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Clinical trials have played a central role in converting many of the once fatal childhood cancers into conditions in which the vast majority of children with these diagnoses can be cured. For example, much of the progress in improving survival rates for children with acute lymphoblastic leukemia (ALL) can be attributed to the conduct of sequential phase 3 clinical trials in which more effective treatment approaches for children with ALL were reliably identified and carried forward as the standard of care that replaced less effective therapies. The end result of these series of clinical trials conducted over more than 4 decades has been the identification of treatments that produce 5-year survival rates exceeding 90%, much higher than those previously achieved (Fig. 443-1).

Figure 443-1

Five-year relative survival rates for children (< 15 years) with acute lymphoblastic leukemia. (Data from the National Cancer Institute’s Surveillance, Epidemiology, and End Results Program.)

Pediatric oncologists continue to feel that it is generally appropriate to offer families the opportunity to participate in clinical trials, because even the best currently available treatments are not optimal for many childhood cancers as there are still a substantial proportion of children who do not achieve long-term survival with current standard treatments. Furthermore, many treatment approaches cause short- and long-term treatment-related sequelae that reduce quality of life and survivorship. Although participation in clinical trials cannot provide guaranteed benefit to individual study subjects, the potential for such benefit is real and the conduct of well-designed clinical trials addressing critical questions of therapy, often linked to correlative biologic studies, remains the path forward for identifying more effective and less toxic treatments for children with cancer.

The general ethical principles that apply to research involving children are especially important in the pediatric oncology setting, given the vulnerability of children with these life-threatening diseases. Subpart D of the Code of Federal Regulations represents the regulatory embodiment of these principles, and institutional review boards are responsible for ensuring adherence to these principles. As cancer therapies evaluated in the research setting inherently involve greater than a minor increase over minimal risk, participation by children in cancer treatment clinical trials must offer the prospect of direct benefit as prescribed by 45 CFR 46.405. The risks associated with clinical trial participation must be justified by the anticipated benefit, and the relation of benefit to risk must be at least as favorable as current treatment alternatives for the population being studied.

Phase 1 clinical trials for children with cancer are a key step in the introduction of new treatment approaches into the pediatric setting. The standard approach to these “first in children” clinical trials of novel anticancer agents generally requires studies defining the toxicity profile of the agent and establishing a recommended phase 2 dose (RP2D) for the agent in adult cancer patients. This adult ...

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