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Early phase trials provide crucial information about new medicines that allow them to be taken forward into larger confirmatory studies. Paediatric early phase studies are becoming more common, particularly in the era of precision therapy. There are almost 600 active paediatric phase I/II trials listed on clinicaltrials.gov. Conventionally, early phase dose-escalation trials use rule-based designs such as the 3+3 to guide dose decisions. A trial is considered to have a rule-based design if predefined rules are used to guide decisions to escalate, continue or de-escalate based on the observed toxicities at the current dose.
Though it is well established that model-based design is generally superior to rule-based design, its uptake remains low. Trials with a model-based design use statistical models to guide decisions on which dose levels to give the next patient(s), based on the targeted toxicity level and previous information. In this article, we review one of the most commonly used model-based designs, the continual reassessment method.
The goal of any phase I study is to find a recommended dose of a new therapy to advance in subsequent studies. This can be defined in different ways; one of the most common being the maximum tolerated dose (MTD). One key question is: ‘What level of toxicity is acceptable based on the expected benefits of treatment?’ The MTD is defined as the dose expected to cause a degree of medically undesirable dose-limiting toxicity (DLT) in an acceptable specified proportion of participants. The latter is referred to as the target toxicity level (TTL). This level will differ depending on the expected benefits of the treatment as well as the severity of the expected toxicity for the specific intervention. This relationship is illustrated in figure 1.
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