Pediatric Cardiovascular Drug Trials, Lessons Learned

Abstract

Few drugs have been labeled for pediatric cardiovascular indications and many children with cardiac disease are prescribed drugs off-label. Recent initiatives have narrowed this gap and as a result there are an increasing number of cardiology trials in the pediatric population. Many studies, however, have either failed to show a dose response in children or have not shown efficacy in children when they have established efficacy in adults. Clinical trials are challenging in children; many factors such as lack of development of a liquid formulation, failure to fully incorporate pharmacokinetic information into trial design, poor dose selection, the lack of clinical equipoise, and the use of difficult surrogate and composite primary endpoints have led to the difficulties and failures observed in several pediatric cardiovascular trials. These lessons learned may help to inform future pediatric clinical trial development.Randomized clinical trials have resulted in remarkable advances in cardiovascular care. During the 1990s, results from more cardiovascular clinical trials were published than in the previous three decades combined, ushering in the current era of evidence-based cardiovascular medicine. (1) Cardiovascular trials have established novel treatments resulting in major improvements in patient outcomes and have also enhanced our understanding of heart disease and the impact of risk factors and adverse events. Certain populations, however, have been underrepresented in cardiovascular clinical trials, including women, the elderly, minority populations, and children (1-3).Many barriers impede the design and conduct of randomized clinical trials in children, including the relative rarity of specific diseases, disease heterogeneity, incompletely defined natural history, lack of research infrastructure, ethical issues in pediatric research, and difficulty in identifying valid clinical endpoints. Systematic controlled studies of medications in children with congenital heart disease have thus been limited and most medications are not labeled for pediatric use. Therefore, treatment decisions in this population are often based on clinical experience, small observational studies, and extrapolation from adult data, rather than clinical trial evidence. Fewer than 25% of approved drugs marketed in the USA have sufficient pediatric data to support approval for labeling for dosing, safety, and efficacy in children. Inadequate dosing and safety information places children at risk for adverse events and denies them potential therapeutic benefits. Pediatricians must therefore prescribe drugs to children for whom the dose, efficacy, and safety have not been studied. This practice known as "off label use" may result in benefit, no effect, or harm. This lack of information has had a negative impact on pediatric therapeutics, including reliance on anecdotal practice patterns, adaptation of data from adult trials that may not be applicable to children, and the use of extemporaneous formulations that may be inconsistently bi...

Characteristics and Changes of Pediatric Therapeutic Trials under the Best Pharmaceuticals for Children Act

“…The challenge encountered with these conditions is that the pathophysiology is often less well-understood and pediatric validated clinical endpoints are often lacking. 16,17 …”

Status of the Pediatric Clinical Trials Enterprise: An Analysis of the US ClinicalTrials.gov Registry

“…Although there may be a lower cost associated with small individual trials, it is possible that if resources were instead directed toward large trials aimed at answering the most important questions, more useful evidence could be generated without increasing total costs. [1][2][3] Third, it is noteworthy that the distribution of trials with regard to therapeutic area seems to generally mirror overall disease burden in children, and there is a higher percentage of trials focused on disease prevention in children. There have been concerns that trials in children may not reflect disease burden because of financial incentives in place for the pharmaceutical industry in the Pediatric Exclusivity Provision to study drugs with a large adult market.…”

“…Recently, several questions have been raised regarding the conduct of clinical trials in children, including how best to prioritize and stimulate research in the areas of greatest clinical need, funding and regulatory issues, and the globalization of research. [1][2][3] In addition, the general underrepresentation of children in clinical research and the limited pediatric evidence-base has lead to several recent federal initiatives aimed at stimulating research in children, beginning with the Pediatric Exclusivity Provision in 1997. [4][5][6] However, it has been difficult to assess the current status of the clinical trial enterprise as a whole, both in terms of characterizing the overall scope of trials being performed and describing changes over time.…”

Perioperative Methylprednisolone and Outcome in Neonates Undergoing Heart Surgery

“…It is also often true, as in this case, that new therapies become widely adopted into routine pediatric practice, based on extrapolation from adults or small pediatric studies, making conducting more rigorous large-scale studies difficult due to the lack of clinical equipoise. 20 However, more recent analyses of large data sets have shown that there is in fact widespread variation in the way corticosteroids are used in this setting, and have questioned the clinical benefit associated with corticosteroids. 1,6 These data support the feasibility and necessity of a large randomized trial.…”