New tools, applications, and techniques allow for improving and advancing pediatric drug development. Historically, pediatric patients are difficult to enroll into clinical trials so it’s hard to meet the target sample size to assess efficacy and safety. One tool that has been useful in overcoming this challenge is extrapolation. Extrapolation allows for sponsors and organizations to assess the level of clinical knowledge needed to establish the safety and efficacy of drugs for pediatric patients based on the similarities in disease, drug pharmacology, and treatment response between adult and pediatric patients. The use of extrapolation helps to identify gaps in existing knowledge and streamlines the process of conducting pediatric clinical trials.
Here are some strategies used in pediatric extrapolation.
Clinical trials and extrapolation
The key principle of extrapolation is leveraging the available adult information to draw conclusions about the efficacy and safety of drugs in children. Extrapolation can be utilized to lower the required pediatric sample size. In many clinical trials with pediatric patients, a placebo control arm may not be used due to ethical reasons. A concurrent control (e.g., dose response, active treatment) can be used instead alongside comparable reference data (e.g., a study done in adults). Borrowing or bridging information from one group to another will result in an elevated type 1 error, which is to be expected and must be justified clinically. Pediatric extrapolation has led to several advancements in pediatric drug development and continues to pave the way for other tools in the space.
Matching the pediatric drug exposure to the adult exposure shown to be safe and effective can be used in pediatric drug development. Exposure matching, such as pharmacokinetic studies, enables scientists to establish efficacy by comparing the pediatric exposure in adults and pediatrics. If the results are similar, scientists can identify a pediatric dose that is efficacious and safe using a smaller pediatric sample size than would otherwise be required.
Matching clinical response in addition to exposure is another option that scientists can use if there is uncertainty about whether matching the adult exposure would correlate to pediatric response. To bridge this gap in the use of extrapolation, pharmacodynamic biomarkers can be used to confirm similar results in adult and pediatric patients. For example, the biomarker, NT-proBNP, was used in the approval for Entreso for pediatric heart failure. Entreso lowers NT-proBNP in adults, which correlated to similar results in pediatric patients in a similar disease state.
Safety extrapolation in pediatric patients
Extrapolation from adults may be used to assess drug safety in adolescents and younger children with the same disease and drug class exposure. Safety may also be extrapolated from the same drug exposure in similar pediatric diseases, such as psoriasis and psoriatic arthritis, and from populations exposed to drugs with the same mechanism of action.
Before using extrapolation, an understanding of disease, drug pharmacotherapy, and treatment response should be well documented. Growth and developmental changes in children can affect how the drug works in the body, which could affect its clinical efficacy and safety.
To learn more about the evidence supporting the use of extrapolation in pediatric drug development, watch this presentation I gave at the 2021 New Horizons in Pediatric Drug Development symposium!