Missing Data in Confirmatory Clinical Trials

Abstract

Missing data for key efficacy and safety endpoints in clinical trials have the potential to undermine the scientific integrity of the study and prevent definitive conclusions regarding the safety and efficacy of an experimental product. Much of the missing data is the result of poor protocol design and a lack of agreement in the scientific community regarding the collection of study data after treatment discontinuation instead of an inability to collect the data. Rather than dealing with the fundamental causes of missing data, the statistical community has traditionally attempted to explicitly impute the missing data based upon observed data or more recently through the use of statistical models that implicitly impute the missing data. In this article, the causes for missing data are described and a number of approaches to maintain the integrity of the studies are described.

Choice of estimand and analysis methods in diabetes trials with rescue medication

“…If so, then we have to somehow deal with the effect of rescue medication. Flyer and Hirnan argue that ‘the use of continuous measures should be abandoned if at all possible and a binary endpoint should be used that allows for the incorporation of treatment failure’ . While this may be uncontroversial in terms of testing the null hypothesis of no treatment effect, such dichotomization is undesirable because of its statistical inefficiency .…”

A Multiple Imputation Method for Sensitivity Analyses of Time-to-Event Data with Possibly Informative Censoring

“…A rationale for this practice is that it provides potentially useful information about the experiences of these patients for their remaining follow-up time until their planned (or premature) discontinuation from the study (Flyer and Hirman, 2009; Walton, 2009). However, the role of this information can be unclear when patients receive effective rescue treatment after discontinuing their assigned treatment (Flyer and Hirman, 2009). For example, the comparison of regimens that begin with test treatment or placebo followed by effective rescue therapy after their discontinuation could erroneously suggest that an ineffective test treatment is effective solely because it forces more patients to switch to rescue therapy than placebo (Permutt and Pinheiro, 2009).…”

“…Alternatively, discontinuation from treatment can be specified as clinical failure when the event of interest is unfavorable (Flyer and Hirman, 2009). In this case, one has a composite endpoint (i.e., time to the event of interest or discontinuation), and it expresses the time period for which a patient has had favorable experience with treatment.…”

Methodological Issues on a Clinical Trial to Test Tapentadol Prolonged release vs. Oxycodone/Naloxone Prolonged release

“…Pain (NRS) and PainDETECT scores in these patients were allowed to be slightly lower at enrollment due to the use of co‐analgesics, expecting that scores would rise after their mandatory washout and they had to be ≥ 6 (for NRS) and “unclear” (PainDETECT) at randomization (baseline) for all patients. Imputation: The use of any type of imputation or no imputation represents a form of bias. As per the EMA guidance for missing data, there is no universally applicable method of handling missing data . The imputation method was fully prespecified at the beginning of the trial.…”