The FDA Guidance, “General Clinical Pharmacology Considerations for Pediatric Studies for Drugs and Biological Products” addresses pharmacokinetics (PK), pharmacodynamics (PD) and pharmacogenomics (PG), as well as pediatric study design. It also outlines ethical considerations and the six areas of importance for PK studies.
The FDA has been working to address inadequacies in pediatric testing and use this information in drug development and product labeling.
Three Recognized Pediatric Study Design Approaches
Clinical Pharmacology studies in pediatric populations should be conducted in patients receiving therapy for a particular indication, or in rare instances, those at risk for the condition of interest. The Center for Drug Evaluation and Research generally divides the pediatric population into the following four groups: Neonates (birth up to 1 month), Infants (1 month up to 2 years), Children (2 up to 12 years) and Adolescents (12 up to 16 years).
The identification of the appropriate ages to clinical studies and decisions about how to stratify data by age are drug-specific and require scientific justification, taking into consideration developmental biology and pharmacology.
There are three recognized approaches to provide evidence to support safe and effective use of drugs in pediatric populations. For each approach, the extent of required pediatric safety studies may take into account:
- Prior experience with similar drugs in pediatric populations
- Seriousness of the adverse effects (AEs) in adults or pediatric populations
- Feasibility of conducting studies in pediatric patients
The first approach uses evidence from adequate, well-controlled studies of a pediatric indication different from the approved indication in adults. This approach generally requires a full pediatric development program.
The second uses evidence from adequate, well-controlled studies in pediatric populations to support the same indication approved in adults. This approach usually involves using prior disease and exposure-response from adult studies and relevant pediatric information to design and analyze new pediatric studies.
Finally, for the last approach, evidence from adequate, well-controlled adult studies can be used, bolstered by additional information for the specific pediatric population. This assumes that the course of the disease and effects of the drug are sufficiently similar in the pediatric and adult populations. With this approach, a pediatric study is usually conducted to determine the dose that provides similar drug exposure in the pediatric population as seen in the adult population.
PK Considerations in Clinical Pharmacology
PK parameters such as peak exposure (Cmax), area under the concentration-time curve (AUC), clearance, half-life and volume of distribution are important in describing the systemic exposure of the drug in pediatric populations. Growth and developmental changes in factors affecting absorption, distribution, metabolism and excretion (ADME) can lead to changes in PK parameters. Special areas of importance in planning pediatric PK studies include ADME, protein binding, and clearance.
Additionally, growth and developmental changes create substantial changes in ADME. PK parameters may need to be described as a function of age or be related to a measure of body size (height, weight, body surface area). Maturation changes in transporters and metabolizing enzymes should also be considered.