Extrapolation of Efficacy and Dose Selection in Pediatrics: A Case Example of Atypical Antipsychotics in Adolescents With Schizophrenia and Bipolar I Disorder.

Pediatric labeling information for novel atypical antipsychotics can be significantly delayed as the result of time lag between initial drug approval in adults and the completion of pediatric clinical trials. This delay can lead health care providers to rely on limited evidence-based literature to make critical therapeutic decisions for pediatric patients. Effective and scientifically justified dosing recommendations are needed to improve treatment outcomes in pediatric patients with schizophrenia and bipolar I disorder. 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 US Food and Drug Administration (FDA) released a general advice letter to sponsors highlighting the acceptance of extrapolating efficacy of atypical antipsychotics to pediatric patients. This review provides insight into the FDA's justification for extrapolating efficacy from adult to pediatric patients and provides a rationale for dose selection in pediatric patients with schizophrenia and bipolar I disorder.

The Trend of Increasing Placebo Response and Decreasing Treatment Effect in Schizophrenia Trials Continues: An Update From the US Food and Drug Administration.

OBJECTIVE: Concerns of increasing placebo response and declining treatment effect in acute schizophrenia trials have been reported for new drug applications (NDAs) submitted to the US Food and Drug Administration (FDA) during an 18-year period from 1991 through January 2009 (ie, the pre-2009 period). Current exploratory analyses provide an update in the trends observed in placebo response, treatment effect, and dropout rates for NDAs submitted from February 2009 to 2015 (ie, the post-2009 period). DATA SOURCES: Clinical trial data from all acute schizophrenia trials that were submitted as part of NDAs to the US FDA during a 24-year period from 1991 to 2015. STUDY SELECTION: Aggregate trial-level efficacy data from multicenter, multiregional, randomized, placebo-controlled, 4- to 8-week, fixed- and flexible-dose trials in adult schizophrenia patients were compiled. There were 12 NDAs pre-2009 (32 trials, N = 11,567) and 3 NDAs post-2009 (14 trials, N = 6,434). DATA EXTRACTION: Baseline demographic and disease variables and scores on the Positive and Negative Syndrome Scale (PANSS) were summarized and compared for the two time periods (pre-2009 and post-2009). The primary efficacy measure was mean change from baseline to endpoint in total PANSS score obtained by last-observation-carried-forward analysis. Regional differences in placebo response and treatment effect were explored for the two time periods based on baseline patient characteristics, sample size, and dropout rates. RESULTS: Trials were predominantly multiregional (10/14; 71%) during the post-2009 period compared to the pre-2009 period (11/32; 34%). The overall trial success rates were 57% (8/14) and 78% (25/32) during the post-2009 and pre-2009 periods, respectively. Comparing the pre-2009 and post-2009 periods, the mean placebo response (change from baseline in PANSS score) increased from -6.4 to -10.5 and the mean treatment effect (drug response - placebo response) declined from -8.6 to -5.8 , with substantial differences observed especially in North American trials. In North American trials, placebo response increased from -4.3 (pre-2009) to -8.5 (post-2009), and treatment effect decreased from -9.0 (pre-2009) to -3.4 (post-2009). The difference in placebo response (pre- and post-2009: -10.0 and -11.3 ) and treatment effect (pre and post-2009: -8.1 and -6.4 ) in multiregional trials for the two time periods remained minimal. Baseline disease severity remained similar in the pre- and post-2009 time periods, with PANSS scores ranging between 85 and 100. Trials with higher mean baseline PANSS scores tended to show higher treatment effect irrespective of the time period and region. Post-2009, dropout rates were higher (55%) in North American trials compared with 33% in multiregional trials, similar to the pre-2009 trend. CONCLUSIONS: The continuing trend of increasing placebo responses and decreasing treatment effects in schizophrenia trials over the 24-year period does remain of great concern, especially with respect to North American trials. However, given the current global nature of drug development, close attention to trial conduct and reexamination of design elements for future trials may be warranted.

Assessment of Similarity in Antipsychotic Exposure-Response Relationships in Clinical Trials Between Adults and Adolescents With Acute Exacerbation of Schizophrenia.

