04. Simulation Study of Hypothetical Estimands Used In Rescue Medication

In interventional clinical trials, rescue medication refers to an alternative treatment administered, in addition to or as a replacement for the study intervention, to trial participants for reasons such as alleviating the worsening of symptoms. While it may benefit the patient, rescue medication may distort the true effect of the intervention being studied. It may then lead to study results that may not align with the original research question. The International Council of Harmonisation (ICH) comprising of representatives from regulatory agencies and pharmaceutical companies provides guidelines on how to handle intercurrent events of which rescue medication is a special case. ICH recommends five strategies. This talk will focus on one of these strategies, namely the hypothetical strategy, and discuss some methods to handle use of rescue. Of particular interest are methods based on the balanced estimand, inverse probability weights, and Loh g-estimation. We illustrate the concepts and methods applied to data from a completed trial on myasthenia gravis, a rare neurological disease. We also conducted simulation studies based on different scenarios to evaluate the performance of these methods and determine which is best in estimating the treatment effect in the presence of rescue medication regarding bias, variance, and mean squared error in the case of small to moderate sample sizes.

Estimands

Intercurrent events

Rescue medication

Randomized clinical trials

Small sample trials

Hypothetical Strategy 

Mid-Level

Knowledge

Women in Statistics and Data Science 2025