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.

Lead in pharmaceutical products and dietary supplements.

The objective of this study is to determine lead concentrations in a variety of widely used pharmaceutical products, and to assess the risk of lead exposure from using these products. Lead concentrations of 45 products were measured with inductively-coupled plasma mass spectrometry. Six products had lead concentrations greater than 100 parts per billion (ppb), and the highest measured concentration was 500 ppb. The average mass of lead delivered to consumers by all products examined in this study when taken as directed was 0.22 micrograms per day, which is expected to increase the blood lead level of an adult by less than 1%. Five products were found to deliver more than 1 microg of lead per day when used as directed. Current tolerable lead limits in pharmaceutical substances vary widely, and in some cases exceed 10,000 ppb. The products examined in this study have lead concentrations far below these levels. However, in light of recent research demonstrating adverse effects in both children and adults from low level lead exposure, current lead limits for pharmaceutical substances are unacceptably high. Uniform lead limits that reflect current manufacturing capabilities are needed to insure the lowest achievable exposure to lead from these products.