History

Contents
Background
First Funding Cycle 1994 - 1998
Second Funding Cycle 1999 - 2003
Third Funding Cycle 2004- 2008

Background

At the inception of the PPRU Network in 1994, most drugs (75-80%) were not labeled as safe and effective for infants and children and off label use was the norm for these therapeutic orphans. Practitioners, parents and the government were not aware of this issue or of it potential consequences.

The pharmaceutical industry was reluctant to perform studies to generate this information because there was little economic incentive and because of the perceived liability and ethical concerns about conducting research in children.

Essential differences between the pharmacology of drugs in adults and children required studies with a carefully orchestrated interplay between developmental pharmacology (the use of drugs to elucidate the ontogeny of physiologic processes) and pediatric pharmacology (the study of therapeutic agents in infants, children and adolescents) to develop the paradigm for studying drugs in children.

The PPRU Network was developed to facilitate an informal collaboration among NIH, academia, and industry to address this problem. Under the NICHD umbrella and in concert with the pharmaceutical industry the Network catalyzed the integration of a crucial mass of research subjects, pediatric sub-specialists, pediatric clinical trials experts and pediatric clinical pharmacologists to begin to address these issues and conduct pediatric pharmacology research.

The Network evolved from its early emphasis on pediatric labeling studies (that were supported and directed by industry) to a more comprehensive program in developmental/pediatric clinical pharmacology. While clinical labeling studies continued to be performed, studies of off patent drugs which are clinically relevant and widely used, as well as basic and translational research have moved to the forefront.

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First Funding Cycle 1994 - 1998

During the first five years, the over-riding goal of the PPRU network was to create a platform to conduct pediatric studies that would support pediatric labeling but with a continued interest in supporting investigator-initiated studies on PD/PK of drugs in children and training physicians and pharmacologists. Five geographically dispersed sites conducted PK studies and labeling studies and were specifically focused on drugs of interest to the pharmaceutical industry.

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Second Funding Cycle 1999 - 2003

The start of the second funding cycle saw the polarization of the Network into the complementary core competencies including study design, analytical pharmacology, pharmacometrics, pharmacogenomics and data sharing/data mining emerged which influenced both investigator initiated as well as industry sponsored study designs.

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Third Funding Cycle 2004- 2008

During the second and third PPRU funding cycles a number of PIs with training in both pediatric pharmacology and a sub-specialty (e.g., neonatology, asthma, infectious diseases, intensive pediatric care, oncology, diabetes) joined the Network. The scientific bridge between pediatric clinical pharmacology and sub-specialties has been a vital asset of the Network and allows for the translation of pediatric pharmacology into clinical practice.

Recently, efforts have focused on investigator initiated studies and inroads into multi-disciplinary/multi-investigator projects within the PPRU and across networks. Earlier cycle emphasis on pharmacokinetic (PK) and labeling studies and the evaluation of ontogeny of drug response and drug disposition evolved over time. Efforts in disease oriented therapeutics with an increased focus on patient oriented therapeutics and the molecular determinants of drug responsiveness to explain pharmacokinetics, pharmacogenetics, drug toxicity, and lack of efficacy characterized the later work of the Network as it moved from pediatric pharmacology to pediatric therapeutics and from drug and disease oriented therapeutics to patient oriented therapeutics. Studies in bioavailability, formulations, drug metabolism, pharmacokinetics, pharmacodynamics, safety, and effectiveness of new and marketed drugs have been performed and meet the changing internal and external realities. Efforts to develop and validate non-invasive pharmacodynamic measurements, develop and/or adapt PK/PD modeling technology, apply pharmacogenomic and proteomic tools in clinical studies and implement studies on the developmental characteristics and genetic polymorphisms of drug metabolizing enzymes (DMEs), transporters, and receptors and their phenotypic-genotypic correlations are underway. Efforts to identify biomarkers of disease activity began on a limited basis and will continue into the future.

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