title: The analysis of a multiple-dose, combination-drug clinical trial using response surface methodology.
abstract: We consider the situation where a multiple-dose, combination-drug clinical trial is conducted to identify one or more combinations that satisfy regulatory requirements. Generally, these requirements involve a compound hypothesis with multiple comparisons. The min test has been shown to be an optimal alpha-level test for testing a single combination drug. Analysis procedures in a multiple-dose, combination-drug study have typically involved classical ANOVA models or multiple regression models in a response surface methodology (RSM) framework. An inferential procedure based on an ANOVA model uses a screening test to address multiple comparison issues and multiple min tests to explicitly identify combinations satisfying regulatory requirements. An exploratory procedure based on RSM modeling is used to build a segmented linear model and a stairstep linear model to describe dose-response relationships. The two procedures are mutually supportive of one another in providing a broader assurance in the identification of effective combinations.
authors.affiliation: Quintiles, Inc., Research Triangle Park, North Carolina 27709-3979.
authors.forename: J A
authors.initials: JA
authors.lastname: Phillips
authors.forename: V
authors.initials: V
authors.lastname: Cairns
authors.forename: G G
authors.initials: GG
authors.lastname: Koch
mesh_terms: D000704:Analysis of Variance; D000959:Antihypertensive Agents / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004338:Drug Combinations; D006801:Humans; D006852:Hydrochlorothiazide / Q000627:therapeutic use; D006973:Hypertension / Q000188:drug therapy; D008954:Models, Biological; D015337:Multicenter Studies as Topic; D017257:Ramipril / Q000627:therapeutic use; D016032:Randomized Controlled Trials as Topic / Q000706:statistics & numerical data*
chemical_list: D000959:Antihypertensive Agents; D004338:Drug Combinations; D006852:Hydrochlorothiazide; D017257:Ramipril