Considerations in the Rational Design and Conduct of Phase I/II Pediatric Clinical Trials: Avoiding the Problems and Pitfalls

Abstract

Over the past decade, there has been a heightened awareness of the need to include children in the drug development process. With this awareness has come an expansion of the infrastructure for conducting studies in children and an increase in the sponsorship of pediatric clinical trials. However, the growth in pediatric research has, in many cases, not been accompanied by an increase in the involvement of trained pediatric investigators when it comes to trial design and/or interpretation. Pediatric phase I/II protocols continue to span a spectrum from those that are carefully constructed to those that are poorly designed. This paper highlights the basic elements of phase I/II protocols that merit unique consideration when the clinical trial involves children. Illustrations are provided from our experience, which highlight problems that may arise when trials are not designed with the pediatric patient in mind.

Impact of the CYP2C19*17 Allele on the Pharmacokinetics of Omeprazole and Pantoprazole in Children: Evidence for a Differential Effect

“…The reasons underlying the discrepant findings between omeprazole and pantoprazole in pediatric patients as presented in the current study are not entirely clear. Variability associated with pharmacokinetic parameters within a genotype group composed of a relatively small number of subjects (a common feature for pediatric pharmacokinetic studies conducted to support product labeling) (Abdel-Rahman et al, 2007) may be one factor that contributed to the lack of association between genotype and omeprazole AUC (Fig. 1C).…”

Clinical trials in children

“…Because of differences in body composition in different age groups, pharmacokinetic studies have sometimes resulted in incomplete and incorrect conclusions [96]. Trials that include different paediatric ages may need appropriate dose adjustments by weight or body surface area [96,106]. Researchers are increasingly recognizing the importance of qualitative outcome measures that are relevant to the child and family, including the impact of the illness and treatment on the quality of life [16].…”

“…For example children's aversion to needles makes obtaining blood samples challenging. To address this burden and protect children from unnecessary testing, the volume of blood sampling generally allowed in paediatric trials is less than 3% of the estimated circulating blood volume over a 2 to 8 week period [20,96,97]. Alternative appropriate sampling techniques, for example finger or heel pricks or salivary samples, may be preferred as they minimize discomfort for children [15,20,96,97].…”

“…The requirements of child friendly formulations may differ in resource limited settings where there may be a lack of refrigeration facilities which may impact on the stability and efficacy of the medicine [104]. When there is a lack of paediatric appropriate formulations, the use of adult dose forms such as tablets and capsules can be problematic for younger children who cannot swallow tablets as crushing tablets or opening capsules and dispersing in liquids may compromise the palatability and bioavailability of the medicine and affect the trial results [96]. The inclusion of extemporaneous preparation guidelines in paediatric trials which use solid oral dosage forms, will improve the accuracy and reproducibility of the preparation [73].…”

“…When designing how to measure these outcomes, researchers need to consider using age-appropriate tools such as the face pain scale [57,105]. Because of differences in body composition in different age groups, pharmacokinetic studies have sometimes resulted in incomplete and incorrect conclusions [96]. Trials that include different paediatric ages may need appropriate dose adjustments by weight or body surface area [96,106].…”