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Papers of the Week

Papers: 23 May 2020 - 29 May 2020

Human Studies

2020 May 22


Estimands and missing data in clinical trials of chronic pain treatments: advances in design and analysis.


Cai X, Gewandter JS, He H, Turk DC, Dworkin RH, McDermott MP
Pain. 2020 May 22.
PMID: 32453131.


In clinical trials of treatments for chronic pain, the percentage of participants who withdraw early can be as high as 50%. Major reasons for early withdrawal in these studies include perceived lack of efficacy and adverse events. Commonly employed strategies for accommodating missing data include last observation carried forward, baseline observation carried forward, and more principled methods such as mixed model repeated measures and multiple imputation. All of these methods require strong and untestable assumptions concerning the conditional distribution of outcomes after dropout given the observed data. We review recent developments in statistical methods for handling missing data in clinical trials, including implications of the increased emphasis being placed on precise formulation of the study objectives and the estimand (treatment effect to be estimated) of interest. A flexible method that appears to be well-suited for the analysis of chronic pain clinical trials is control-based imputation, which allows a variety of assumptions to be made concerning the conditional distribution of post-dropout outcomes that can be tailored to the estimand of interest. These assumptions can depend, for example, on the stated reasons for dropout. We illustrate these methods using data from four clinical trials of pregabalin for the treatment of painful diabetic peripheral neuropathy and postherpetic neuralgia. When planning chronic pain clinical trials, careful consideration of the trial objectives should determine the definition of the trial estimand, which in turn should inform methods used to accommodate missing data in the statistical analysis.