Safe and Effective Medicines for Children Pediatric Studies Conducted Under the Best Pharmaceuticals for Children Act and the Pediatric Research Equity Act (2012) / Chapter Skim
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2 Children's Growth and Development and Pediatric Drug Studies
2 Children's Growth and Development and Pediatric Drug Studies
Pages 43-62
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From page 43... ...
Such disparities underscore the necessity for pediatric drug studies. This chapter also discusses how differences between children and adults may require alterations in the design, conduct, and analysis of such studies.
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From page 44... ...
was soon followed by the report of a randomized clinical trial to evaluate the effectiveness of prophylactic antibiotics in reducing mortality in premature newborns following prolonged premature rupture of membranes (Burns et al., 1959)
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Individual dosages of water-soluble drugs for premature newborns must often be increased to adjust for this increased body water so that the drugs reach an effective concentration in the bloodstream. After enzymatic changes, many drugs are eliminated in the urine.
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From page 46... ...
In developing children, the individual enzymes for drug metabolism and conjugation usually do not mature at the same rate, nor does the maturation of an individual enzyme occur at a constant rate. For newborns and young children, the dose of a drug is often adjusted to the child's body weight or body surface area to take into account not only size but also the maturation of enzymes that occurs with growth.
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A National Institutes of Health (NIH) working group on adolescent therapeutics has recommended more research on a number of topics, including how pubertal development and body weight affect drug distribution and metabolism (NICHD, 2010)
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From page 48... ...
As in other areas, the developmental variability described in the first part of this chapter adds complexity and may limit the generalization to children of findings from pharmacogenomic studies with adults. For example, researchers recently reported that a pharmacogeneticsbased dosing algorithm for warfarin that was derived from adult data consistently overestimated the pediatric dose of the drug (Biss et al., 2012)
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From page 49... ...
Incorporation of pharmacogenomics in clinical trial designs to better identify patient characteristics associated with differences in drug response could reduce the number of pediatric trials that fail to show efficacy because of a lack of sufficient information on such characteristics. Incorporation of pharmacogenomics could likewise allow reductions in sample sizes, which is a particular issue in pediatric studies.
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. In the absence of appropriate pediatric formulations and pediatric labeling of medications, pharmacists may create an extemporaneous formulation that differs from the formulation provided and studied by the drug makers.
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For younger children who cannot reliably match inhalations to medication release from a handheld metered dose inhaler, companies have developed spacers or chambers that can hold the released medication so that coordinated breathing is not required. Each new drug delivery modality requires extensive documentation from clinical trials to show that the drug is delivered as anticipated or reaches effective concentrations in children.
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From page 52... ...
As discussed further in Chapter 5, efficacy endpoints in pediatric clinical trials may differ from the endpoints in studies with adults and may also vary across pediatric age groups. Alternative and Surrogate Endpoints Efficacy measures used for adults or older pediatric age groups are sometimes not suitable for use with younger age groups.
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From page 53... ...
FDA has recognized in various contexts the value of surrogate measures in pediatric trials. For example, in 2000 draft guidance on pediatric oncology studies, the agency emphasized that approval of a drug for pediatric use could be based on a drug's effect on tumor size or other surrogate measure that was likely to predict clinical benefit (CDER/ CBER, 2000)
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From page 54... ...
Because infection with HIV can negatively affect children's growth, growth has been incorporated into composite endpoint measures for some pediatric studies of antiretroviral drugs. Although changes in weight were the initial focus, studies have suggested that changes in height are more closely related to survival (Benjamin et al., 2004)
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From page 55... ...
(It also shows -- without explanation -- that FDA released the sponsor from the requirement for the deferred clinical studies with children in the 2- to 5-year-old age group.) Studies with Different Pediatric Populations As explained above, developmental differences within the pediatric population often require that separate clinical studies be undertaken with individuals in different age groups.
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From page 56... ...
As a result, with FDA and institutional review board agreement, sponsors of pediatric drug studies typically develop needed pharmacokinetic evidence by using a combination of data from previous studies with adults and new data from studies involving children who have the condition being studied. For example, the clinical pharmacology review for the drug sotalol (Betapace)
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. Other Modifications in Trial Design Among other advances in strategies for designing clinical studies, adaptive trial designs are potentially helpful in pediatric drug studies.
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, and crossover and multiple-crossover designs. Infrastructure for Research in Pediatric Therapeutics The kinds of challenges outlined above have prompted efforts to create and maintain research resources to support drug studies that appropriately accommodate developmental variability.
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From page 59... ...
. In 2010, NICHD announced a contract for Duke University to create the Pediatric Trials Network to develop a stronger infrastructure for clinical trials in support of the institute's BPCA program, which focuses on high-priority studies of off-patent drugs (Berezny et al., 2011)
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To the extent that those involved in implementing the initiative for clinical trials consider developmental issues and solicit pediatric expertise, it should in the future yield improvements in the value of pediatric studies requested under BPCA or required under PREA.
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From page 61... ...
Thus, in an editorial discussing statins and children, Stein (2007) suggested that "given the residual uncertainty of the impact on safety, growth, and sexual development in the younger age groups and the fact that clinical events do not appear until the mid to late 20s at the earliest, it would still appear prudent to delay the start of statin and other lipid-lowering drug therapy until the age and sexual development stage outlined by the recent AHA [American Heart Association]
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From page 62... ...
The exclusivity incentive and other features of BPCA and PREA explicitly recognize and accommodate some distinctive features of pediatric research. Notably, with direction from Congress and on its own initiative, FDA has applied additional expertise in pediatrics and pediatric research to the oversight of pediatric study requests or requirements, discussions with sponsors about acceptable research designs, and appropriate review of submitted pediatric data (see Chapters 3 and 4)
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