Why Pediatric Studies and a Special Focus on Safety Reporting are Necessary?

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Chapter: Pharmacovigilance: Pharmacovigilance in Pediatrics

There are fewer patients affected with pediatric diseases or conditions and trial designs reflect this pragmatic recognition of what is reasonable to expect versus what may be ideal.


In addition to reasons outlined in other chapters of this book as to why some safety issues are not identified until after a product has been approved and on the market (postmarket), there are seven aspects of pediatric drug development and use which contribute to the probability a safety signal may not be identified in the pediatric population until postmarketing.

The first of these aspects is the relatively small number of pediatric patients who are often involved in pediatric trials. There are fewer patients affected with pediatric diseases or conditions and trial designs reflect this pragmatic recognition of what is reasonable to expect versus what may be ideal.

·   Children are less frequently involved in early phase 1 pharmacokinetic and safety and phase 2 dose-finding and safety studies. This means development of larger phase 3 pediatric trials may be based on information obtained in adults and some pharma-cokinetic studies in pediatrics.

·   There is intrinsic variation that exists across pedi-atric age groups. Product development programs in pediatrics specifically focus on attempting to iden-tify appropriate changes in dosing due to differ-ences in absorption, metabolism, distribution and elimination in the various pediatric age groups. As a result of these differences, one subpopulation of pediatrics may be more or less likely to experience higher levels and/or differences in response to a therapy. Again, because the numbers become very limited when dealing with a subpopulation in pedi-atrics, it becomes even more difficult to ascertain the real frequency of an adverse event prior to its use in a larger postmarketing population.

·   There is extensive off-label use of products within the pediatric population. This off-label use encom-passes both use in pediatric subgroups which have not been studied for an indication obtained in one pediatric subgroup, and for other indications which have not been studied in any or most pediatric subgroups, but are marketed for adults.

·   Children have unique exposures through pre-natal (in-utero exposure) and breast milk. Breast-milk exposures are not routinely evaluated for effects on the child. Animal models are utilized to attempt to determine teratogenicity of a product but have limi-tations as to identification of long-term outcomes not associated with being a teratogen.

·   Because of a lack of pediatric-appropriate formu-lations, there is frequent use of compounded or extemporaneous preparations which are usually not tested for bioavailability, drug–drug or drug– food interactions and may contain excipients with unknown risks thereby increasing the potential for errors in dosing, delivery and adverse events.

·   The growing and evolving nature of children requires attention to potential effects on physical growth, puberty, cognition, and other developmen-tal parameters. Most studies in children are directed to defining the safety and efficacy of a product for a condition during a certain age or develop-ment time frame. No one realistically expects that one can study all the possible adverse effects a product used at one stage of development may have on all latter stages of a child’s development. Recognizing a product may have delayed effects on growth, puberty, behaviour, development and cognitive abilities, there is a clear need to develop focused, long-term studies and surveillance which involve follow-up directed at answering questions regarding the potential longer-term effects of some therapies.

All of these pediatric-unique issues increase the need for specific, focused, active postmarketing pediatric surveillance systems.

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