title: A structured framework for assessing sensitivity to missing data assumptions in longitudinal clinical trials.
abstract: The objective of this research was to demonstrate a framework for drawing inference from sensitivity analyses of incomplete longitudinal clinical trial data via a re-analysis of data from a confirmatory clinical trial in depression. A likelihood-based approach that assumed missing at random (MAR) was the primary analysis. Robustness to departure from MAR was assessed by comparing the primary result to those from a series of analyses that employed varying missing not at random (MNAR) assumptions (selection models, pattern mixture models and shared parameter models) and to MAR methods that used inclusive models. The key sensitivity analysis used multiple imputation assuming that after dropout the trajectory of drug-treated patients was that of placebo treated patients with a similar outcome history (placebo multiple imputation). This result was used as the worst reasonable case to define the lower limit of plausible values for the treatment contrast. The endpoint contrast from the primary analysis was - 2.79 (p = .013). In placebo multiple imputation, the result was - 2.17. Results from the other sensitivity analyses ranged from - 2.21 to - 3.87 and were symmetrically distributed around the primary result. Hence, no clear evidence of bias from missing not at random data was found. In the worst reasonable case scenario, the treatment effect was 80% of the magnitude of the primary result. Therefore, it was concluded that a treatment effect existed. The structured sensitivity framework of using a worst reasonable case result based on a controlled imputation approach with transparent and debatable assumptions supplemented a series of plausible alternative models under varying assumptions was useful in this specific situation and holds promise as a generally useful framework.
authors.affiliation: Eli Lilly & Co., Lilly Corporate Center, Indianapolis, IN, USA. cmallinc@lilly.com
authors.forename: C H
authors.initials: CH
authors.lastname: Mallinckrodt
authors.forename: Q
authors.initials: Q
authors.lastname: Lin
authors.forename: M
authors.initials: M
authors.lastname: Molenberghs
mesh_terms: D000928:Antidepressive Agents / Q000627:therapeutic use; D015982:Bias; D017326:Clinical Trials, Phase III as Topic / Q000706:statistics & numerical data*; D003627:Data Interpretation, Statistical; D003863:Depression / Q000175:diagnosis / Q000188:drug therapy / Q000523:psychology; D004311:Double-Blind Method; D006801:Humans; D016013:Likelihood Functions; D008137:Longitudinal Studies; D015233:Models, Statistical; D010352:Patient Dropouts; D016032:Randomized Controlled Trials as Topic / Q000706:statistics & numerical data*; D012189:Retrospective Studies; D013997:Time Factors; D016896:Treatment Outcome
chemical_list: D000928:Antidepressive Agents