Accelerating Pediatric Drug Development: Master Protocols May Be a Way to Go

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Pediatric drug development should be coordinated with that for adults as part of an overall program.
— Gregory Reaman, MD

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Development of pediatric cancer drugs has long lagged behind adult drug development for two major reasons: The process is more difficult, and childhood cancer is rarer by far than adult cancer. These and other phenomena in pediatric oncology were the subject of a workshop held by the Friends of Cancer Research (Friends) and sponsored by St. Baldrick’s Foundation, Monrovia, California.1

Not only is cancer in children uncommon, significant differences in etiology mean that each type is that much rarer, resulting in logistical challenges for clinical trials. Generally, pediatric patients do not participate in adult trials, and pediatric trials of new drugs have often been undertaken years after a drug is approved for adults—if at all. This means that off-label use of agents can be widespread, thus negatively affecting accrual to pediatric trials and skewing safety and tolerability data.

Nevertheless, “pediatric drug development should be coordinated with that for adults as part of an overall program,” stated Gregory Reaman, MD, Associate Director for Oncology Sciences, U.S. Food and Drug Administration (FDA) Office of Hematology and Oncology Products, and former Chair of the Children’s Oncology Group.

He added that current approaches should continue but need to be modernized and streamlined. Although the patient pool is small and resources are limited, the drug development community must increase its knowledge of the genomic basis and heterogeneity of pediatric cancers; evaluate the  goal of generating “large treatment effects in small numbers of subjects”; and follow compressed adult drug development timelines using  innovative trial designs, which could then be applied to pediatrics.

Master Protocols

Master protocols can overcome many of the challenges in pediatrics, said Mark Fleury, PhD, Principal, Policy Development, Emerging Science, American Cancer Society Cancer Action Network. “Pediatric cancers are not the same as adult cancers, even if they carry the same name. Like acute lymphoblastic leukemia, for example, they can be biologically different.”

Pediatric cancers are not the same as adult cancers, even if they carry the same name. Like acute lymphoblastic leukemia, for example, they can be biologically different.
— Mark Fleury, PhD

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Master protocols include testing a variety of diseases, treatments, and molecular markers. Thus, the infrastructure can be used for rapid inclusion of new agents without rewriting the entire study. Moreover, they bring multiple stakeholders together to improve efficiency and streamline regulatory review.

Dr. Fleury called workshop attendees’ attention to a recently published report by the American Cancer Society, Translating Discovery Into Cures for Children With Cancer.2 It makes the following critical points:

  • Treatment often results in significant and long-lasting toxicity.
  • Children have been given special protective status, which affects not only the types of research they can participate in but the approval process as well.
  • The rarity of childhood cancer makes accrual to studies difficult because of the small pool of potential subjects. Therefore, competition among research projects is fierce.
  • The rarity of occurrence means that the financial incentives to develop new treatments may be thin.

An ideal master protocol, said Dr. -Reaman, has a central governance structure, a centralized institutional review board, and a repository of data and specimens. It incorporates multiple drugs, each targeting more than one biomarker or tumor, to assess early signs of activity; this creates flexibility to add or remove drugs.

Proposed Master Trial Platform

The centerpiece of the workshop was a master protocol modeled after a Friends-supported design for a multi-stakeholder approach in lung cancer. Raphaël F. Rousseau, MD, PhD, Senior Group Medical Director and Global Franchise Head, Pediatrics, Product Development Oncology, Genentech, described its aims: to create a phase I/II master trial platform to screen multiple agents across different pediatric tumor types and to standardize targeted approaches to ensure consistent interpretation of data for accelerated and widespread adoption, and sustainability.

