The FDA Pediatric Advisory Committee met in November to review drug trials and safety data for several medications under consideration for pediatric-specific labeling. Drugs included the antipsychotics olanzapine (Zyprexa) and risperidone (Risperdal). Although not yet finding sufficient evidence of safety and efficacy in this population, the committee specified additional information that could be submitted for the applications to be reconsidered. FDA approval of the supplemental New Drug Applications (sNDAs) could occur without the advisory committee support. If approved, product patent and “exclusivity” from generics is extended for the pediatric indications under the Best Pharmaceuticals for Children Act (BPCA) reauthorization, passed September 2007 to encourage pediatric drug testing for age-specific labeling.
Thomas Laughren, MD, director of the FDA Division of Psychiatric Products, summarized the agency’s evaluation of the olanzapine studies for the committee. He indicated that the data generally support the sNDA for acute mania of bipolar disorder and for schizophrenia in pediatric patients.
A 3-week randomized, placebo- controlled, flexible-dose study was conducted in multiple sites in the United States and Puerto Rico in adolescents 13 to 17 years of age with acute mania in bipolar disorder type I. A 6-week trial was also conducted at sites in the US and in Russia with patients of that age-group who had schizophrenia.
In his summary assessment, Laughren indicated that results in those with bipolar disorder were “highly favorable” to olanzapine. The study was characterized as positive in demonstrating efficacy: active drug was associated with significantly greater improvement of symptoms from baseline, measured in total score on an Adolescent Structured Young Mania Rating Scale (YMRS). There were fewer dropouts attributed to lack of efficacy (20% with olanzapine vs 35% with placebo).
The number of patients who discontinued therapy because of a lack of efficacy was even greater in the study on schizophrenia: 14% of the olanzapine recipients and 51% of placebo recipients left the study. “This finding by itself is almost enough, in my view, to convince one of the benefits in this condition,” Laughren said.
Although olanzapine treatment was also superior to placebo in improving symptoms of schizophrenia, measured with a children’s version of the Brief Psychiatric Rating Scale (BPRS-C), there was a disparity in results between the US and Russian sites. Treatment effect of olanzapine was comparable at sites in both countries; however, the placebo response was much larger in the US, and the statistical superiority of olanzapine was largely derived from the Russian data. In addition, the Russian sites appeared to be more successful than those in the US in recruiting study participants.
These disparities—and reliance on non-US sites for a statistically favorable outcome—had been of particular concern to one FDA analyst, Laughren noted, and were considered a possible basis for finding the application “unapprovable.”