Evaluating dose response from flexible dose clinical trials.docVIP

BMC Psychiatry BioMedCentral Research article Open Access Evaluating dose response from flexible dose clinical trials Ilya Lipkovich*1, David H Adams1, Craig Mallinckrodt1, Doug Faries1, David Baron2 and John P Houston1 Address: 1Lilly Research Laboratories, Eli Lilly and Company, Indianapolis Indiana, USA and 2Department of Psychiatry and Behavioral Sciences, Temple University School of Medicine, Philadelphia Pennsylvania, USA Email: Ilya Lipkovich* - lipkovichia@; David H Adams - adamsda@; Craig Mallinckrodt - cmallinc@; Doug Faries - d.faries@; David Baron - dbaron@; John P Houston - houstonjp@ * Corresponding author Published: 7 January 2008 Received: 3 April 2007 Accepted: 7 January 2008 BMC Psychiatry 2008, 8:3 doi:10.1186/1471-244X-8-3 This article is available from: /1471-244X/8/3 ? 2008 Lipkovich et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Abstract Background: The true dose effect in flexible-dose clinical trials may be obscured and even reversed because dose and outcome are related. Methods: To evaluate dose effect in response on primary efficacy scales from 2 randomized, double-blind, flexible-dose trials of patients with bipolar mania who received olanzapine (N = 234, 5–20 mg/day), or patients with schizophrenia who received olanzapine (N = 172, 10–20 mg/day), we used marginal structural models, inverse probability of treatment weighting (MSM, IPTW) methodology. Dose profiles for mean changes from baseline were evaluated using weighted MSM with a repeated measures model. To adjust for selection bias due to non-random dose assignment and dropouts, patient-specific time-dependent weights were determined as products of (i) stable weights based on inverse prob