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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