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These results are consistent with those obtained previously from smaller pooled data sets, and suggest that duloxetine is safe and well tolerated in patients with MDD.

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 ANOVA 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.

Valid analyses of longitudinal data can be problematic, particularly when subjects dropout prior to completing the trial for reasons related to the outcome. Regulatory agencies often favor the last observation carried forward (LOCF) approach for imputing missing values in the primary analysis of clinical trials. However, recent evidence suggests that likelihood-based analyses developed under the missing at random framework provide viable alternatives. The within-subject error correlation structure is often the means by which such methods account for the bias from missing data. The objective of this study was to extend previous work that used only one correlation structure by including several common correlation structures in order to assess the effect of the correlation structure in the data, and how it is modeled, on Type I error rates and power from a likelihood-based repeated measures analysis (MMRM), using LOCF for comparison. Data from four realistic clinical trial scenarios were simulated using autoregressive, compound symmetric and unstructured correlation structures. When the correct correlation structure was fit, MMRM provided better control of Type I error and power than LOCF. Although misfitting the correlation structure in MMRM inflated Type I error and altered power, misfitting the structure was typically less deleterious than using LOCF. In fact, simply specifying an unstructured matrix for use in MMRM, regardless of the true correlation structure, yielded superior control of Type I error than LOCF in every scenario. The present and previous investigations have shown that the bias in LOCF is influenced by several factors and interactions between them. Hence, it is difficult to precisely anticipate the direction and magnitude of bias from LOCF in practical situations. However, in scenarios where the overall tendency is for patient improvement, LOCF tends to: 1) overestimate a drug's advantage when dropout is higher in the comparator and underestimate the advantage when dropout is lower in the comparator; 2) overestimate a drug's advantage when the advantage is maximum at intermediate time points and underestimate the advantage when the advantage increases over time; and 3) have a greater likelihood of overestimating a drug's advantage when the advantage is small. In scenarios in which the overall tendency is for patient worsening, the above biases are reversed. In the simulation scenarios considered in this study, which were patterned after acute phase neuropsychiatric clinical trials, the likelihood-based repeated measures approach, implemented with standard software, was more robust to the bias from missing data than LOCF, and choice of correlation structure was not an impediment to its implementation.

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