A recent survey of orphan drug approvals is shedding light on how researchers determine drug doses for children with rare diseases, such as thymidine kinase 2 deficiency (TK2d), despite major challenges posed by small patient populations and scarce clinical data.
The study, published in Clinical and Translational Science, reviewed orphan drugs approved by the U.S. Food and Drug Administration between 2013 and 2022 that included pediatric indications at the time of approval. Researchers analyzed the strategies used to select initial doses for children and the clinical trial designs used to evaluate those doses.
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The researchers found that pediatric dosing decisions were frequently supported by several different types of evidence. Among 63 analyzed drugs, 37% used data from adults with the same disease to determine pediatric dosing, while 33% relied on studies in healthy adult volunteers. Another 14% depended mainly on nonclinical data, such as laboratory and animal studies, when human data were unavailable.
Nearly half of the reviewed drugs used more than one source of information to guide dosing decisions, reflecting efforts to overcome the limited data typically available in rare diseases.
The survey also examined how clinical trials were designed to evaluate pediatric doses. About half of the studies tested multiple dose levels, while one-third allowed dose increases within the same patient based on treatment response or safety findings. Some trials also included interim evaluations of drug levels in the body to help guide dose adjustments during the study.
Developing medicines for pediatric rare diseases can be especially difficult because traditional dose-finding studies often are not feasible in very small patient populations. Children also process medicines differently than adults, particularly during infancy and early childhood when organs and metabolic pathways are still developing.
The study additionally highlighted the growing role of model-informed drug development (MIDD), which uses mathematical and computer-based models to predict how medicines may behave in the body. These strategies can combine information from clinical studies, laboratory research and other available data sources to support dose selection when large pediatric trials are not possible.
Although modeling and simulation approaches (MIDD) were explicitly reported in only about one-fifth of the reviewed drug programs, the researchers said MIDD could become an important driver of future advances in pediatric rare disease drug development.
According to the research, these approaches may help balance the need to collect reliable dosing data while minimizing risks for children participating in clinical trials.
“Integrating various data sources and strategies together can lead to a paradigm shift toward more flexible, data-efficient, and mechanistically informed pediatric dose prediction in rare disease drug development,” the researchers concluded.
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