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Please use this identifier to cite or link to this item: http://hdl.handle.net/1942/2208

Title: Choice of the primary analysis in longitudinal clinical trials
Authors: Mallinckrodt, Craig H.
Watkin, John G.
Molenberghs, Geert
Carroll, Raymond J.
Issue Date: 2004
Citation: PHARMACEUTICAL STATISTICS, 3(3). p. 161-169
Abstract: Missing data, and the bias they can cause, are an almost ever-present concern in clinical trials. The last observation carried forward (LOCF) approach has been frequently utilized to handle missing data in clinical trials, and is often specified in conjunction with analysis of variance (LOCF ANOVA) for the primary analysis. Considerable advances in statistical methodology, and in our ability to implement these methods, have been made in recent years. Likelihood-based, mixed-effects model approaches implemented under the missing at random (MAR) framework are now easy to implement, and are commonly used to analyse clinical trial data. Furthermore, such approaches are more robust to the biases from missing data, and provide better control of Type I and Type II errors than LOCF ANOVA. Empirical research and analytic proof have demonstrated that the behaviour of LOCF is uncertain, and in many situations it has not been conservative. Using LOCF as a composite measure of safety, tolerability and efficacy can lead to erroneous conclusions regarding the effectiveness of a drug. This approach also violates the fundamental basis of statistics as it involves testing an outcome that is not a physical parameter of the population, but rather a quantity that can be influenced by investigator behaviour, trial design, etc. Practice should shift away from using LOCF A NOVA as the primary analysis and focus on likelihood-based, mixed-effects model approaches developed under the MAR framework, with missing not at random methods used to assess robustness of the primary analysis. Copyright (C) 2004 John Wiley Sons Ltd.
Notes: Eli Lilly & Co, Lilly Corp Ctr, Indianapolis, IN 46285 USA. Limburgs Univ Ctr, Ctr Stat, Diepenbeek, Belgium. Texas A&M Univ, Dept Stat, College Stn, TX 77843 USA.Mallinckrodt, CH, Eli Lilly & Co, Lilly Corp Ctr, Indianapolis, IN 46285 USA.cmallinc@lilly.com
URI: http://hdl.handle.net/1942/2208
Link to publication: https://www.academia.edu/8393357/Choice_of_the_primary_analysis_in_longitudinal_clinical_trials
DOI: 10.1002/pst.124
ISI #: 000224261600002
ISSN: 1539-1604
Category: A1
Type: Journal Contribution
Validation: ecoom, 2005
Appears in Collections: Research publications

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