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Regulatory News | 25 March 2016 | By Michael Mezher
In a recently published article, officials from the US Food and Drug Administration (FDA) say that studies comparing the effects of drugs in juvenile animal populations against their effects in adult animals are generally not useful in guiding pediatric clinical development, especially if such studies delay the launch of a clinical trial.
The authors of the article, John Leighton, Haleh Saber, Gregory Reaman and Richard Pazdur, of FDA's Office of Hematology and Oncology Products (OHOP) in the Center for Drug Evaluation and Research, reached their conclusion after evaluating data from both publicly available and non-public juvenile animal studies submitted to the agency to support pediatric oncology studies.
In 2006, FDA published its guidance, Nonclinical Safety Evaluation of Pediatric Drug Products, to help sponsors design nonclinical studies in animals to assess whether drugs' effects are different in children compared to adults, in situations where it would be unethical or difficult to assess in pediatric trials.
Later, in 2010, the International Conference on Harmonization (ICH) developed its guidance, ICH S9: Nonclinical Evaluation for Anticancer Pharmaceuticals, which makes recommendations on what types of nonclinical studies should be conducted before testing cancer drugs in humans. The ICH guidance favors expediency in launching pediatric participation in Phase I trials, stating, "studies in juvenile animals are not usually conducted in order to support inclusion of pediatric populations for the treatment of cancer."
ICH's recommendation is based on the rationale that data from adult patients and heightened safety monitoring can offset the risk to pediatric patients enrolling in these trials, given the life threatening nature of their disease.
Several recent papers have taken contrasting views of the value of juvenile animal studies used to support pediatric clinical trials. Two papers, The value of juvenile animal studies: "What have we learned from preclinical juvenile toxicity studies? II" (Baily and Marien, 2011) and Juvenile animal testing in drug development--is it useful? (Baldrick, 2010) dispute whether such studies provide useful or actionable data, while another paper, Use of juvenile animal studies to support oncology medicine development in children (Duarte, 2015), argues that the data are useful, as nearly a quarter of drugs the author examined "revealed some differences in toxicity between adult and juvenile animals."
To address these conflicting viewpoints, OHOP reviewed the studies highlighted by Duarte, as well as non-publicly available studies submitted to the agency by sponsors developing cancer drugs.
"After examining available JAS data, and considering factors such as the short life expectancy and the serious nature of the disease, OHOP concluded that juvenile animal studies conducted to date have not provided useful information to support [first-in-pediatric] development for anticancer drugs, consistent with the recommendations outlined in ICH S9," they write.
Additionally, the authors found that data from juvenile animal studies did not influence how pediatric trials were conducted, nor did they guide dose selection. In some cases, they write, the only effects identified by juvenile animal studies were already expected or previously described in the literature.
According to FDA's 2006 guidance, the one of the primary goals of conducting juvenile animal studies is to detect whether drugs might have an effect on a child's growth and development. However, due to the short life expectancy of pediatric oncology patients, the long-term follow up that this would require is "difficult, if at all possible."
However, the authors say juvenile animal studies are useful at times when "clinical and/or nonclinical data available do not provide sufficient information on toxicities," but should be conducted to "address a specific safety concern."
An FDA Oncology View of Juvenile Animal Studies in Support of Initial Pediatric Trials for Anticancer Drugs
Tags: Juvenile animal studies, pediatric trials, Richard Pazdur