FDA’s ODAC Discusses Framework for Decision-Making in Pediatric Assessments

During the first day of a recent Oncologic Drug Advisory Committee (ODAC) meeting, the Pediatric Oncology Subcommittee discussed how to develop a framework to inform the decision-making of the FDA regarding the required pediatric assessment of new drugs.¹

The framework is intended to help guide the FDA and the European Medicines Agency (EMA) at times when multiple products are being developed simultaneously or when a new same-in-class product emerges. This could be during or following the pediatric clinical investigation of another product.

Members of the committee addressed the need for a consistent and transparent approach to developing a conceptual framework on sponsor plans as well as requests for waivers of early pediatric investigations of molecularly-targeted cancer drugs and biologics.

Previously, the Pediatric Research Equity Act (PREA) was created to protect children during mandated clinical investigation to make sure the safety and efficacy of a drug resulted in advances for various diseases which occur in children and lead to the development of drugs. However, it has had no impact on providing new treatment options for children with cancer.^1,2

This is due to the fact that orphan designations cause new drug applications to be excluded from PREA requirements. Additionally, waivers from the requirement for pediatric assessments were permitted for drugs intended to treat cancers found in adults that either occur rarely in children or not at all. Examples of these cancers include breast and lung.

To address this unplanned exclusion of some patients and cancer types, the Research to Accelerate Cures and Equity (RACE) for Children Act was signed into law on August 18, 2017. The act requires the evaluation of new molecularly targeted drugs and biologics, intended for the treatment of adult cancers and directed at a molecular target substantially relevant to the growth or progression of pediatric cancer, when it is subject to an initial new drug application or biologic license application.^1,3

The molecularly-targeted pediatric cancer investigation is a clinically meaningful study using formulations, regarding dosing, safety, and preliminary efficacy, to inform potential pediatric labeling. The study, described in the Agreed Initial Pediatric Study Plan (iPSP), had its data included as part of planned application and aims to lead to the elimination of orphan exemption for pediatric studies for cancer drugs directed at relevant molecular targets.¹

Experts noted that RACE was able to positively alter the regulatory landscape for cancer drug development for children and have a global impact because of its close alignment of decisions of EMA Pediatric Investigation Plans (PIPs) and FDA iPSPs.

Waiver considerations discussed during the meeting for agents directed at relevant targets included consideration for full or age-dependent partial waive, feasibility and practicability of small study populations to be addressed by limiting study requirements, creating new and innovative study designs, and having multiple in class products without compelling evidence of substantial differences in efficacy, safety, pharmacokinetic, or formulation to warrant additional pediatric studies. As of August 18, 2020, a total of 16 agreed plans for full waivers for same-in-class products have been made.

With the goal of the FDA and EMA working together to develop a consistent contextual framework with input from relevant stakeholders to help when making decisions in this space, the Subcommittee experts shared their thoughts on what amount of sufficient data should be included by sponsors to address the features discussed in iPSPS to inform assessment and decision-making. Further, the features that should be considered in decision-making about waiving requirements to investigate multiple same-in-class drugs was brought up.

“It seems very pertinent in same class drugs given the data flow will be different on different drugs if there is a good drug in adults in tumor setting x, if it is inactive in multiple places in pediatric settings that are logical as well as a second one. I think the lack of pediatric activity regardless of comparative adult efficacy is a big driver,” Albert Kraus, global regulatory portfolio lead, oncology, Pfizer, Inc, said during the meeting. “Often, we are doing multiple tumor types in the initial trials so it might not just be the first one, but it might be a couple of same class drugs that are not having success in areas we hoped.”

When discussing unmet clinical needs in a specific disease context, the members of the Subcommittee generally agreed that those needs should not significantly influence the decision to grant waiver requests for pediatric studies of multiple same-in-class novel agents. While members believe unmet needs should not be forgotten completely, several noted other factors that should be balanced with unmet clinical needs including the rarity of the disease, the feasibility of investigations, toxicity profile of the agent, disease prognosis, and degree of efficacy.

It was also agreed by a majority of the Subcommittee members that when available, both comparative efficacy and comparative toxicity data results of same-in-class agents in adults are important when evaluating more than 1 same-in-class agent in children.

