Pediatric cardiovascular safety: challenges in drug and device development and clinical application.

Development of pediatric medications and devices is complicated by differences in pediatric physiology and pathophysiology (both compared with adults and within the pediatric age range), small patient populations, and practical and ethical challenges to designing clinical trials. This article summarizes the discussions that occurred at a Cardiac Safety Research Consortium-sponsored Think Tank convened on December 10, 2010, where members from academia, industry, and regulatory agencies discussed important issues regarding pediatric cardiovascular safety of medications and cardiovascular devices. Pediatric drug and device development may use adult data but often requires additional preclinical and clinical testing to characterize effects on cardiac function and development. Challenges in preclinical trials include identifying appropriate animal models, clinically relevant efficacy end points, and methods to monitor cardiovascular safety. Pediatric clinical trials have different ethical concerns from adult trials, including consideration of the subjects' families. Clinical trial design in pediatrics should assess risks and benefits as well as incorporate input from families. Postmarketing surveillance, mandated by federal law, plays an important role in both drug and device safety assessment and becomes crucial in the pediatric population because of the limitations of premarketing pediatric studies. Solutions for this wide array of issues will require collaboration between academia, industry, and government as well as creativity in pediatric study design. Formation of various epidemiologic tools including registries to describe outcomes of pediatric cardiac disease and its treatment as well as cardiac effects of noncardiovascular medications, should inform preclinical and clinical development and improve benefit-risk assessments for the patients. The discussions in this article summarize areas of emerging consensus and other areas in which consensus remains elusive and provide suggestions for additional research to further our knowledge and understanding of this topic.

Essential fatty acid supplementation of DHA and ARA and effects on neurodevelopment across animal species: a review of the literature.

Docosahexanoic acid (DHA) and arachidonic acid (ARA) are long chain essential fatty acids used as supplements in commercial infant formula. DHA/ARA deficient states are associated with adverse neurological outcomes in animals and humans. Preterm infants are at risk for DHA/ARA deficiency. A few clinical reports on the effects of fatty acid supplementation have shown benefit in preterm, low birth weight, and normal infants in the first year of life, whereas others did not. Studies in animals have reported shortened gestation, fetal growth retardation, reduced infant body mass, and increased fetal mortality with consumption of fatty acids during pregnancy. To understand the data that support fatty acid supplementation in infant formula, a review of the animal model literature was undertaken, to examine the effects of DHA/ARA on neurodevelopment, including the effects on visual acuity. Several points emerged from this review. (1) Animal studies indicate that requirements for DHA/ARA vary depending on developmental age. Alterations of the ratio of DHA/ARA can impact developmental outcome. (2) The available studies suggest that while supplementation of DHA/ARA in an appropriate ratio can increase tissue levels of these fatty acids in the brain and retina, tissues sensitive to depletion of fatty acids, the benefit of routine supplementation remains unclear. Few studies measure functional outcome relative to changes in physiologic pools of DHA/ARA after supplementation. (3) Animal literature does not support a clear long-term benefit of replenishing DHA/ARA tissue levels and administration of these fatty acids at concentrations above those in human milk suggests adverse effects on growth, survival, and neurodevelopment.

Juvenile animal studies and pediatric drug development retrospective review: use in regulatory decisions and labeling.

Juvenile animal toxicity studies are conducted to support applications for drugs intended for use in children. They are designed to address specific questions of potential toxicity in the growing animal or provide data about long-term safety effects of drugs that cannot be obtained from clinical trials. Decisions to conduct a juvenile animal study are based on existing data, such as a safety signal already identified in adult studies, or previous knowledge of the drug or chemical class for its potential to impair growth or developmental milestones. In 2006, the FDA issued an industry guidance in which considerations for determining when a juvenile animal study is warranted were outlined. A retrospective study was conducted covering years both before and after the issued guideline to examine the contribution of juvenile animal toxicity studies to the risk/benefit assessment of pediatric drugs at the FDA. The initial findings were presented as part of the May 2010 HESI workshop on the value of juvenile animal studies. The objective of the review was to better understand the value that the juvenile animal study contributes to regulatory decision making for pediatric drug development by looking at when the studies have been included in the product assessment; what, if any, impact the studies had on the regulatory decisions made; and whether the data were incorporated into the label. The data described below represent a first look at impact of the juvenile animal study since the pediatric legislation and the juvenile animal guidance were issued in the US.

