Extrapolation of atypical antipsychotics for the treatment of schizophrenia from adults to adolescents

ObjectivesAntipsychotic drug development in pediatric patients is often challenged by disease heterogeneity, patient recruitment, clinical trial attrition, and ethical concerns. Regulatory agencies have explored various pathways to expedite pediatric drug development over the last decade. Extrapolation-based drug development strategies rely on leveraging prior data to reduce evidentiary requirements for newer data in establishing drug efficacy. On January 13, 2020, the FDA released a general advice letter to sponsors highlighting the acceptance of extrapolating the efficacy of atypical antipsychotics to pediatric patients. This presentation provides insight into the FDA’s justification for extrapolating the efficacy of atypical antipsychotics.MethodsA schizophrenia database was developed using sponsor-submitted applications to the FDA and consisted of 9 adult (N = 17,778) and 6 adolescent (N = 2122) second-generation antipsychotic programs. Similarity of placebo and antipsychotic exposure-response relationships were assessed using the change from baseline in total positive and negative syndrome scale scores. Differences in major adverse effects were analyzed using FDA-authored reviews and approved products labels.ResultsSymptomatic changes and disease course in patients receiving placebo were similar between adults and adolescents across all trials. Pharmacokinetic exposures across antipsychotic dose ranges and trends in exposure-response relationships were also similar between both populations. Analysis of negative adolescent programs also demonstrated consistent trends in placebo and exposure-response. Although no new adverse events were found in the adolescent trials, differences in sedation, metabolic changes, and extrapyramidal symptoms were present between the adults and adolescents.ConclusionsAnalyses of trials evaluating second-generation atypical antipsychotics suggest similar symptomatic changes, responses to intervention, and an exposure-response relationship between adults and pediatric patients. Although a dedicated efficacy study may not be warranted to support efficacy, several additional studies are needed to justify adolescent dose selection and to characterize safety in the adolescent population.PPC, SZ, R ObjectivesAntipsychotic drug development in pediatric patients is often challenged by disease heterogeneity, patient recruitment, clinical trial attrition, and ethical concerns. Regulatory agencies have explored various pathways to expedite pediatric drug development over the last decade. Extrapolation-based drug development strategies rely on leveraging prior data to reduce evidentiary requirements for newer data in establishing drug efficacy. On January 13, 2020, the FDA released a general advice letter to sponsors highlighting the acceptance of extrapolating the efficacy of atypical antipsychotics to pediatric patients. This presentation provides insight into the FDA’s justification for extrapolating the efficacy of atypical antipsychotics. Antipsychotic drug development in pediatric patients is often challenged by disease heterogeneity, patient recruitment, clinical trial attrition, and ethical concerns. Regulatory agencies have explored various pathways to expedite pediatric drug development over the last decade. Extrapolation-based drug development strategies rely on leveraging prior data to reduce evidentiary requirements for newer data in establishing drug efficacy. On January 13, 2020, the FDA released a general advice letter to sponsors highlighting the acceptance of extrapolating the efficacy of atypical antipsychotics to pediatric patients. This presentation provides insight into the FDA’s justification for extrapolating the efficacy of atypical antipsychotics. MethodsA schizophrenia database was developed using sponsor-submitted applications to the FDA and consisted of 9 adult (N = 17,778) and 6 adolescent (N = 2122) second-generation antipsychotic programs. Similarity of placebo and antipsychotic exposure-response relationships were assessed using the change from baseline in total positive and negative syndrome scale scores. Differences in major adverse effects were analyzed using FDA-authored reviews and approved products labels. A schizophrenia database was developed using sponsor-submitted applications to the FDA and consisted of 9 adult (N = 17,778) and 6 adolescent (N = 2122) second-generation antipsychotic programs. Similarity of placebo and antipsychotic exposure-response relationships were assessed using the change from baseline in total positive and negative syndrome scale scores. Differences in major adverse effects were analyzed using FDA-authored reviews and approved products labels. ResultsSymptomatic changes and disease course in patients receiving placebo were similar between adults and adolescents across all trials. Pharmacokinetic exposures across antipsychotic dose ranges and trends in exposure-response relationships were also similar between both populations. Analysis of negative adolescent programs also demonstrated consistent trends in placebo and exposure-response. Although no new adverse events were found in the adolescent trials, differences in sedation, metabolic changes, and extrapyramidal symptoms were present between the adults and adolescents. Symptomatic changes and disease course in patients receiving placebo were similar between adults and adolescents across all trials. Pharmacokinetic exposures across antipsychotic dose ranges and trends in exposure-response relationships were also similar between both populations. Analysis of negative adolescent programs also demonstrated consistent trends in placebo and exposure-response. Although no new adverse events were found in the adolescent trials, differences in sedation, metabolic changes, and extrapyramidal symptoms were present between the adults and adolescents. ConclusionsAnalyses of trials evaluating second-generation atypical antipsychotics suggest similar symptomatic changes, responses to intervention, and an exposure-response relationship between adults and pediatric patients. Although a dedicated efficacy study may not be warranted to support efficacy, several additional studies are needed to justify adolescent dose selection and to characterize safety in the adolescent population.PPC, SZ, R Analyses of trials evaluating second-generation atypical antipsychotics suggest similar symptomatic changes, responses to intervention, and an exposure-response relationship between adults and pediatric patients. Although a dedicated efficacy study may not be warranted to support efficacy, several additional studies are needed to justify adolescent dose selection and to characterize safety in the adolescent population.