Innovative Study Designs Optimizing Clinical Pharmacology Research in Infants and Children

Abstract

Almost half of recent pediatric trials failed to achieve labeling indications, due in large part to inadequate study design. Therefore, innovative study methods are crucial to optimize trial design while also reducing the potential harms inherent with drug investigation. Several methods exist to optimize the amount of pharmacokinetic (PK) data collected from the smallest possible volume and with the fewest number of procedures, including the use of opportunistic and sparse sampling, alternative and non-invasive matrices, and micro-volume assays. In addition, large research networks using master protocols promote collaboration, reduce regulatory burden, and increase trial efficiency for both early- and late-phase trials. Large pragmatic trials that leverage electronic health records can capitalize on central management strategies to reduce costs, enroll patients with rare diseases on a large scale, and augment study generalizability. Further, trial efficiency and safety can be optimized through Bayesian adaptive techniques that permit planned protocol changes based on analyses of prior and accumulated data. In addition to these trial design features, advances in modeling and simulation have paved the way for systems-based and physiologically-based models that individualize pediatric dosing recommendations and support drug approval. Lastly, given the low prevalence of many pediatric diseases, collecting de-identified genetic and clinical data on a large scale is a potentially transformative way to augment clinical pharmacology research in children.

Exposure–Response Assessment in Pediatric Drug Development Studies Submitted to the US Food and Drug Administration

“…Several areas may be considered for future directions. First, the incorporation of innovative and quantitative approaches into E–R modeling should be considered, such as Bayesian statistics . Second, a clear need to obtain robust clinical data in adults to characterize the E–R relationship should be part of every drug development program.…”

Developmental Pharmacotherapy: The Interface Between Ontogeny and Drug Effect

“…With the broad acceptance, utilization, and continuously improving detail and accuracy of patient data being incorporated into the electronic medical record, the value of mining "big data sets" cannot be overstated, providing a broad view of drug use, response, and safety in the real-world setting. Each of these four articles [6][7][8][9] provides insight and substance to the importance of data-informed modeling and simulation-guided clinical trial design; study execution; data-driven modification, if necessary;…”

“…Clinical trials in target pediatric patients with targeted disease(s) are fundamental to a better understanding of age‐size influenced disposition characteristics and the definition of optimal age‐appropriate drug doses in children . Four detailed, expert reviews address the current status of drug development in children and the incorporation of innovative study designs available to best capture the most from limited data sets. The data derived from clinical trials integrated with modern modeling and simulation methodologies enhances the accuracy of dose projections for a patient population as well as the individual patient.…”

“…With the broad acceptance, utilization, and continuously improving detail and accuracy of patient data being incorporated into the electronic medical record, the value of mining “big data sets” cannot be overstated, providing a broad view of drug use, response, and safety in the real‐world setting. Each of these four articles provides insight and substance to the importance of data‐informed modeling and simulation‐guided clinical trial design; study execution; data‐driven modification, if necessary; successful trial conclusion; and proper analysis with relevant, accurate interpretation. Pediatric health care providers are best served when the results from a comprehensive, multifaceted, thoughtful, methodical clinical drug development program is included in the sanctioned official product labeling for all to use in their pharmacotherapeutic decision tree.…”

Perinatal Asphyxia: Predicting and Improving Outcome

“…The pharmacokinetics of allopurinol are well known for infants with HIE that are not treated with therapeutic hypothermia, but this knowledge is not yet available for infants with HIE that are treated with therapeutic hypothermia (64). Therefore, as part of the ALBINO trial a pharmacokinetic sub-study was performed.…”