Do Paediatric Investigation Plans (PIPs) Advance Paediatric Healthcare?

Abstract

Since 2007, new drugs need a paediatric investigation plan (PIP) for EU registration. The PIPs' justifications can be traced back to concerns expressed by Shirkey that label warnings against paediatric use made children "therapeutic orphans", and the American Academy of Pediatrics' claim that all children differ considerably from adults. US legislation first encouraged, then also required, separate, adult-style safety and efficacy studies in all paediatric subpopulations. This triggered paediatric regulatory studies by the pharmaceutical industry. There were also negative outcomes, as a result of using the legal definition of childhood as a medical/physiological term. The "therapeutic orphans" concept became dogma that supported/expanded adult-style regulatory testing into all age groups even when poorly justified in adolescents or where other methods are available to generate needed data. PIPs are especially problematic because they lack the limitations imposed on the Food and Drug Administration's (FDA's) regulatory actions and more practical approaches used in the USA. Many PIP studies are medically senseless or even questionable and/or unfeasible with poor risk/benefit ratios. For example, physiologically mature adolescents have been exposed to treatments and doses known to be suboptimal in adults. Unfeasible PIP studies in rare diseases may harm patients by preventing their participation in more beneficence-driven studies. PIP-required studies can prevent effective treatment of allergic rhinitis during years of placebo treatment, exposing minors to the risk of disease progression to asthma. The PIP system should be revised; more should be done by key players, including institutional review boards/ethics committees, to ensure that all paediatric clinical studies are medically justified, rather than legislation driven, and can produce scientifically valid results.