“It's critically important, especially for these patients. All of those factors play a huge role both in terms of the our ability to effectively use those agents over the long term, our ability to ethically conduct clinical trials in the shorter term, and to identify based on the example for central nervous system [CNS] penetration particular drugs for particular populations, I think this is absolutely critical,” said Will Parsons, MD, PhD, deputy director at Texas Children's Cancer and Hematology Centers.

Subcommittee members added other thoughts including how the limited availability of data may play a role in the decision to evaluate more than 1 same-in-class product in children, and how anaplastic lymphoma kinase (ALK) inhibitors are a good example of showing the importance of comparative efficacy results in both adults and children.

Additionally, another Subcommittee member stated that by understanding biological similarities and differences in adult malignancies vs in childhood malignancies can be helpful. Seeing the comparison between these age groups in certain diseases may show the relative efficacy to be similar. Regarding toxicity and for comparative toxicity data, other members of the Subcommittee believe that experts should also consider the relevance of certain toxicities that are seen especially in children.

Most experts agreed and believed that product quality indicators, dosage forms, and route of administration, were important in terms of clinical benefit considerations and making the decision to investigate multiple same-in-class products. Multiple experts brought up additional factors to watch out for including, drug-drug interactions, CNS penetration, dosing schedule, frequency of administration, palatability, and the potential for agents to be administered in combination with other therapies.

When discussing the importance of non-clinical efficacy data on whether pediatric investigations of more than 1 same-in-class products are warranted in children and whether pre-clinical studies in pediatric-specific models should be necessary, Subcommittee member, Ira J. Dunkel, MD, explained that clinical data is more important than pre-clinical data in determining whether pediatric investigation of more than 1 same-in-class product is warranted in children.

“The clinical data certainly would be more important than the preclinical data. If there were relevant pediatric clinical models demonstrating significantly different efficacy and/or toxicity, I think that should be taken into consideration,” stated Dunkel, pediatric oncologist, Memorial Sloan Kettering Cancer Center.

Julia Glade Bender, MD, another Subcommitte member agreed that clinical data is more important than pre-clinical data. She added that non-clinical data can be helpful when discussing pediatric tumors deemed to be rare.

“Clinical data should trump pre-clinical data. But in that space where we discussed very rare tumors where the opportunity to study multiple agents will be very difficult, I think the non-clinical data is very helpful. For example, there are very few pediatric patients with ALK mutations, and I think the pre-clinical data on neuroblastoma and certain ALK-mutated neuroblastoma contributed significantly to moving forward some of the newer agents in class. This helps us with the rare disease issue,” added Glade Bender, pediatric oncologist, vice chair for clinical research at Memorial Sloan Kettering Cancer Center.

Lastly, Subcommittee members discussed specific pharmacological parameters they believe should be considered when decision making as well as the importance of CNS penetration when primary CNS tumors may be of interest. Answers for this primarily focused on the fact that CNS penetration is important and should be considered when evaluating the need for pediatric investigation of more than 1 same-in-class agent.

Dunkel added his thoughts on CNS penetration by explaining how it should be considered more broadly with any available clinical data in regard to drug efficacy.

“The converse could also be true. For a drug that has central nervousness or a class of agents that has potential CNS toxicity, if the disease of that being considered is not one with CNS metastatic potential or not a primary CNS tumor, that lack of blood brain barrier penetration could be advantageous. It could work in both directions,” stated Dunkel.

Moving forwards, the Subcommittee will attempt to put together a guidance to better inform investigators on what is to follow in regard to evaluating the decision making with respect to early planned requests for waivers using their discussion on unmet needs, pharmacological parameters, sufficient data, and more.

Reference:

Oncologic Drugs Advisory Committee (ODAC) Meeting. May 11, 12, 2022. FDA website. Accessed July 15, 2022.S.650 - Pediatric Research Equity Act of 2003. Congress.gov. Accessed July 15, 2022. https://bit.ly/3aEzWZB

• H.R.1231 - RACE for Children Act. Congress.gov. Accessed July 15, 2022. https://bit.ly/3IHkU1U