It is probably not desirable or feasible to conduct multiple confirmatory trials in each rare tumor type identified in the master trial. Data collected in early-phase studies, however, can still inform the label….
— Raphaël F. Rousseau, MD, PhD

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Master trials appear to be working well in adult disease. Despite a lack of pediatric-specific endpoints, they can be adapted for children for several reasons: (1) Information about pediatric cancer biology is growing; (2) Patients with cancer are falling into increasingly smaller molecular subsets; (3) Pediatric clinical trial networks are firmly established; and (4) Multiple targeted agents can be assessed simultaneously in relatively small patient populations under a single overarching protocol.

Dr. Reaman noted that optimally before initiating clinical studies, there ought to be evidence that the product to be tested has preclinical activity against a certain tumor; it will be beneficial and reasonably safe; and there is sufficient information to choose an appropriate starting dose.

The proposed iMATRIX master trial protocol, sponsored by Genentech and Roche, will take the biology of each pediatric tumor type included in the study and the mechanism of action of each drug into account, with an eye toward exposing fewer children to ineffective or unsafe agents. The trial will be gated (to evaluate initial pharmacokinetics) and early-phase activity signals in order to: quickly identify molecules with sufficient efficacy and safety to pursue further development; stop development early for molecules that are ineffective or unsafe; establish optimal doses; and identify biomarkers.

In addition, the trial will start out investigating pediatric solid and brain tumors and proceed to hematopoietic malignancies. The strength of the match between the molecule’s mechanism of action and the biology of the tumor type will be assessed through review of published literature, the prevalence of the molecular target in the tumor type, and additional mechanistic proof of concept in relevant preclinical models of pediatric tumors, if available.

Study inclusion and exclusion criteria will reflect the limited availability of pediatric clinical data for any given molecule. Patients up to age 30 who have pediatric tumor types will be enrolled.

Dr. Rousseau noted that mechanism-of-action–based phase I/II iMATRIX ­trials have already been initiated by ­Genentech and Roche in children with relapsed/refractory tumors and have enrolled 100+ patients in Europe and the United States over a 12-month period. Genentech and Roche have had very constructive, joint discussions with the FDA and European Medicines Agency to adapt this trial concept into a Master protocol platform and invite other sponsors to join in these efforts so as to harmonize and accelerate the conduct of pediatric investigations of innovative, targeted drugs.

Regulatory and Approval Issues

When master protocols are at issue, the regulatory process ought to be more flexible, especially as it applies to meeting obligations and qualifying for incentives, according to Dr. Rousseau. “It is probably not desirable or feasible to conduct multiple confirmatory trials in each rare tumor type identified in the master trial. Data collected in early-phase studies, however, can still inform the label, and further study can be pursued by other means, such as investigator-initiated trials, for instance.” A pediatric master trial with global collaboration is challenging, but the United States and the European Union have regulations in place that mandate studies in some instances and provide incentives in others. Leveraging the regular communications between the FDA and the EMA can facilitate the implementation and conduct of international master protocols.

Dr. Reaman described two American laws that apply to pediatric drug development. The Pediatric Research Equity Act authorizes the U.S. Food and Drug Administration (FDA) to require pediatric assessment of a drug for the same indication in children. It is triggered by a new drug application or a supplementary application with a new indication, active ingredient, dosage form, dose regimen, or route of administration. Drugs with Orphan Drug designation are exempt from the Pediatric Research Equity Act; thus, the law has little relevance to cancer.

The Best Pharmaceuticals for Children Act provides a financial incentive to companies that voluntarily conduct pediatric studies under a pediatric Written Request. A sponsor may solicit a Written Request as a proposed pediatric study request (containing the rationale, design, and plans for development), or the FDA may issue one without the sponsor. ■

Disclosure: Dr. Reaman reported no potential conflicts of interest. Dr. Rousseau is a full-time employee of Genentech, a member of the Roche group, and holds shares of Roche stock.


1. Friends of Cancer Research: Accelerating Pediatric Drug Development. Friends of Cancer Research Forum. Session 1. Presented February 21, 2017.

2. American Cancer Society: Translating Discovery Into Cures for Children With Cancer. Childhood Cancer Research Landscape Report. Available at Accessed March 22, 2017.