherapy better than both children and older adults.

They discussed preclinical testing where Malcolm Smith, MD, PhD, associate branch chief for the National Cancer Institute, emphasized the importance of robust tumor regressions as a success criterion for preclinical studies. He noted that historical data shows only a small percentage of models exhibit objective responses, which aligns with clinical outcomes.

The committee recognized the limitation of using immunocompromised preclinical models, with Gorlick suggesting the need for models with intact immune systems for evaluating certain agents.

“Most of the preclinical testing that we're doing is in immunocompromised mice…In certain agents, we may have to start considering doing testing in mice that have intact immune systems to better define the activity of some agents,” highlighted Alberto Pappo, MD, head solid tumor at St. Jude Children's Research Hospital, during the meeting.

Overall, the committee agreed that preclinical testing is valuable for identifying promising agents for pediatric trials.

For the last discussion question, the critical role of pediatric clinical trial networks and international collaboration efficiently was discussed in regard to developing new drugs for pediatric patients with cancer. Gorlick started by discussing the need for large collaborations due to the increasingly small subgroups created by molecularly defined diseases.

Some challenges highlighted were linked with information sharing, regulatory differences, and data monitoring. Experts explained that past advances in pediatric oncology have been achieved through collaborative efforts, suggesting there is a need for overcoming barriers to continue making progress with molecularly targeted therapies.

The complexity and costs associated with highly specific trials were also discussed, and the committee determined there is a need for national and international efforts.

Overall, the committee agreed on the importance of breaking down privacy and regulatory barriers and explained that international collaboration is key to help identify treatment response differences among minority populations, which is crucial for advancing pediatric cancer treatment.

Conclusions

This ODAC meeting offered a comprehensive overview of FDARA's impact on pediatric cancer drug development. Significant progress has been made; however, challenges remain and require continuous refinement of regulatory frameworks and enhanced collaboration.

Through prioritizing molecularly targeted investigations, having international collaboration, and ensuring proactive regulatory engagement, FDARA holds the potential to better pediatric oncology care and improve outcomes for young patients with cancer across the globe.