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In 2014, the US FDA approved liraglutide for weight management. The statistical review of the application presented various challenges related to the handling of missing data. The ability of the drug to cause weight loss was not in question. The challenge centered on obtaining a reliable estimate of the intention-to-treat effect to support the risk-benefit evaluation. Subjects in the trials that stopped treatment prior to the endpoint were encouraged to attend the primary endpoint visit. Data from the subjects that returned for a primary efficacy assessment played a significant role in the statistical review. They were used to illustrate shortcomings of the applicant's primary efficacy analysis and sensitivity analyses. They were also used in the FDA analyses to address missing data. The goal of this article is to illustrate challenges and considerations associated with the handling of missing data in clinical trials.

While randomized controlled trials may not be considered efficient for investigating rare adverse events based on their size, biases associated with other epidemiological designs may justify the additional resources. In certain contexts it may be appropriate, for example, to inflate the noninferiority (NI) margin to decrease the sample size, provided the excess risk that will be ruled out remains clinically relevant. The implication of a reduced sample size on the number of events anticipated from the trial is often not considered at the study design phase but may have important ramifications. To assess the implications of modifying study design parameters, approximations are presented for (a) how likely it is that no events will be observed, (b) how many events should be anticipated, and (c) how likely it is that v or more events will be observed. The approximations presented are intended to serve as tangible a priori expectations from the study. This work is motivated from an FDA Advisory Committee meeting regarding a discussion at the association between long-acting beta-agonists and asthma-related deaths.