Guest Column | December 12, 2019

Pediatric Oncology Trials Under FDARA Section 504 — How To Prepare

By Sandra H. Blumenrath, Ph.D., Drug Information Association (DIA)

Pediatric Cancer Trials: Is There A Solution?

Although the development of cancer drugs for children is riddled with challenges, the requirements in Section 504 of the FDA Reauthorization Act of 2017 (FDARA) represent a significant paradigm shift in pediatric oncology. Historically, legislative initiatives that support pediatric drug development have had much less impact in oncology than in other clinical areas. With FDARA Section 504, the agency can now require pediatric assessments of new therapies when their molecular targets are substantially relevant to children’s cancers. Effective in August 2020, the act also ended an existing exemption for oncology drugs with orphan status and stipulated numerous statutory requirements for the agency itself.

Much of the debate on cancer drug development for children revolves around the question of how to get the right medication to the right patient at the right time. A quick literature search reveals an active debate, with a variety of opinions, findings, and proposals from key stakeholders. The effort is certainly palpable on many fronts; with FDARA Section 504 and the recognition that many targeted agents in adult cancers are likely applicable to cancers in children, too, some of this debate has entered regulatory lawmaking. But what are the new requirements, and how will they impact clinical pediatric oncology development?

New Provisions In FDARA Section 504

Although outcomes for children with cancer have significantly improved over the past 40 years, pediatric cancer drug development is still lagging far behind development of cancer drugs for adults. Clinical trial options are generally limited, and (due to a lack of a useful regulatory mechanism until the passage of FDARA 2017) sponsors have been able to request and obtain waivers for conducting clinical assessments of adult cancer drugs in pediatric patients.

FDARA Section 504 now requires pediatric assessments of new therapies when the molecular targets are substantially relevant to children’s cancers, thus eliminating orphan exemptions for pediatric cancer drug studies at these molecular targets. To fulfill a commitment made under FDARA 2017 and to further leverage the new provisions, the FDA in 2018 developed a Pediatric Molecular Target List (i.e., a public list of relevant molecular targets) containing more than 205 molecular targets for pediatric cancer research. The primary objective of creating and maintaining the list is to help guide industry in planning for initial pediatric study plan submissions. For example, there needs to be enough evidence to show that a therapeutic intervention addressing one of these targets has the desired effect and indeed alters the disease process.

The sponsor requirements defined in Section 505b of the FD&C Act have so far required sponsors to have an initial pediatric study plan (iPSP) prior to the submission of a new drug or biological license application. Under the 2005 Pediatric Research Equity Act (PREA), all applications “for new active ingredients, new indications, new dosage forms, new dosing regimens, or new routes of administration” were required to include a plan for assessing the safety and effectiveness of the product for the listed indication in pediatric patients, unless the sponsor received a waiver or deferral. After August of 2020, the PREA requirement for applications of new active ingredients changes from indication to the molecular mechanism of action of an investigational product, including products for which there is an orphan designation — a change that will have a major impact on automatic waivers.

Realizing that transparency is needed to be successful, Section 504 also requires the FDA to work collaboratively with numerous other stakeholders on implementation and study requirements, convene a public meeting, and issue an implementation guidance. The overall intent of FDARA Section 504, including the statutory requirements for the agency itself, is to speed up pediatric evaluations early in the development timeline rather than simply increasing the number of pediatric Phase 1 studies.

This new regulatory approach — emphasizing molecular mechanism of action rather than indication — no doubt presents both challenges and opportunities for industry and academic researchers. To navigate the complex landscape of pediatric oncology research, stakeholders have turned their attention increasingly toward industry-initiated public-private partnerships and uniform, international master protocols for biomarker directed studies – strategies that in combination may help advance drug development for pediatric cancers with significantly fewer roadblocks.

Doing Away With Inefficiencies

Pediatric Master Protocols

The rarity of pediatric cancers and the logistical challenges associated with designing and executing pediatric oncology trials are just some of the key challenges in conducting pediatric cancer trials. Master protocol types, such as umbrella trials, basket trials, and platform trials, have the potential to overcome some of these difficulties and may offer an important opportunity to study childhood cancers safely and effectively.

The very design of master protocols allows for efficient and effective testing of one or more targeted agents in relatively small patient subpopulations and gives multiple stakeholders and sponsors the opportunity to work together. This in turn conserves resources and increases efficiency and patient safety. By matching targeted therapies to children, master protocols can – in theory – accelerate pediatric drug development while limiting exposure of children to potentially ineffective therapies. With their ability to quickly assess the safety and effectiveness of new therapies, master protocols can significantly speed up early-phase clinical testing of novel therapeutics and, thus, the approval of new drugs for children.

