Evaluating dose response from flexible dose clinical trials.
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 probability of receiving the sequence of dose assignments that was actually received by a patient up to given time multiplied by (ii) stable weights based on inverse probability of patient remaining on treatment by that time. Results were compared with those by unweighted analyses.


RESULTS
While the observed difference in efficacy scores for dose groups for the unweighted analysis strongly favored lower doses, the weighted analyses showed no strong dose effects and, in some cases, reversed the apparent "negative dose effect."


CONCLUSIONS
While naïve comparison of groups by last or modal dose in a flexible-dose trial may result in severely biased efficacy analyses, the MSM with IPTW estimators approach may be a valuable method of removing these biases and evaluating potential dose effect, which may prove useful for planning confirmatory trials.
Lipkovich
Ilya
I
Lilly Research Laboratories, Eli Lilly and Company, Indianapolis Indiana, USA. lipkovichia@lilly.com
Adams
David H
DH
Mallinckrodt
Craig
C
Faries
Doug
D
Baron
David
D
Houston
John P
JP
D000208:Acute Disease; D000328:Adult; D014150:Antipsychotic Agents / Q000008:administration & dosage*; D001569:Benzodiazepines / Q000008:administration & dosage*; D001714:Bipolar Disorder / Q000175:diagnosis / Q000188:drug therapy*; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D000077152:Olanzapine; D011336:Probability; D011618:Psychotic Disorders / Q000175:diagnosis / Q000188:drug therapy*; D016032:Randomized Controlled Trials as Topic / Q000706:statistics & numerical data*; D012107:Research Design; D018967:Risperidone / Q000008:administration & dosage*; D012559:Schizophrenia / Q000175:diagnosis / Q000188:drug therapy*; D015983:Selection Bias; D016896:Treatment Outcome
D014150:Antipsychotic Agents; D001569:Benzodiazepines; D018967:Risperidone; D000077152:Olanzapine