Value of juvenile animal studies.

The Developmental and Reproductive Toxicology Technical Committee of the ILSI Health and Environmental Sciences Institute has undertaken a project to address the impact of juvenile animal studies on pediatric drug development. A workshop, sponsored and organized by the Health and Environmental Sciences Institute Developmental and Reproductive Toxicity Technical Committee, was held on May 5-6, 2010, in Washington, DC, to discuss the outcome of a global survey and the value of juvenile animal studies in the development of drugs intended for use in pediatric patients. During this workshop, summary data from the 2009-2010 survey were presented, and breakout sessions were used to discuss specific case studies to try to assess the impact of juvenile animal studies performed to support specific pediatric drug development. The objectives of the Workshop on The Value of Juvenile Animal Studies were to (1) provide a forum for scientists representing industry, academia, and regulatory agencies to discuss the impact of juvenile animal studies on pediatric drug development, (2) evaluate summary data from the survey to understand how the juvenile study data are being used and their impact in labeling and risk assessment, (3) discuss selected case studies from the survey to highlight key findings, and (4) identify the areas of improvement for the designs of juvenile animal studies. The take home message that resonated from the workshop discussions was that well-designed juvenile animal studies have demonstrated value in support of certain pediatric drug development programs. However, it was also clear that a juvenile animal study is not always warranted.

Comparison of developmental toxicology of aspirin (acetylsalicylic acid) in rats using selected dosing paradigms.

BACKGROUND: Analysis of the literature for nonsteroidal anti-inflammatory drugs (NSAIDs) suggests that a low incidence of developmental anomalies occurs in rats given NSAIDs on specific days during organogenesis. Aspirin (acetylsalicylic acid [ASA]), an irreversible cyclooxygenase 1 and 2 inhibitor, induces developmental anomalies when administered to Wistar rats on gestational day (GD) 9, 10, or 11 (Kimmel CA, Wilson JG, Schumacher HJ. Teratology 4:15-24, 1971). There are no published ASA studies using the multiple dosing paradigm of GDs 6 to 17. Objectives of the current study were to compare results between Sprague-Dawley (SD) and Wistar strains when ASA is administered on GD 9, 10, or 11; to compare the malformation patterns following single and multiple dosings during organogenesis in SD rats; and to test the hypothesis that maternal gastrointestinal toxicity confounds the detection of low incidence malformations with ASA when a multiple dosing paradigm is used. METHODS: ASA was administered as a single dose on GD 9 (0, 250, 500, or 625 mg/kg), 10 (0, 500, 625, or 750 mg/kg), or 11 (0, 500, 750, or 1000 mg/kg) and from GD 6 to GD 17 (0, 50, 125, or 250 mg/kg a day) in the multiple dose study to SD rats. Animals were killed on GD 21, and fetuses were examined viscerally. RESULTS: The literature evaluation suggested that NSAIDs induce ventricular septal defects (VSDs) and midline defects (MDs) in rats and diaphragmatic hernia (DH), MDs, and VSDs in rabbits (Cook JC et al., 2003); hence, the present study focused on these malformations, even though ASA induces several other low-incidence malformations. In single dose studies, DH, MD, and VSD were induced on GDs 9 and 10. VSD also was noted following treatment on GD 11. In contrast, DH and MD were noted in the multiple dose study design only in the high-dose group, and VSD was noted across all dose groups. CONCLUSIONS: High concordance in major developmental anomalies between Wistar and SD rats were noted with the exception of VSD in the SD rats and hydrocephalus in the Wistar rats. Variations and malformations were similar when ASA was administered as a single dose or during the period of organogenesis (GDs 6 to 17). It was also evident that, by titrating the dose to achieve a maximum tolerated dose, malformations that normally occur at low incidence, as reported from previous single dose studies, could also be induced with ASA given at multiple doses.