Although some of the same principles and requirements of adult oncology trials apply to pediatric oncology trials, pediatric master protocols do require a few unique considerations. For example, eligibility criteria should not be overly restrictive and should instead consider the unique characteristics of pediatric populations, such as metabolic differences between various age groups and the potential risk of developmental toxicities. Study endpoints may also be different for pediatric master protocols, and sponsors, investigators, and regulators may need to collaborate closely to identify what is most clinically meaningful to pediatric patients and their parents. And, to reduce the risk of serious adverse reactions or to eliminate poorly performing agents early on, stopping rules may need to be modified. The development of pediatric master protocols also must account for pediatric laws and regulations across countries or regions and may require early conversations with regulatory authorities to fulfill regulatory obligations. To be successful and to optimize the safety of children in clinical trials, collaboration among stakeholders once again is critical. Involving pediatric oncologists and other experts throughout the process (from trial design to conduct) will most likely maximize patient safety and ensure that the clinical study is feasible and scientifically rigorous.

The use of master protocols in pediatric oncology has indeed gained some traction: The National Cancer Institute (NCI) Pediatric MATCH, for example, is a multi-product, multi-pharma master protocol launched in 2018 that focuses on solid tumors (including non-Hodgkin lymphomas, brain tumors, and histiocytosis) in children and adolescents between 1 and 21 years old. The other example is the Leukemia & Lymphoma Society (LLS) PedAL study. Due to launch in 2020, this master protocol study will test multiple targeted therapies simultaneously at 200 clinical sites across the globe.

Master Protocols and Public-Private Partnerships

A successful combination of both strategies (industry-initiated public-private partnerships and uniform master protocols for biomarker-directed studies) to tackle the challenges of pediatric oncology studies can be seen in two innovative ongoing trials directed by the Foundation for the National Institute of Health. Both the I-SPY 2 platform trial (launched in 2010) and the LUNG-MAP umbrella trial (launched in 2014) use a master protocol and were started as public-private partnerships. I-SPY 2 uses a master protocol that investigates multiple treatments for advanced breast cancer in the same study, whereas Lung-MAP initially focused only on squamous cell lung cancer but has since expanded its research to all types of advanced non-small cell lung cancer.

With multiple companies involved, I-SPY 2 and Lung-MAP share risks and costs, provide organizational efficiencies, and have become solid evidence for how master protocols can work. Of particular importance for the ongoing success of these trials were an early definition of the nature and structure of the public-private partnership (who needs to be at the table and when), strong, cohesive project management, the flexibility of the master protocol to adapt to changes in the evolving treatment landscape, and centralized IRBs to ensure long-term enrollment.


As requirements for FDARA Section 504 go into effect in August 2020, sponsors will need to find a way to comply with these requirements effectively, safely, and in a financially sensible manner. From a cost perspective, master protocols and the use of public-private partnerships will reduce expenses for a company because of the collaborative effort and the shared infrastructure. Public-private partnerships have increased efficiencies and reduced costs in drug development programs in many other therapeutic areas and are therefore likely to offer similar advantages in pediatric cancer research as well. Similarly, there is a growing appreciation of master protocols and their ability to use a single infrastructure, design, and protocol to simultaneously evaluate multiple drugs and/or disease populations. In addition to organizational and cost efficiencies, master protocols may provide biopharma companies with a mechanism to prioritize their development portfolios.

Lessons learned from ongoing oncology trials clearly show that master protocols can be effective and efficient options for certain cancer treatments, speeding up the development of therapies in a rational and scientifically driven manner. They also show that successful pediatric master protocols will require unified efforts and cooperation among investigators, patient groups, industry, and regulatory agencies to incorporate the needs of all stakeholders. Only then can we expect to see enough incentive toward innovative clinical trials like master protocols that will accelerate the development of new and potentially more effective therapeutic options for children with cancer.

About The Author:

A biologist by training, Sandra Blumenrath, Ph.D., M.S., serves as science writer for DIA. She brings extensive experience in scientific research, education, and communication to her role at DIA, where she produces scientific and healthcare-related content for a variety of audiences. She graduated with an M.S. from the University of Copenhagen and earned her Ph.D. at the University of Maryland, College Park. Prior to joining DIA, Blumenrath worked as a scientist, educator, and content developer at the University of Maryland, CP; the Howard Hughes Medical Institute (HHMI), and the American Association for the Advancement of Science (AAAS).