title: Trial design issues and treatment effect modeling in multi-regional schizophrenia trials.
abstract: In recent years, we have seen an increasing trend of foreign data as part of clinical trial data submitted in new drug applications (NDA) to US Food and Drug Administration (FDA). To understand the design and analysis characteristics, we studied schizophrenia multi-regional clinical trials (MRCTs). The schizophrenia data set consisted of a total of 12,585 patients collected from 33 clinical trials with 63.8% patients from North America, the largest region. The data set constituted 10 schizophrenia drug programs in support of NDAs submitted to FDA from December 1993 to December 2005. Two main objectives were pursued. First, we investigated some study design issues including potential heterogeneity of treatment effect via meta analysis and placebo response pattern over time. Second, we performed empirical modeling in two ways, supervised and unsupervised, to explain potential impact of baseline covariates on treatment effect in MRCTs. Based on our analysis results, placebo response appeared to increase over time and primarily attributed to US region. On average, the observed treatment effect in the US was generally smaller than non-US region. Both supervised and unsupervised empirical modeling selected baseline Positive and Negative Syndrome Scale total score as one of the most important covariates explaining a treatment effect. Region also played a role in explaining potential treatment effect heterogeneity. When baseline body weight was considered as a covariate in an empiric model, our results indicated that it alone did not seem to be an important factor in explaining regional difference.
authors.affiliation: Division of Biometrics I, HFD-710, Food and Drug Administration, 10903 New HampshireAvenue, Building 21, Room 4610, Silver Spring, MD 20993-0002, USA. yehfong.chen@fda.hhs.gov
authors.forename: Yeh-Fong
authors.initials: YF
authors.lastname: Chen
authors.forename: Sue-Jane
authors.initials: SJ
authors.lastname: Wang
authors.forename: Ni A
authors.initials: NA
authors.lastname: Khin
authors.forename: H M James
authors.initials: HM
authors.lastname: Hung
authors.forename: Thomas P
authors.initials: TP
authors.lastname: Laughren
mesh_terms: D000328:Adult; D014150:Antipsychotic Agents / Q000627:therapeutic use; D003661:Decision Support Techniques; D017277:Drug Approval / Q000706:statistics & numerical data; D015507:Drugs, Investigational; D005260:Female; D005843:Geography; D006801:Humans; D038622:Internationality; D008297:Male; D008875:Middle Aged; D015233:Models, Statistical; D015337:Multicenter Studies as Topic / Q000379:methods / Q000706:statistics & numerical data; D009656:North America; D011569:Psychiatric Status Rating Scales / Q000706:statistics & numerical data; D016032:Randomized Controlled Trials as Topic / Q000379:methods / Q000706:statistics & numerical data; D012107:Research Design / Q000706:statistics & numerical data; D012559:Schizophrenia / Q000188:drug therapy; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D014150:Antipsychotic Agents; D015507:Drugs, Investigational