Despite agreement that early-onset schizophrenia is continuous with the adult-onset form, quantitative relationships between antipsychotic exposure and clinical response are relatively unexplored in adolescents, compared to adults. Clinical efficacy data from second-generation antipsychotic development programs (N = 5951 adults and N = 1035 adolescents ranging from 12 to 17 years old) were collected from available new drug applications submitted to the US Food and Drug Administration from 1993 to 2017. The developed disease-drug trial models adequately predicted the longitudinal trend in total positive and negative syndrome scale scores in both adults and adolescents using a Weibull placebo response, time-delayed drug effect, and a Weibull structural dropout model. Maximum drug effect was similar between the two populations and was estimated to be between a range of 5% to 11% in adults and 5% to 7% in adolescents. Half maximal effective concentration parameter estimates also indicated similar exposure-response relationships in adults and adolescents across all 4 antipsychotics. Simulated adolescent data using final model parameter estimates from the adult model were in agreement with adolescent observations. This analysis confirms similarity in exposure-response for efficacy and could expedite the development of second-generation antipsychotics for adolescents.

A Quantitative Justification of Similarity in Placebo Response Between Adults and Adolescents With Acute Exacerbation of Schizophrenia in Clinical Trials.

Early-onset schizophrenia, or "adolescent schizophrenia," has a global incidence ranging up to 4% of all schizophrenia cases. Clinical data from antipsychotic programs were collected from new drug applications submitted to the US Food and Drug administration from 1993 to 2015. A placebo response-dropout model was developed to describe the time course of total positive and negative syndrome scale (PANSS) scores in adults and adolescents. The final model in both populations suggested that patients with higher baseline scores exhibited a greater absolute reduction from baseline. Higher baseline total PANSS, enrollment in US trials, and increases or small improvements in total PANSS were found to be predictors of dropout in both populations. Simulated adolescent data using the final adult placebo response model resembled the observed adolescent data. By confirming similar changes in disease symptomology during an acute exacerbation, efficient regulatory pathways for adolescents can be facilitated by using the extrapolation paradigm.

Proton magnetic resonance spectroscopic imaging in pediatric major depression.

BACKGROUND: Neurobiologic abnormalities in dorsolateral prefrontal cortex (DLPFC) are believed to be involved in the pathophysiology of major depressive disorder (MDD). Although MDD commonly emerges during childhood and adolescence, to our knowledge, no prior study has examined the DLPFC in pediatric patients with MDD. METHODS: In this study, choline compounds (Cho), N-acetylaspartate (NAA), and creatine/phosphocreatine (Cr) were measured in left and right DLPFC using a multislice proton magnetic resonance spectroscopic imaging sequence with validated phantom replacement methodology in 11 treatment-naïve MDD patients, 10-16 years of age, and 11 case-matched healthy control subjects. RESULTS: A significant increase in Cho was observed in left but not right DLPFC in MDD patients versus control subjects (32.5% higher). No significant differences in NAA or Cr were observed between case-control pairs. CONCLUSIONS: These results provide new evidence of localized functional neurochemical marker alterations in left DLPFC in pediatric MDD. Our results must be considered preliminary, however, given the small sample size.

Hypoplasia of the corpus callosum and obsessive-compulsive symptoms.

Abnormalities in the corpus callosum, which connects the cerebral hemispheres, have been implicated in the pathogenesis of obsessive-compulsive disorder. This is a report of two cases of obsessive-compulsive disorder associated with hypoplasia of the corpus callosum. These data provide further support for corpus callosum-mediated dysfunction in obsessive-compulsive disorder.

Practice parameter for child and adolescent forensic evaluations.

This Parameter addresses the key concepts that differentiate the forensic evaluation of children and adolescents from a clinical assessment. There are ethical issues unique to the forensic evaluation, because the forensic evaluator's duty is to the person, court, or agency requesting the evaluation, rather than to the patient. The forensic evaluator clarifies the legal questions to be answered and structures the evaluation to address those issues. The forensic examination may include a review of collateral information, interviews and other assessments of the child or adolescent, and interviews with other relevant informants. The principles in this Parameter suggest the general approach to the forensic evaluation of children and adolescents and are relevant to delinquency, child custody, child maltreatment, personal injury, and other court-ordered and noncourt-ordered evaluations.