Laughren acknowledged that the concern raised questions about study conduct at the Russian sites but assured the committee that the sites had been inspected and that there was no evidence of misconduct.
“It is also important to point out,” Laughren indicated, “that there are alternative explanations for more successful recruitment at the Russian sites and also a more successful outcome.”
Among the factors that could lead to the geographic disparity, Laughren explained, is the greater catchment area and less competition for recruitment in Russian sites. “If difficulty in recruitment in the US sites led to enrollment of a more heterogeneous group of subjects,” he noted, “this could have led to a higher placebo response rate.”
In concluding his report, Laughren pointed to the demonstrated efficacy of olanzapine(Drug information on olanzapine) in adults and argued that the geographic disparity in the pediatric data was not sufficient to find the sNDA nonapprovable. He indicated, however, that the agency would ask the sponsoring manufacturer“to further address this concern.”
The pharmacokinetic data for olanzapine did not indicate significant differences between adolescents and adults, although the younger population tended to be exposed to higher dosages in relation to body weight. The adverse event profile and other safety parameters were also similar to those in adults but with some greater magnitude in the younger patients. Laughren indicated that these distinctions could be reflected in modified labeling.
“In addition,” Laughren informed the committee, “we have recently asked the sponsor to provide more complete information generally with regard to effects on weight, glucose regulation, and lipid levels, so that labeling for olanzapine can be enhanced with regard to these risks.”
The committee voted unanimously to recommend that the agency continue to evaluate the safety of olanzapine in the pediatric population and to implement additional risk-management regulatory actions concerning the monitoring of metabolic changes.
Assessing Risperdal, drug class The FDA staff analysis of the Risperdal studies was prepared by Mitchell Mathis, MD, deputy director of the Division of Psychiatry Products. Two 6-week randomized, placebo-controlled trials were conducted in children and adolescents who had schizophrenia, and one 3-week trial was conducted in patients who had bipolar disorder. Active treatment groups in the schizophrenia study received daily doses of either 1 to 3 mg or 4 to 6 mg. Groups in bipolar disorder study received either 0.5 to 2.5 mg or 3 to 6 mg/d.
The data supported the applications. The most useful dosages were 3 mg/d for schizophrenia and 2.5 mg/d for bipolar disorder. Higher dosage was not associated with additional benefit in these studies but with an increase in adverse effects. Mathis suggested that the optimal dosages in the studies should be considered as targets rather than ceilings in pediatric populations.
“While I believe we should certainly label the drug with the information learned from the clinical trials, and even identify target dose . . . ,” he indicated, “I think it would be too restrictive to the prescriber to limit the dose to a maximum when we know that doses up to 6 mg/d were also shown to be efficacious in the same studies that demonstrated efficacy for the lower dose ranges.”
The review of risperidone(Drug information on risperidone) adverse events from the pediatric studies, presented by Felicia Collins, MD, medical officer at the FDA, indicated an adverse-effect profile similar to that in adults. As to whether the standard ongoing safety monitoring is adequate for the expanded indication to pediatrics, the committee unanimously recommended several additional measures for the use of risperidone, olanzapine, and this class of antipsychotics:
• Assess on-label and off-label product use with specific attention to age and indication and concomitant drug use.
• Follow up on metabolic syndrome, growth, sexual maturation, hyperprolactinemia, and extrapyramidalside effects.
• Conduct studies—possibly with the NIH—on long-term effects in the pediatric population.
The committee voted unanimously to withhold recommendation on labeling until this additional information is provided. It also recommended that no public communications be issued on the sNDAs for pediatric populations before the committee has received and discussed data from these measures.